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Early postnatal administration of antibiotics has been linked to lasting effects on brain development and behavior. Research conducted on animals that are free from germs has demonstrated that the impact of microbiome colonization on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and neuroendocrine pathways is substantial, which play a crucial role in stress management. Nevertheless, it is still uncertain if the exposure to antibiotics in rat dams (F0-generation) before weaning is associated with neurobehavioral changes in rat offspring (F1-generation) during adulthood. In order to investigate the effects, we perturbed the intestinal microbiota of rat dams (F0 generation) by administering cefixime (CEF), an antibiotic commonly used for obstetric purposes, at clinically relevant doses (1 mg/kg, 2.5 mg/kg or 5 mg/kg). Anxiety-like behaviors in adult offspring was evaluated through the utilization of elevated plus maze (EPM) and open field paradigm (OFP) following a six-week interval from birth (PND42). Subsequent to behavioral assessments, the rats were euthanized, and their brains and blood was collected for biochemical analysis. Plasma corticosterone concentration was used to assess HPA activity, whereas the quantitative real-time polymerase chain reaction (PCR) was employed to determine the transcription levels of the glucocorticoid receptor (GR) Nr3c1. The offspring of F1 that were administered antibiotics before being weaned spent less time in the EPM open arm. The alterations were accompanied by increased levels of corticosterone in the bloodstream. The gene expression study revealed a decrease in the levels of mRNA transcription of Nr3c1. This research emphasizes the possible long-term effects of antibiotic exposure before weaning on the development of anxiety in offspring upon adulthood.

Aims: Anxiety often coexists with migraine, and both conditions share a commonality in oxidative/nitrosative stress and mitochondrial dysfunction contributing to their pathogenesis. β-Sitosterol, a plant sterol, has shown promise in mitigating oxidative/nitrosative stress, enhancing mitochondrial function, and exerting neuroprotective effects. In this study, we investigated the impact of β-sitosterol on migraine-associated anxiety and whether this effect was associated with alleviation of oxidative/nitrosative stress and improvement in mitochondrial function., Methods: Nitroglycerin was used to induce migraine in adult male Wistar rats. β-Sitosterol treatment consisted of daily intraperitoneal injections (10 mg/kg) for 10 days following migraine induction. Anxiety levels were evaluated using open-field test (OFT) and hole-board test (HBT). Frontal cortex samples were analyzed for malondialdehyde (MDA), glutathione (GSH), reactive oxygen/nitrogen species, nitric oxide (NO) (markers of oxidative/nitrosative stress), and ATP (indicator of mitochondrial function)., Results: Migraine induction led to impaired performance in both the OFT and the HBT. Concurrently, it elevated MDA, reactive oxygen/nitrogen species, and NO levels while diminishing GSH levels in the frontal cortex, signifying heightened oxidative/nitrosative stress. Moreover, ATP levels decreased, indicating mitochondrial dysfunction. Treatment with β-sitosterol significantly restored performance in both behavioral assays and normalized the levels of MDA, GSH, reactive oxygen/nitrogen species, NO, and ATP., Conclusion: β-Sitosterol exerted anxiolytic effects in migraine, which can be attributed to its ability to ameliorate oxidative/nitrosative stress and enhance mitochondrial function., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Increasing evidence indicates that neuroinflammation, oxidative stress, and neurotrophic factors play a key role in the pathophysiology of major depressive disorder (MDD). In addition, the attenuation of inflammatory response has been considered a putative mechanism for MDD treatment. PT-31 is an imidazolidine derivative and a putative α₂-adrenoceptor agonist that has previously demonstrated antinociceptive activity. The present study aimed to investigate the effect of PT-31 on depressive-like behavior and lipopolysaccharide-induced neurochemical changes. To this end, mice received intraperitoneally saline or lipopolysaccharide (600 µg/kg), and 5 h postinjection animals were orally treated with saline, PT-31 (3, 10, and 30 mg/kg), or fluoxetine (30 mg/kg). Mice were subjected to the open field test (OFT) 6 and 24 h after lipopolysaccharide administration and to the tail suspension test (TST) 24 h postlipopolysaccharide. Subsequently, animals were euthanized, and brains were dissected for neurochemical analyses. The administration of lipopolysaccharide-induced sickness- and depressive-like behaviors, besides promoting an increase in myeloperoxidase activity and a reduction in brain-derived neurotrophic factor (BDNF) levels. Noteworthy, PT-31 3 mg/kg attenuated lipopolysaccharide-induced decreased locomotor activity 6 h after lipopolysaccharide in the OFT. All tested doses of PT-31 significantly reduced the immobility time of animals in the TST and attenuated lipopolysaccharide-induced increased myeloperoxidase activity in the cortex of mice. Our results demonstrate that PT-31 ameliorates behavioral changes promoted by lipopolysaccharide in OFT and TST, which is possibly mediated by attenuation of the inflammatory response., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

One aspect of reproducibility in preclinical research that is frequently overlooked is the physical condition in which physiological, pharmacological, or behavioural recordings are conducted. In this study, the physical conditions of mice were altered through the attachments of wireless electrophysiological recording devices (Neural Activity Tracker-1, NAT-1). NAT-1 devices are miniaturised multichannel devices with onboard memory for direct high-resolution recording of brain activity for >48 h. Such devices may limit the mobility of animals and affect their behavioural performance due to the added weight (total weight of approximately 3.4 g). The mice were additionally treated with saline (control), N-methyl-D-aspartate (NMDA) receptor antagonist MK801 (0.85 mg/kg), or the muscarinic acetylcholine receptor blocker scopolamine (0.65 mg/kg) to allow exploration of the effect of NAT-1 attachments in pharmacologically treated mice. We found only minimal differences in behavioural outcomes with NAT-1 attachments in standard parameters of locomotor activity widely reported for the open field test between the drug treatments. Hypoactivity was globally observed as a consistent outcome in the MK801-treated mice and hyperactivity in scopolamine groups regardless of NAT-1 attachments. These data collectively confirm the reproducibility for combined behavioural, pharmacological, and physiological endpoints even in the presence of lightweight wireless data loggers. The NAT-1 therefore constitutes a pertinent tool for investigating brain activity in, e.g., drug discovery and models of neuropsychiatric and/or neurodegenerative diseases with minimal effects on pharmacological and behavioural outcomes.

Cognitive impairment is a commonly observed complication following myocardial infarction; however, the underlying mechanisms are still not well understood. The most recent research suggests that extracellular signal-regulated kinase (ERK) plays a critical role in the development and occurrence of cognitive dysfunction-related diseases. This study aims to explore whether the ERK inhibitor U0126 targets the ERK/Signal Transducer and Activator of Transcription 1 (STAT1) pathway to ameliorate cognitive impairment after myocardial infarction. To establish a mouse model of myocardial infarction, we utilized various techniques including Echocardiography, Hematoxylin-eosin (HE) staining, Elisa, Open field test, Elevated plus maze test, and Western blot analysis to assess mouse cardiac function, cognitive function, and signal transduction pathways. For further investigation into the mechanisms of cognitive function and signal transduction, we administered the ERK inhibitor U0126 via intraperitoneal injection. Reduced total distance and activity range were observed in mice subjected to myocardial infarction during the open field test, along with decreased exploration of the open arms in the elevated plus maze test. However, U0126 treatment exhibited a significant improvement in cognitive decline, indicating a protective effect through the inhibition of the ERK/STAT1 signaling pathway. Hence, this study highlights the involvement of the ERK/STAT1 pathway in regulating cognitive dysfunction following myocardial infarction and establishes U0126 as a promising therapeutic target., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Riparin A is a synthetic form of natural riparins. Acute scale studies that take into consideration the structure-activity relationship have shown preliminary evidence of antidepressant and anxiolytic effects of riparin A, similar to that already known for other riparins. However, for better pharmacological characterization of this new compound, further studies are required. The aim of this work was to evaluate the effect of chronic treatment with riparin A (10 mg/kg; intraperitoneally) on depressive-like behavior in the forced swimming test and tail suspension test, as well as the reduction of anhedonia in the sucrose preference test, and on anxiety-like behavior in the open field and elevated plus maze apparatus, triggered in rats previously subjected to unpredictable chronic mild stress by 4 weeks. In addition, a pentobarbital-induced sleep time test was also used. Riparin A reduced the duration of immobility in both the forced swimming test and tail suspension test, as well as attenuated the anhedonia in the sucrose preference test. Furthermore, riparin A appears to produce anxiolytic effects in rats exposed to an open field and elevated plus maze, while increasing the alertness/vigilance in rats submitted to pentobarbital-induced sleep time test, without altering their locomotor integrity. Our results suggest that chronic riparin A appears to be a potential pharmacological target for new studies on the control of depression- and anxiety-like behaviors in stressed rats., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Depression is a debilitating mood disorder affecting millions worldwide and continues to pose a significant global health burden. Due to the multifaceted nature of depression, the current treatment regimens are not up to mark in terms of their multitargeting potential and least side effect profile. Molecules within the isoflavone class demonstrate promising potential in alleviating depression and associated conditions, offering a multifaceted approach to manage mental health concerns. Therefore, the current study was designed to explore the potential of glycitein, an isoflavone in managing reserpine-induced depression and associated comorbidities in mice. Reserpine (0.5 mg/kg; i.p.) administration for the first 3 days induced depression and associated comorbidities as evidenced by increased immobility time in forced swim test (FST) and tail suspension test (TST), along with reduced locomotor activity in the open field test (OFT) and increased latency to reach the platform in the Morris water maze (MWM) test. Reserpine treatment also upregulated and downregulated the brain thiobarbituric acid reactive substance (TBARS) and glutathione (GSH) levels, respectively. Furthermore, reserpine administration also uplifted the level of TNF-α in the serum samples. Glycitein (3 mg/kg and 6 mg/kg; p.o.) treatment for 5 days prevented the depressive effect of reserpine. It also improved the spatial memory at both dose levels. Moreover, in biochemical analysis, glycitein also reduced the brain TBARS and serum tumor necrosis factor-alpha (TNF-α) levels. Whereas, no significant effect was seen on the brain GSH level. Glycitein (6 mg/kg) was found to be more effective than the 3 mg/kg dose of glycitein. Overall results delineate that glycitein has the potential to manage depression and impaired memory by inhibiting lipid peroxidation and inflammatory stress., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Continuous antipsychotic treatment is often recommended to prevent relapse in schizophrenia. However, the efficacy of antipsychotic treatment appears to diminish in patients with relapsed schizophrenia and the underlying mechanisms are still unknown. Moreover, though the findings are inconclusive, several recent studies suggest that intermittent versus continuous treatment may not significantly differ in recurrence risk and therapeutic efficacy but potentially reduce the drug dose and side effects. Notably, disturbances in fatty acid (FA) metabolism are linked to the onset/relapse of schizophrenia, and patients with multi-episode schizophrenia have been reported to have reduced FA biosynthesis. We thus utilized an MK-801-induced animal model of schizophrenia to evaluate whether two treatment strategies of clozapine would affect drug response and FA metabolism differently in the brain. Schizophrenia-related behaviors were assessed through open field test (OFT) and prepulse inhibition (PPI) test, and FA profiles of prefrontal cortex (PFC) and hippocampus were analyzed by gas chromatography-mass spectrometry. Additionally, we measured gene expression levels of enzymes involved in FA synthesis. Both intermittent and continuous clozapine treatment reversed hypermotion and deficits in PPI in mice. Continuous treatment decreased total polyunsaturated fatty acids (PUFAs), saturated fatty acids (SFAs) and FAs in the PFC, whereas the intermittent administration increased n-6 PUFAs, SFAs and FAs compared to continuous administration. Meanwhile, continuous treatment reduced the expression of Fads1 and Elovl2, while intermittent treatment significantly upregulated them. This study discloses the novel findings that there was no significant difference in clozapine efficacy between continuous and intermittent administration, but intermittent treatment showed certain protective effects on phospholipid metabolism in the PFC., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ketamine is a rapid-acting antidepressant associated with various cognitive side effects. To mitigate these side effects while enhancing efficacy, it can be co-administered with other antidepressants. In our study, we adopted a similar strategy by combining ketamine with environmental enrichment, a potent sensory-motor paradigm, in adult male Wistar rats. We divided the animals into four groups based on a combination of housing conditions and ketamine versus vehicle injections. The groups included those housed in standard cages or an enriched environment for 50 days, which encompassed a 13-day-long behavioral testing period. Each group received either two doses of ketamine (20 mg/kg, IP) or saline as a vehicle. We tested the animals in the novel object recognition test (NORT), forced swim test (FST), open field test (OFT), elevated plus maze (EPM), and Morris water maze (MWM), which was followed by ex vivo c-Fos immunohistochemistry. We observed that combining environmental enrichment with ketamine led to a synergistic antidepressant effect. Environmental enrichment also ameliorated the spatial memory deficits caused by ketamine in the MWM. There was enhanced neuronal activity in the habenula of the enrichment only group following the probe trial of the MWM. In contrast, no differential activity was observed in enriched animals that received ketamine injections. The present study showed how environmental enrichment can enhance the antidepressant properties of ketamine while reducing some of its side effects, highlighting the potential of combining pharmacological and sensory-motor manipulations in the treatment of mood disorders., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Open-field activity is a commonly used measure of anxiety-related behavior in rodents. The inbred High and Low Activity strains of mice, selected for extreme differences in open-field activity, have been used as a genetic model of anxiety-related behaviors. These selected strains have been thoroughly studied through extensive behavioral testing, quantitative trait locus (QTL) mapping, whole-genome sequencing, and RNA sequencing, to uncover phenotypic and genotypic differences related to anxiety-related behavior. However, the effects of anxiolytic drugs on anxiety-related behavior in these strains have not been studied previously. This study allowed us to expand on previous findings to further characterize the anxiety-related behavior of these unique strains, using an anxiolytic drug. The goal of this study was to determine whether the treatment of adult male and female High Activity (low anxiety) and Low Activity (high anxiety) mice with diazepam, an agonist at the benzodiazepine allosteric site on the GABA A receptor and a drug commonly prescribed to treat anxiety disorders in humans, led to decreases in anxiety-like defensive behavioral responses as assessed in the open-field test (OFT) and elevated plus-maze (EPM). We tested the effects of three doses of diazepam (0, 0.5, 1.0, 3.0 mg/kg, i.p.), given 30 min before behavioral testing to one High Activity strain (H2) and two Low Activity strains (L1 and L2). There was an anxiolytic effect of diazepam observed in the High Activity strain, with more entries into the open arms of the elevated plus-maze, an effect similar to that seen in common mouse strains. However, the only anxiolytic effect of diazepam seen in the Low Activity strains was a reduction in stretch attend posture (SAP). Low Activity strains also displayed freezing behavior in both the OFT and EPM. The combination of the observed freezing behavior, that was not reduced by diazepam, and the reduction in SAP seen with diazepam, suggests a more complex phenotype that includes a component of innate fear in addition to anxiety-related risk assessment behaviors. Since fear and anxiety are distinguishable traits, and both contribute to human anxiety disorders, these results provide novel insight about interpretation of previous genetic and phenotypic differences observed between the High and Low Activity strains., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Nitric oxide is a small gaseous molecule that plays important roles in the majority of biological functions. Impairments of NO-related pathways contribute to the majority of neurological disorders, such as Alzheimer's disease (AD), and mental disorders, such as schizophrenia. Cognitive decline is one of the most serious impairments accompanying both AD and schizophrenia. In the present study, the activities of NO donors, slow (spermine NONOate) or fast (DETANONOate) releasers, and selective inhibitor of neuronal nitric oxide synthase N(ω)-propyl-l-arginine (NPLA) were investigated in pharmacological models of schizophrenia and AD. Cognitive impairments were induced by administration of MK-801 or scopolamine and were measured in novel object recognition (NOR) and Y-maze tests. The compounds were investigated at doses of 0.05-0.5 mg/kg. The dose-dependent effectiveness of all the compounds was observed in the NOR test, while only the highest doses of spermine NONOate and NPLA were active in the Y-maze test. DETANONOate was not active in the Y-maze test. The impact of the investigated compounds on motor coordination was tested at doses of 0.5 and 1 mg/kg. Only NPLA at a dose of 1 mg/kg slightly disturbed motor coordination in animals., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The increasing use of aluminum nanoparticles (nano-Al) leads to increased human exposure and might affect human health. Considering the suggested connection between aluminum exposure and Alzheimer's disease (AD) pathogenesis, there is a concern about the effect of nano-Al on cognitive function and brain health. This study was aimed to assess the effect of a 5-day oral gavage of aluminum oxide nanoparticle (nano-Al) on memory and the phosphorylation levels of hippocampal p38, JNK (c-Jun N-terminal kinase), ERK (extracellular signal-regulated kinase) as well as cleaved caspase-3 in mice. Adult male NMRI mice were treated with nano-Al in doses 5 and 10 mg/kg/oral gavage for 5 days. The test session of novel object recognition (NOR) task was performed on day 5. Following the NOR test, the hippocampi were isolated for western blot analysis to determine the total and phosphorylated levels of p38, JNK, ERK as well as cleaved caspase-3 proteins. The results showed that nano-Al oral gavage in doses of 5 and 10 mg/kg impairs NOR memory in mice. Moreover, the memory impairing effect of nano-Al coincided with a dose dependent increase in phosphorylated p38 and cleaved caspase-3 in the hippocampus. It also increased the ratio of phosphorylated to total content of ERK in the hippocampus while JNK signaling was not affected by nano-Al. This study showed that nano-Al in doses as low as 5 and 10 mg/ kg ingested for 5 days impairs NOR memory and activates p38, ERK and cleaved caspase-3 in the hippocampus., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Methionine (Met) is considered the most toxic amino acid in mammals. Here, we investigated biochemical and behavioral impacts of ad libitum one-week feeding of high-Met diets on mice. Adult male mice were fed the standard rodent diet that contained 0.44% Met (1×) or a diet containing 16 graded Met doses (1.2×-13×). High-Met diets for one-week induced a dose-dependent decrease in body weight and an increase in serum Met levels with a 2.55 mM peak (versus basal 53 µM) on the 12×Met diet. Total homocysteine (Hcy) levels were also upregulated while concentrations of other amino acids were almost maintained in serum. Similarly, levels of Met and Hcy (but not the other amino acids) were highly elevated in the cerebrospinal fluids of mice on the 10×Met diet; the Met levels were much higher than Hcy and the others. In a series of behavioral tests, mice on the 10×Met diet displayed increased anxiety and decreased traveled distances in an open-field test, increased activity to escape from water soaking and tail hanging, and normal learning/memory activity in a Y-maze test, which were reflections of negative/positive symptoms and normal cognitive function, respectively. These results indicate that high-Met ad libitum feeding even for a week can induce bipolar disorder-like disease models in mice.

The present study investigated the role of neuroinflammation and brain oxidative stress induced by neonatal treatment with lipopolysaccharides (LPS) on the development of autism spectrum disorder (ASD)-like behaviors and disruptive hippocampal neurogenesis in rats by exploring the chemopreventive effects of alpha-glycosyl isoquercitrin (AGIQ) as an antioxidant. AGIQ was dietary administered to dams at 0.25% or 0.5% (w/w) from gestational day 18 until postnatal day (PND) 21 on weaning and then to pups until the adult stage on PND 77. The pups were intraperitoneally injected with LPS (1 mg/kg body weight) on PND 3. At PND 6, LPS alone increased Iba1 + and CD68 + cell numbers without changing the CD163 + cell number and strongly upregulated pro-inflammatory cytokine gene expression (Il1a, Il1b, Il6, Nfkb1, and Tnf) in the hippocampus, and increased brain malondialdehyde levels. At PND 10, pups decreased ultrasonic vocalization (USV), suggesting the induction of pro-inflammatory responses and oxidative stress to trigger communicative deficits. By contrast, LPS alone upregulated Nfe2l2 expression at PND 6, increased Iba1 + , CD68 + , and CD163 + cell numbers, and upregulated Tgfb1 at PND 21, suggesting anti-inflammatory responses until the weaning period. However, LPS alone disrupted hippocampal neurogenesis at weaning and suppressed social interaction parameters and rate of freezing time at fear acquisition and extinction during the adolescent stage. On PND 77, neuroinflammatory responses had mostly disappeared; however, disruptive neurogenesis and fear memory deficits were sustained. AGIQ ameliorated most changes on acute pro-inflammatory responses and oxidative stress at PND 6, and the effects on USVs at PND 10 and neurogenesis and behavioral parameters throughout the adult stage. These results suggested that neonatal LPS treatment induced acute but transient neuroinflammation, triggering the progressive disruption of hippocampal neurogenesis leading to abnormal behaviors in later life. AGIQ treatment was effective for ameliorating LPS-induced progressive changes by critically suppressing initial pro-inflammatory responses and oxidative stress., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The spontaneous object recognition (SOR) task is one of the most widely used behavioral protocols to assess visual memory in animals. However, only recently was it shown that nonhuman primates also perform well on this task. Here we further characterized this new monkey recognition memory test by assessing the performance of adult marmosets after an acute systemic administration of two putative amnesic agents: the competitive muscarinic acetylcholine receptor antagonist scopolamine (SCP; 0.05 mg/kg) and the noncompetitive N-methyl-d-aspartate glutamate receptor antagonist MK-801 (0.015 mg/kg). We also determined whether the acetylcholinesterase inhibitor donepezil (DNP; 0.50 mg/kg), a clinically-used cognitive enhancer, reverses memory deficits caused by either drug. The subjects had an initial 10 min sample trial where two identical neutral objects could be explored. After a 6 h retention interval, recognition was based on an exploratory preference for a new rather than familiar object during a 10 min test trial. Both SCP and MK-801 impaired the marmosets' performance on the SOR task, as both objects were explored equivalently. Co-administration of 0.50 mg/kg of DNP reversed the SCP- but not the MK-801-induced memory deficit. These results indicate that cholinergic and glutamatergic pathways mediate object recognition memory in the monkey SOR task., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The mitochondrial inhibitor 3-nitropropionic acid (3-NP) induces excitotoxicity. The authors hypothesized that CTK 01512-2, a recombinant peptide calcium channel N-type blocker, and the TRPA1 antagonist, could show neuroprotective effects. The male Wistar rats received 3-NP [25 mg/kg (i.p.) for 7 days], and a treatment of CTK 01512-2 was delivered intrathecally (i.t.), thrice a week. The neuroprotective effects were evaluated by [ 18 F]FDG MicroPET analysis. The CTK 01512-2 toxin was able to reestablish similar glucose uptakes on the control animals. To detect the neurobehavioral effects from 3-NP, three protocols (6.25, 12.5, 18.75 mg/kg of 3-NP (i.p.), for 3, 4, and 6 days, respectively) were evaluated by performance tests (open field test, walk footprint, elevated plus-maze, Y-maze, and the object recognition test). Important disabilities in the gait of the rats were seen, as well as memory deficits, and anxious behavior in the animals that were treated with all 3-NP protocols. The dose of 18.75 mg/kg (for 3 days) showed the most pronounced behavioral effects and lethality, while the rats treated with 12.5 mg/kg (for 4 days) showed behavioral effects similar to the 6.25 mg/kg dose (for 6 days). The third protocol was then repeated and the rats were treated with the CTK 01512-2 toxin to be evaluated behaviorally again. The recombinant peptide prevented all of the gait-evaluated parameters that were induced by 3-NP at a 6.25 mg/kg dose, which displayed an improvement in the exploratory activities. Overall, these results have reinforced the positive effects of CTK 01512-2 against the behavioral changes that were induced by the mitochondrial inhibitor 3-NP., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Manganese (Mn) is an essential micronutrient but excessive levels induce neurotoxic effects. Increasing evidence suggests a deficit of bioavailable Mn in Huntington disease (HD), an inherited neurodegenerative disease characterized by motor and cognitive disturbances. Previous studies have shown rescue of some molecular HD phenotypes by acute Mn exposure. This study simultaneously examined the potential for chronic Mn exposure to attenuate HD behavioral phenotypes, and for the HD genotype to offer protection against detrimental effects of chronic Mn exposure. In two independent studies a chronic Mn exposure paradigm was implemented in the YAC128 mouse model of HD and behavior was assessed at several timepoints. Study 1 exposed WT and YAC128 mice to twice weekly subcutaneous injections of 0, 5, 15, or 50 mg/kg MnCl[2] tetrahydrate from 12 to 32 weeks of age. A promising protective effect against motor coordination decline in 5 mg/kg MnCl[2] tetrahydrate-treated YAC128 mice was detected. Study 2 thus exposed WT and YAC128 mice to either 0 or 5 mg/kg MnCl[2] tetrahydrate from 12 to 52 weeks of age (with a partial randomized treatment crossover at 31 weeks). The same protective effect was not observed under these conditions at higher statistical power. We report subtle toxicological changes in exploratory behavior and total activity induced by chronic Mn exposure in WT mice only, despite similar total increases in brain Mn in WT and YAC128 mice. Further, chronic Mn treatment resulted in a 10-12 % decrease in striatal NeuN positive cell density in WT mice but not YAC128 mice, despite vehicle cell counts already being reduced compared to WT mice as expected for the HD genotype. The subtle changes observed in specific outcome measures, but not others, following long-term low-level Mn exposure in WT mice delineate the neurobehavioral and neuropathological effects at the threshold of chronic Mn toxicity. We conclude that these chronic low-dose Mn exposures do not significantly rescue behavioral HD phenotypes, but YAC2128 mice are protected against the subtle Mn-induced behavioral changes and decreased striatal neuron density observed in Mn-exposed WT mice., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Metformin is currently used as a first-line drug to treat patients with type 2 diabetes. Previous studies have demonstrated that metformin has antioxidant properties and reduces neuroinflammation and hippocampal neuronal cell loss, which eventually improves memory. Methotrexate (MTX) is an antimetabolite chemotherapeutic agent reported to activate cognitive impairment found in many patients. Moreover, MTX negatively affects the spatial working memory, related to neurogenesis reduction in animal models. Therefore, the present study aimed to investigate the antioxidant effect of metformin on the reduction of memory and neurogenesis caused by MTX. Male Sprague-Dawley rats were divided into four groups: control, MTX, metformin, and MTX+metformin. MTX (75 mg/kg, i.v.) was administered on days 7 and 14. Rats were administered metformin (200 mg/kg, i.p.) for 14 days. Memory was determined using novel object location (NOL) and novel object recognition (NOR) tests. Furthermore, cell cycle arrest was quantified by p21 immunostaining. Levels of neuronal protein expression, scavenging enzymes activity, and malondialdehyde (MDA) level changes in the hippocampus and prefrontal cortex were investigated. Rats receiving only MTX showed memory impairment. Decreases in scavenging enzyme activity and BDNF, DCX, and Nrf2 protein expressions levels were detected in the MTX-treated rats. In addition, MTX significantly increased p21-positive cell numbers and MDA levels. However, these adverse MTX effects were counteracted by co-administration with metformin. These results demonstrate that metformin can improve memory impairments, increase BDNF, DCX and Nrf2 protein expressions and antioxidant capacities, and decrease MDA levels in MTX-treated rats., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

As an N-methyl-D-aspartate (NMDA) receptor inhibitor, ketamine has become a popular recreational substance and currently is used to address treatment-resistant depression. Since heavy ketamine use is associated with persisting psychosis, cognitive impairments, and neuronal damage, the safety of ketamine treatment for depression should be concerned. The nutrient supplement betaine has been shown to counteract the acute ketamine-induced psychotomimetic effects and cognitive dysfunction through modulating NMDA receptors. This study aimed to determine whether the adjunctive or subsequent betaine treatment would improve the enduring behavioral disturbances and hippocampal synaptic abnormality induced by repeated ketamine exposure. Mice received ketamine twice daily for 14 days, either combined with betaine co-treatment or subsequent betaine post-treatment for 7 days. Thereafter, three-chamber social approach test, reciprocal social interaction, novel location/object recognition test, forced swimming test, and head-twitch response induced by serotonergic hallucinogen were monitored. Data showed that the enduring behavioral abnormalities after repeated ketamine exposure, including disrupted social behaviors, recognition memory impairments, and increased depression-like and hallucinogen-induced head-twitch responses, were remarkably improved by betaine co-treatment or post-treatment. Consistently, betaine protected and reversed the reduced hippocampal synaptic activity, such as decreases in field excitatory post-synaptic potentiation (fEPSP), long-term potentiation (LTP), and PSD-95 levels, after repeated ketamine treatment. These results demonstrated that both co-treatment and post-treatment with betaine could effectively prevent and reverse the adverse behavioral manifestations and hippocampal synaptic plasticity after repeated ketamine use, suggesting that betaine can be used as a novel adjunct therapy with ketamine for treatment-resistant depression and provide benefits for ketamine use disorders., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The number of people with dementia worldwide is estimated at 50 million by 2018 and continues to rise mainly due to increasing aging and population growth. Clinical impact of current interventions remains modest and all efforts aimed at the identification of new therapeutic approaches are therefore critical. Previously, we showed that JM-20, a dihydropyridine-benzodiazepine hybrid molecule, protected memory processes against scopolamine-induced cholinergic dysfunction. In order to gain further insight into the therapeutic potential of JM-20 on cognitive decline and Alzheimer's disease (AD) pathology, here we evaluated its neuroprotective effects after chronic aluminum chloride (AlCl 3 ) administration to rats and assessed possible alterations in several types of episodic memory and associated pathological mechanisms. Oral administration of aluminum to rodents recapitulates several neuropathological alterations and cognitive impairment, being considered a convenient tool for testing the efficacy of new therapies for dementia. We used behavioral tasks to test spatial, emotional- associative and novel object recognition memory, as well as molecular, enzymatic and histological assays to evaluate selected biochemical parameters. Our study revealed that JM-20 prevented memory decline alongside the inhibition of AlCl 3 -induced oxidative stress, increased AChE activity, TNF-α and pro-apoptotic proteins (like Bax, caspase-3, and 8) levels. JM-20 also protected against neuronal damage in the hippocampus and prefrontal cortex. Our findings expanded our understanding of the ability of JM-20 to preserve memory in rats under neurotoxic conditions and confirm its potential capacity to counteract cognitive impairment and etiological factors of AD by breaking the progression of key steps associated with neurodegeneration., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aluminum is a widespread environmental neurotoxicant that can induce Alzheimer's disease (AD)-like damage, such as neuronal injury and impairment of learning and memory. Several studies have shown that aluminum could reduce the synaptic plasticity, but its molecular mechanism remains unclear. In this study, rats were treated with aluminum maltol (Al(mal) 3 ) to establish a toxic animal model and PMA was used to interfere with the expression of PKC. The Morris water maze and open field test were used to investigate the behavioral changes of the rats. Western blotting and RT-PCR were used to detect the expression levels of NMDAR subunits, PKC and CaMKII. The results showed that Al(mal) 3 damaged learning and memory function and reduced anxiety in rats. During this process, the expression of PKC was downregulated and it inhibited the expression of NMDARs through the phosphorylation of CaMKII., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In the present study, we aimed to investigate the effects of probucol on aging-related hippocampus-dependent cognitive impairment and explore the potential mechanisms., Methods: D-galactose (100 mg/kg, once daily for 6 weeks) was subcutaneously injected to induce aging in mice. Then the mice were administered with probucol or vehicle once a day for 2 weeks. The hippocampus-related cognition was evaluated with Morris water maze test, novel object recognition test, and contextual fear conditioning test. Moreover, synaptic plasticity was assessed, and RNA-sequencing was applied to further explore the molecular mechanisms., Results: Aging mice induced by D-galactose showed conspicuous learning and memory impairment, which was significantly ameliorated by probucol. Meanwhile, probucol enhanced the spine density and dendritic branches, improved long-term potentiation, and increased the expression of PSD95 of aging mice. Probucol regulated 70 differentially expressed genes compared to D-galactose group, of which 38 genes were upregulated and 32 genes were downregulated. At last, RNA-sequencing results were verified by quantitative reverse transcription-polymerase chain reaction., Conclusions: Probucol improved learning and memory in aging mice through enhancing synaptic plasticity and regulating gene expression, indicating the potential application of probucol to prevent and treat aging-related disorders., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The growing concern surrounding bisphenol A (BPA) has led to increased industrial production and application of its analog bisphenol S (BPS). The goals of this study were: (1) To examine the generational effects in the nematode C. elegans for up to three generations following developmental exposure to BPS (0.1, 1.0, 5.0 and 10.0 μM), and (2) To examine the neurotoxicity and metabolic toxicity in NODEF mouse offspring exposed to BPS (3 μg/kg BW) in utero throughout gestation once/day via oral pipette. First, worms were exposed to BPS developmentally for a single period of 48 hours and then propagated for 2 additional generations. Exposure to 0.1 and 1.0 μM BPS decreased lifespan and the number of progeny with an ability to recover in subsequent generations. In contrast, worms exposed to 5.0 or 10.0 μM BPS exhibited a continuous effect in the second generation, e.g., decreased lifespan and reduced number of progeny. Only worms exposed to 10.0 μM BPS continued to have a significant long-term effect (e.g., decreased lifespan) through the third generation. In addition, worms developmentally exposed to BPS at 5.0 μM and 10.0 μM also showed decreases in body bends. In contrast, worms exposed to 0.1 μM BPS exhibited a significant increase in head thrashes. When the multigenerational effects were examined by exposing worms to BPS for 48 hours developmentally at each generation for three generations, an accumulative effect was observed in worms treated with 0.1 or 1.0 μM BPS for two generations, but not for three generations, suggesting a threshold existed. Worms exposed to either 5.0 or 10.0 μM BPS demonstrated accumulative effects through two and three generations. When the developmental effects of BPS were studied in NODEF mice, offspring exposed gestationally exhibited behavioral deficits at 12, but not at 3, weeks of age. Specifically, female offspring had decreases in working and short-term memories while male offspring showed increases in hyperactivity and anxiety-like behaviors. In summary, this study demonstrates the sex-related effects of BPS in NODEF mouse offspring exposed in utero, along with the generational effects observed in C. elegans., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Depressive disorders induced by acute myocardial infarction (AMI) play a pivotal role in the deterioration of cardiac function, and Shuangxinfang (Psycho-cardiology Formula, PCF) was reported to alleviate heart function damage and improve depression-like behavior, but the complex mechanism in such process has not been clarified., Methods: AMI models were established and PCF was administered in rats. Subjects were then assessed in open field test (OFT) and forced swimming test (FST) recapitulating symptoms of depressive disorder. Afterward, pharmacoproteomic profiling of the hippocampus and peri-infarct border zone (BZ) was performed using a label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique, to identify contributing proteins and pathways responsible for myocardial ischemia and behavioral allostasis. Bioinformatics analysis was processed for further investigation, while western blotting was employed for testing dominating proteins to validate proteomic results., Results: Rats in the AMI group showed depression-like behavior in OFT and FST, which was improved by PCF. There were 131 differentially expressed proteins (DEPs) in BZ and 64 proteins in the hippocampus being detected and quantified shared by the sham group, the AMI group, and the PCF group. Subsequently, pertinent pathways and molecular functions were further identified. Altered molecules were discovered to be enriched in the apoptotic process, innate immune response, and NF-κB transcription factor activity in BZ, as well as chemical synaptic transmission, axon, collagen binding, cell adhesion, response to carbohydrate, laminin binding, and cellular response to nitric oxide in the hippocampus. Groups of signal transducers were also able to select multiple pathways, including innate immunity and arginine biosynthesis in the heart, also integrin signaling in the brain. DEPs were intersected from the myocardium and hippocampus to screen out the protein S100A9, which was up-regulated in the AMI group compared with the sham, and showed a down-regulation trend after treatment with PCF., Conclusion: Taken together, we present a comprehensive proteomics analysis of rat models with depression post-AMI. Reviewing the literatures concerned, it's hypothesized that macrophage/microglia inflammation mediated by S100A9 might be the pivotal pathogenic process of psycho-cardiology disease, as well as potential mechanisms for the treatment of PCF., (Copyright © 2021. Published by Elsevier Masson SAS.)

Depression and anxiety, two of the most common mental health disorders, share common symptoms and treatments. Most pharmacological agents available to treat these disorders target monoamine systems. Currently, finding the most effective treatment for an individual is a process of trial and error. To better understand how disease etiology may predict treatment response, we studied mice exposed developmentally to the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX). These mice show the murine equivalent of anxiety- and depression-like symptoms in adulthood and here we report that these mice are also behaviorally resistant to the antidepressant-like effects of adult SSRI administration. We investigated whether tianeptine (TIA), which exerts its therapeutic effects through agonism of the mu-opioid receptor instead of targeting monoaminergic systems, would be more effective in this model. We found that C57BL/6J pups exposed to FLX from postnatal day 2 to 11 (PNFLX, the mouse equivalent in terms of brain development to the human third trimester) showed increased avoidant behaviors as adults that failed to improve, or were even exacerbated, by chronic SSRI treatment. By contrast, avoidant behaviors in these same mice were drastically improved following chronic treatment with TIA. Overall, this demonstrates that TIA may be a promising alternative treatment for patients that fail to respond to typical antidepressants, especially in patients whose serotonergic system has been altered by in utero exposure to SSRIs., (© 2021. The Author(s).)

Background: Quercetin (QUE) is a flavonol reported with anti-inflammatory and antioxidant activities, and previous results from the group of this study have demonstrated its neuroprotective effect against lipopolysaccharide-induced neuropsychiatric injuries. However, little is known about its potential effect on neuropsychiatric injuries induced or accompanied by metabolic dysfunction of glucose and lipids., Methods: A nonalcoholic fatty liver disease (NAFLD) rat model was induced via a high-fat diet (HFD), and glucolipid parameters and liver function were measured. Behavioral performance was observed via the open field test (OFT) and the Morris water maze (MWM). The plasma levels of triggering receptor expressed on myeloid cells-1 (TREM1) and TREM2 were measured via enzyme-linked immunosorbent assay (ELISA). The protein expression levels of Synapsin-1 (Syn-1), Synaptatogmin-1 (Syt-1), TREM1 and TREM2 in the hippocampus were detected using western blotting. Morphological changes in the liver and hippocampus were detected by HE and Oil red or silver staining., Results: Compared with the control rats, HFD-induced NAFLD model rats presented significant metabolic dysfunction, hepatocyte steatosis, and impaired learning and memory ability, as indicated by the increased plasma concentrations of total cholesterol (TC) and triglyceride (TG), the impaired glucose tolerance, the accumulated fat droplets and balloon-like changes in the liver, and the increased escaping latency but decreased duration in the target quadrant in the Morris water maze. All these changes were reversed in QUE-treated rats. Moreover, apart from improving the morphological injuries in the hippocampus, treatment with QUE could increase the decreased plasma concentration and hippocampal protein expression of TREM1 in NAFLD rats and increase the decreased expression of Syn-1 and Syt-1 in the hippocampus., Conclusions: These results suggested the therapeutic potential of QUE against NAFLD-associated impairment of learning and memory, and the mechanism might involve regulating the metabolic dysfunction of glucose and lipids and balancing the protein expression of synaptic plasticity markers and TREM1/2 in the hippocampus., (© 2021. The Author(s).)

Environmental factors are involved in the pathogenesis of neurodevelopmental disorders in addition to genetic factors. In this sense, we demonstrated here that the embryonic exposure of Drosophila melanogaster to Bisphenol A (BPA) 1 mM resulted in changes in development, behavior, and biochemical markers punctuated below. BPA did not alter the oviposition and viability of the eggs, however, it was evidenced a decrease in the rate of pupal eclosion and life span of the hatched flies of the generation filial 1 (F1). F1 flies also developed behavioral changes such as incompatibility in the social interaction between them, and hyperactivity demonstrated by increased locomotion in open field tests, increased grooming, and aggression episodes. Furthermore, decreases in dopamine levels and tyrosine hydroxylase activity have also been observed in flies' heads, possibly related to oxidative damage. Through analyzes of oxidative stress biomarkers, carried out on samples of flies' heads, we observed an increase in malondialdehyde and reactive species, decrease in the activity of the superoxide dismutase and catalase, which possibly culminated in the reduction of cell viability. Thus, it is important to emphasize that BPA developed atypical behaviors in Drosophila melanogaster, reinforce the importance of the environmental factor in the development of neurobehavioral diseases., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Parkinson disease is a chronic and progressive movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The causes of Parkinson disease are not clear but may involve genetic susceptibilities and environmental factors. As in other neurodegenerative disorders, individuals predisposed to Parkinson disease may have an accelerated onset of symptoms following perioperative stress such as anesthesia, surgery, pain, and inflammation. We hypothesized that anesthesia alone accelerates the onset of Parkinson disease-like pathology and symptoms., Methods: A presymptomatic Parkinson rat model (the protein, DJ-1, encoded by the Park7 gene [DJ-1], PARK7 knockout) was exposed to a surgical plane of isoflurane or 20% oxygen balanced with nitrogen for 2 hours on 3 occasions between 6 and 7 months of age. Acute and long-term motor and neuropathological effects were examined from 7 to 12 months of age in male DJ-1 rats, using the ladder rung, rotarod, and novel object recognition assays, as well as the immunohistochemical localization of tyrosine hydroxylase in dopaminergic neurons in the substantia nigra and ionized calcium-binding adaptor protein-1 (Iba-1) microglial activation in the substantia nigra and hippocampus., Results: In the acute group, after the third anesthetic exposure at 7 months of age, the isoflurane group had a significant reduction in the density of dopaminergic neurons in the SNpc compared to controls. However, this reduction was not associated with increased microglial activation in the hippocampus or substantia nigra. With the ladder rung motor skills test, there was no effect of anesthetic exposure on the total number of foot faults or the ladder rung pattern in the acute group. The rotarod test also detected no differences before and after the third exposure in controls. For the long-term group, immunohistochemical analyses detected no differences in the density of dopaminergic neurons or microglial cells compared to unexposed DJ-1 rats from 8 to 12 months of age. The ladder rung test in the long-term group showed no differences in the total number of foot faults with time and exposure or between ladder rung patterns. The rotarod test detected no significant effect of exposure with time or between groups at any time point. The novel object recognition task in the long-term group revealed no differences in short- or long-term memory or in the number of rearings as a function of exposure., Conclusions: Multiple isoflurane exposures in this rat model of Parkinson disease transiently enhanced dopaminergic neurodegeneration in the SNpc that resolved over time and had no effects on progression in this Parkinson disease-like phenotype., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

Stress during pregnancy is not only detrimental to a woman's own physical and mental health, but can also cause changes in the intrauterine environment and even have an impact on later growth and development, this study was designed to understand the changes of gut microbiota in the maternal and offspring caused by prenatal chronic stress, and to explore the regulatory effect of LBP on gut microbiota, and then to improve the emotional damage caused by prenatal chronic stress in the offspring. A rat model of prenatal chronic stress was made and used LBP to intervene by gavage. Fresh feces of offspring were collected, the concentration of microbial metabolites were tested by ELISA. Illumina MiSeqPE300 sequencing technology was used to determine the sequence of 16S rRNA V3-V4 of microorganisms. On the PND 42, the emotional function of offspring were tested by open-field test (OFT), sucrose preference test (SPT) and tail of suspend test (TST). Results indicated that stress factors increased the plasma corticosterone level of rats during pregnancy and they appeared depressive behaviors. The body weight of offspring during prenatal chronic stress was lower than the control group, and the plasma corticosterone level was increased. Prenatal chronic stress had a significant impact on emotional performance of the offspring on OFT, SPT and TST. Alpha diversity of gut microbiota and microbiota composition in offspring of prenatal chronic stress was attenuated and some relationships existed between these parameters. LBP treatment reduced offspring's plasma corticosterone level and improved their body weight, changed the emotional function, increased the diversity of gut microbiota. Collectively, these findings disclose that prenatal chronic stress not only causes emotional injury on the offspring, but also changes the gut microbiota of the mother and offspring; LBP may regulate the intestinal flora of the mother, then reducing the influence of stress factors on the emotional injury of offspring., (Copyright © 2021. Published by Elsevier Masson SAS.)

Bisphenol A (BPA) is noted for its adversative effects by inducing oxidative stress, carcinogenicity, neurotoxicity, inflammation, etc. However, the likely act of BPA in inducing neurodegenerative phenotypes remains elusive in the available literature. Hence, the present study was conducted to decipher the neurodegenerative potential of BPA in inducing Parkinson's disease like phenotypes in zebrafish. Zebrafish were subjected to chronic waterborne exposure to BPA for 56 days. Locomotor activities and neurobehavioral response were assessed by the NTDT (novel tank diving test), OFT (open field test), and LDPT (light-dark preference test). The oxidative stress markers and histopathological observation for pyknosis and chromatin condensation were carried out. Immunohistochemistry for activated caspase-3 and targeted proteins expression study was performed. The basic findings reveal that chronic BPA exposure significantly induces locomotor dysfunction through a significant decline in mean velocity and total distance traveled. As a measure of pyknosis and chromatin condensation, pyknotic and Hoechst positive neurons in telencephalon and diencephalon significantly increased by BPA exposure. A higher concentration of BPA adversely affects the neurobehavioral response, antioxidant status, and neuromorphology in zebrafish. Parkinson-relevant targeted protein expression viz. alpha-synuclein and LRRK2, were significantly upregulated, whereas tyrosine hydroxylase, NeuN, and Nurr1 were significantly downregulated in the zebrafish brain. As an indicator of cell death by apoptosis, the expression of activated caspase-3 was significantly increased in the BPA-exposed zebrafish brain. These basic results of the current study indicate that chronic waterborne exposure to BPA induces neuropathological manifestation leading to the development of motor dysfunction and Parkinsonism-like neurodegenerative phenotypes in zebrafish., (© 2021 Wiley Periodicals LLC.)

Oxytocin (OXT) -"the love hormone"- has been involved in the anti-depressant activity of some selective serotonin reuptake inhibitors (SSRIs). The exact mechanism underlying the OXT pathway in depression is not fully clear. This study aimed to investigate the effect of OXT analogue, carbetocin (CBT) and the SSRI, escitalopram (ESCIT) on depressive-like behaviors following maternal separation (MS). It is worthy to mention that intranasal CBT has been approved by U.S. Food and Drug Administration (FDA) for Prader-Willi syndrome. Adolescent Wistar albino maternally-separated rats were given CBT, (100 µg/animal/d via inhalation route), and, ESCIT, (20 mg kg -1 , per os ( p.o.)) either alone or in combination for 7 d. Repeated 3-h MS demonstrated increased immobility time in forced swim test (FST) and decreased locomotor activity in open field test. MS elevated plasma level of adrenocortico-trophic hormone (ACTH) but notably reduced plasma OXT, with no effect on hippocampal OXT-R expression. Following MS, hippocampal contents of 5-hydroxytryptamine receptors (5HT1A-R), serotonin transporter (SERT) were increased. CBT and ESCIT corrected the behavioral dysfunction in FST and suppressed the high levels of ACTH. Additionally, both treatments boosted OXT level, reduced 5HT1A-R and normalized SERT contents, which reflects increased availability of serotonin. Finally, CBT markedly ameliorated the histopathological damage induced by MS and suppressed the increased glial fibrillary acidic protein. CBT and ESCIT manage depressive-like behavior by positively affecting serotonergic and oxytocinergic systems. Targeting OXT system -using CBT- ameliorated depressive like behaviors induced by maternal separation most probably via enhancing OXT plasma levels, attenuating hormonal ACTH and restoring the expression of hippocampal oxytocin and serotonin mechanisms.

Glutaric acidemia type 1 (GA1) is caused by glutaryl-CoA dehydrogenase deficiency that leads to a blockage in the metabolic route of the amino acids lysine and tryptophan and subsequent accumulation of glutaric acid (GA), 3-hydroxyglutaric acids and glutarylcarnitine (C5DC). Patients predominantly manifest neurological symptoms, associated with acute striatal degeneration, as well as progressive cortical and striatum injury whose pathogenesis is not yet fully established. Current treatment includes protein/lysine restriction and l-carnitine supplementation of (L-car). The aim of this work was to evaluate behavior parameters and pro-inflammatory factors (cytokines IL-1β, TNF-α and cathepsin-D levels), as well as the anti-inflammatory cytokine IL10 in striatum of knockout mice (Gcdh -/- ) and wild type (WT) mice submitted to a normal or a high Lys diet. The potential protective effects of L-car treatment on these parameters were also evaluated. Gcdh -/- mice showed behavioral changes, including lower motor activity (decreased number of crossings) and exploratory activity (reduced number of rearings). Also, Gcdh -/- mice had significantly higher concentrations of glutarylcarnitine (C5DC) in blood and cathepsin-D (CATD), interleukin IL-1β and tumor factor necrosis alpha (TNF-α) in striatum than WT mice. Noteworthy, L-car treatment prevented most behavioral alterations, normalized CATD levels and attenuated IL-1β levels in striatum of Gcdh -/- mice. Finally, IL-1β was positively correlated with CATD and C5DC levels and L-car was negatively correlated with CATD. Our results demonstrate behavioral changes and a pro-inflammatory status in striatum of the animal model of GA1 and, most importantly, L-car showed important protective effects on these alterations., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: Major depressive disorder (MDD) affects approximately 322 million people worldwide and is a common comorbidity in patients with diabetes mellitus (DM). A possible pathophysiological mechanism correlating both diseases is the increased oxidative stress in brain regions due to hyperglycemia. Myrsine coriacea (Primulaceae) is popularly known as "capororoca" and studies have been shown that this plant exhibits several pharmacological properties attributed to myrsinoic acid A (MAA) and B (MAB). Indeed, previous results have been shown its effects on the central nervous system, leading us to explore possible psychotropic effects., Main Methods: The effects of treatment with hydroalcoholic extract of the barks from Myrsine coriacea (HEBMC, 150 mg/kg, o.g.), MAA (5 mg/kg, o.g.), and MAB (3 mg/kg, o.g.) were evaluated in streptozotocin (75 mg/kg, i.p.)-induced diabetic female rats. After 28 days of treatments, rats were submitted to the forced swim test (FST) and open field test (OFT). Also, superoxide dismutase (SOD) and catalase (CAT) activities, reduced glutathione (GSH) and lipid hydroperoxides (LOOH) levels were evaluated in the hippocampus (HIP) and prefrontal cortex (PFC) of these rats., Key Findings: The treatment with MAA or MAB increased the latency of first immobility in diabetic rats, and the HEBMC administration decreased the immobility time, and increase the climbing in FST. However, only MAB treatment reduces the immobility time, increases the climbing, and swimming in FST, and increases the crossing of diabetic animals in the OFT. Besides, this behavioral improvement promoted by MAB administration was accompanied by reducing in oxidative stress in the HIP and PFC, but not reducing hyperglycemia in diabetic rats., Significance: The results suggest that MAB's antioxidant effect in the HIP of diabetic animals may be essential to its antidepressant-like effect., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The increasingly popular combination of "energy drinks" containing high amounts of caffeine and alcohol has been shown to induce a stimulated, rather than sedated, state which may result in increased binge drinking and increased risk for alcohol-attributable accidents. We sought to examine consumption patterns of and withdrawal from alcohol and caffeine using a voluntary co-consumption animal model. Male and female adult C57BL/6J mice were given access to increasing doses of caffeine (0.01-0.05%) and/or alcohol (3-20%) in a two-bottle choice, intermittent access voluntary paradigm with fluid consumption recorded daily. Anxiety-like behavior during withdrawal was assessed via elevated plus maze or open field test in experiment 2. Increasing both alcohol and caffeine simultaneously in Experiment 1 resulted in no significant changes in co-consumption compared to mice given access to only alcohol or caffeine. Experiment 2 held caffeine concentration steady while slowly increasing alcohol content and resulted in mice consuming more alcohol when it was consumed in tandem with low dose caffeine. Both male and female mice consumed more caffeine when it was paired with alcohol; however, no significant differences were observed during withdrawal behavior. These results suggest that caffeine may dose-dependently positively influence alcohol consumption in mice and echo clinical literature suggesting that caffeine and alcohol together may result in a heightened state of stimulation and lead to further binge drinking. The intermittent access paradigm affords increased translational validity regarding investigations of alcohol and caffeine co-consumption and may be useful in identifying the neurobiological mechanisms concerning co-consumption of such substances., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Previous studies have shown that testosterone attenuates stress-induced mood dysfunction and memory deterioration. However, the exact mechanism is still unknown. This study was conducted to investigate the role of long-term testosterone undecanoate on the behavioral responses in AD induced by AlCl3 + D-galactose administration and the possible alteration of the gene expression level of the Na/K ATPase pump. Adult male mice received AlCl3 in drinking water (10 mg/kg/day) and (D-gal 200 mg/kg/day), subcutaneously for 90 consecutive days, then received a single intramuscular (I.M) injection of castor oil (vehicle) on day 91, while treated groups received a single I.M injection of either low (100 mg/kg/45 days) or high dose (500 mg/kg/45 days) respectively of long-acting testosterone undecanoate on day 91. The time spent in the interaction zone during the open field test, preference index to novel objects in the novel object recognition test, spontaneous alternation percentage (SAP) in Y-maze test, and escape latency time in the Morris water maze test were used to measure the locomotor activity, long-term memory, and spatial memory in mice, respectively. The results showed that testosterone undecanoate treatment improved locomotor activity, improved preference to novel objects, improved spatial memory, and reversed anxiety and depression induced by AlCl3 + D-galactose administration in male mice, suggesting the enhancement of behavioral and memory functions brought by testosterone treatment. Moreover, testosterone undecanoate treatment did alter gene expression levels of Na/K ATPase isoforms in the brain hippocampus. In most cases, altered gene expression was significant and correlated with the observed behavioral changes. Taken together, our findings provide new insight into the effects of long-acting testosterone undecanoate administration on locomotor activity, long-term memory, anxiety, and spatial memory in male mice with Alzheimer's disease., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Long-term potentiation (LTP) is a neurobiological mechanism of cognitive function, and the N-methyl-D-aspartate (NMDA) receptors is fundamental for LTP. Previous studies showed that over activation of NMDA receptors may be a crucial cause of LTP and cognitive impairment induced by stress or corticosterone. However, other studies showed that the function of NMDA receptors is insufficient since the NMDA receptors co-agonist D-serine could improve stress-induced cognitive impairment. The purpose of this study is to clarify whether over activation of NMDA receptors or hypofunction of NMDA receptors is involved in hippocampal impairment of LTP by corticosterone and the underlying mechanisms. Results showed that hippocampal LTP and object location recognition memory were impaired in corticosterone-treated mice. Corticosterone increased the glutamate level in hippocampal tissues, neither NMDA receptors antagonist nor its subtype antagonists alleviated impairment of LTP, while enhancing the function of NMDA receptors by D-serine did alleviate impairment of LTP by corticosterone, suggesting that hypofunction of NMDA receptors might be one of the main reasons for impairment of LTP by corticosterone. Further results showed that the level of D-serine and its precursor L-serine did not change. D-serine release-related protein Na + -independent alanine-serine-cysteine transporter-1 (ASC-1) in the cell membrane was decreased and increasing D-serine release by the selective activator of ASC-1 antiporter activity alleviated impairment of LTP by corticosterone. Taken together, this study demonstrates that hypofunction of NMDA receptors may be involved in impairment of LTP by corticosterone and reduced D-serine release may be an important reason for its hypofunction, which is an important complement to existing mechanisms of corticosterone-induced LTP and cognitive impairment., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuroinflammation and oxidative stress coexist and interact in the progression of postoperative cognitive dysfunction (POCD) and other neurodegenerative disease. Mounting studies reveal that Dexmedetomidine (Dex) possesses anti-inflammatory and antioxidant properties. Nevertheless, whether Dex exerts neuroprotective effect on the cognitive sequelae of oxidative stress and inflammatory process remains unclear. A mouse model of abdominal exploratory laparotomy-induced cognitive dysfunction was employed to explore the underlying mechanism of neuroprotective effects exerted by Dex in POCD. Aged mice were treated with Dex (20 µg/kg) 20 min prior to surgery. Open field test (OFT) and Morris water maze (MWM) were employed to examine the cognitive function on postoperative day 3 (POD 3) or POD 7. In the present study, mice underwent surgery exhibited cognitive impairment without altering spontaneous locomotor activity, while the surgery-induced cognitive impairment could be alleviated by Dex pretreatment. Dex inhibited surgery-induced pro-inflammatory cytokines accumulation and microglial activation in the hippocampi of mice. Furthermore, Dex decreased MDA levels, enhanced SOD activity, modulated CDK5 activity and increased BDNF expression in the hippocampus. In addition, Dex remarkably reduced the surgery-induced increased ratio of Bax/Bcl-2 and apoptotic neurons in the hippocampi of aged mice. Collectively, our study provides evidence that Dex may exert neuroprotective effects against surgery-induced cognitive impairment through mechanisms involving its anti-inflammatory and antioxidant properties, as well as the suppression on the mitochondrial permeability transition pore and apoptosis-related pathway., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Increasing studies report that prolonged or multiple anaesthetic exposures early in life are associated with detrimental effects on brain function. Although studies have evaluated the detrimental effects on neurocognitive function, few have focused on long-term neuropsychiatric effects. In the present study, C57BL/6 mice received either three neonatal isoflurane exposures or control exposure. Starting on postnatal day 45, the mice were either exposed or not to a chronic variable stress (CVS) paradigm, and CVS-related neuropsychiatric performance was evaluated using a series of behavioural tests. The expression levels of histone 3 lysine 9 acetylation (acetyl-H3K9), brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein-binding protein, and histone deacetylases 1-4 in the amygdala were measured by immunoblotting or immunohistochemistry analysis. In mice with neonatal isoflurane exposure, the effects of sodium butyrate (NaB), a commonly used HDAC inhibitor, were examined on CVS-related behavioural and molecular alterations. The results showed that repeated neonatal isoflurane exposure did not affect innate depression-like and anxiety-like behaviours under non-stress conditions but facilitated the CVS-induced anxiety-like behavioural phenotype. Increased HDAC2 expression in the amygdala was associated with an increase in the CVS-induced repression of acetyl-H3K9 and BDNF expression and an enhanced CVS-evoked anxiety-like behavioural phenotype in mice neonatal isoflurane exposure. NaB significantly decreased the CVS-induced anxiety level by elevating acetyl-H3K9 and BDNF expression. These results suggested that early anaesthesia exposure facilitated chronic stress-induced neuropsychiatric outcomes, and the HDAC2-related epigenetic dysregulation of BDNF gene expression is involved in the underlying mechanism., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Besides motor disorder, cognitive dysfunction is also common in Parkinson's disease (PD). Essentially no causal therapy for cognitive dysfunction of PD exists at present. In this study, a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD was used to analyze the neuroprotective potential of orally administered silibinin, a proverbial hepatoprotective flavonoid derived from the herb milk thistle (Silybum marianum). Results demonstrated that silibinin administration significantly attenuated MPTP-induced cognitive impairment in behavioral tests. Nissl staining results showed that MPTP injection significantly increases the loss of neurons in the hippocampus. However, these mice were protected by oral administration of silibinin, accompanying reduction in the cell apoptosis in the hippocampus. The hippocampal aggregates of α-synuclein (α-syn) appeared in MPTP-injected mice, but were significantly decreased by silibinin treatment. MPTP injection induced oxidative stress, as evidenced by increased malondialdehyde (MDA) and decreased superoxide dismutase (SOD). The oxidative stress was alleviated by silibinin treatment. Mitochondrial disorder including the decline of mitochondrial membrane potential (MMP) was another signature in the hippocampus of MPTP-treated mice, accompanying increased mitochondrial fission and decreased fusion. Silibinin administration restored these mitochondrial disorders, as expected for the protection against MPTP injury. These findings suggest that silibinin has a potential to be further developed as a therapeutic candidate for cognitive dysfunction in PD., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Traditional Chinese medicine detoxification prescription Chaihu-jia-Longgu-Muli decoction (CLMD) relieves depressive symptoms in patients withdrawing from methamphetamine. In the present study, we assessed the effects of CLMD on methamphetamine withdrawal in rats. A methamphetamine-intoxicated rat model was established. Rats were randomly divided into the control, model, high-dosage, medium-dosage, and low-dosage groups, receiving high, medium, and low doses of CLMD, respectively. Weekly body weight measurements revealed that rats treated with methamphetamine had the lowest body weight. The conditioned place preference (CPP) experiment revealed that methamphetamine-intoxicated rats stayed significantly longer in the drug-paired chamber than the control rats. However, after administering high-dosage CLMD, the amount of time the rats spent in the drug-paired chamber was significantly less than that of the model rats. Our open-field test revealed that the model group had lower crossing and rearing scores than the control group. Additionally, rats that received CLMD treatment exhibited higher crossing and rearing scores than the model rats. Striatal dopamine (DA), 5-hydroxytryptamine (5-HT), and endorphins (β-EP) and serum interleukin (IL)-1α and IL-2 concentrations were estimated. Rats in the model group had lower striatal DA, 5-HT, and β-EP and higher serum IL-1α and IL-2 concentrations than those in the control group. High-dosage CLMD administration significantly changed the concentrations of these molecules, such that they approached normal concentrations. In general, CLMD could prevent the development of methamphetamine-induced withdrawal symptoms in rats by increasing the DA, 5-HT, and β-EP and lowering the IL-1α and IL-2 concentrations., (© 2021 The Author(s).)

Sleep deprivation (SD) is widespread in society causing serious damage to cognitive function. Hydrogen sulfide (H 2 S), the third gas signal molecule, plays important regulatory role in learning and memory functions. Inhibition of excessive autophagy and upregulation of silent information regulator 1 (Sirt-1) have been reported to prevent cognitive dysfunction. Therefore, this present work was to address whether H 2 S attenuates the cognitive impairment induced by SD in Wistar rats and whether the underlying mechanisms involve in inhibition of excessive autophagy and upregulation of Sirt-1. After treatment with SD for 72 h, the cognitive function of Wistar rats was evaluated by Y-maze, new object recognition, object location, and Morris water maze tests. The results shown that SD-caused cognitive impairment was reversed by treatment with NaHS (a donor of H 2 S). NaHS also prevented SD-induced hippocampal excessive autophagy, as evidenced by the decrease in autophagosomes, the down-regulation of Beclin1, and the up-regulation of p62 in the hippocampus of SD-exposed Wistar rats. Furthermore, Sirtinol, an inhibitor of Sirt-1, reversed the inhibitory roles of NaHS in SD-induced cognitive impairment and excessive hippocampal autophagy in Wistar rats. Taken together, our results suggested that H 2 S improves the cognitive function of SD-exposed rats by inhibiting excessive hippocampal autophagy in a hippocampal Sirt-1-dependent way.

At present, the complex pathogenesis, the difficult-to-overcome blood-brain barrier (BBB), the development of the disease course which cannot be prevented, and other problems are serious challenges in the treatment of Alzheimer's disease (AD). In order to enhance the therapeutic effect of drugs through BBB, we synthesized simple and easy-to-obtain selenium quantum dots (SeQDs), with a multitarget therapeutic effect. This new type of SeQDs has an ultrasmall size and can quickly penetrate the BBB. According to the fluorescence characteristics of SeQDs, we can diagnose and track AD. The experimental results show that SeQDs have strong free-radical scavenging activity, protect cells from oxidative stress induced by different stimuli, and show broad-spectrum antioxidant activity. The SeQDs can not only effectively inhibit Aβ aggregation and significantly reduce Aβ-mediated cytotoxicity, thus preventing AD cascade reaction, but also effectively reduce tau protein phosphorylation by down-regulating PHF1 and CP13 and further reduce oxidative stress, restore mitochondrial functions, and maintain nerve cell stability and protect nerve cells from oxidative stress. In vivo studies demonstrate that SeQDs can continuously accumulate in the brain after rapid passage of BBB and can quickly alleviate AD, significantly improve the memory impairment of AD mice, and improve their learning and memory ability. Therefore, the use of SeQDs in the treatment of AD has great advantages compared with traditional single-target drugs and provides a new direction for the combination of prevention and treatment of neurodegenerative diseases.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with decline in memory and cognitive impairments. Phosphodiesterase IV (PDE4) protein, an intracellular cAMP levels regulator, when inhibited act as potent neuroprotective agents by virtue of ceasing the activity of Pro-inflammatory mediators. The complexity of AD etiology has ever since compelled the researchers to discover multifunctional compounds to combat the AD and neurodegeneration. The aim of this study was to probe into role of drotaverine a PDE4 inhibitor in the management of AD. Albino mice were divided into seven groups (n = 10). Group 1 control group received carboxy methyl cellulose (CMC 1 mL/kg), group II diseased group treated with streptozotocin (STZ 3 mg/kg) by intracerebroventricular (ICV) route, group III administered standard drug Piracetam 200 mg/kg and groups IV-VII were given drotaverine (10, 20, 40, and 80 mg/kg i/p respectively). Groups II-VII were given STZ (3 mg/kg, ICV) on 1st and 3rd day of treatment to induce AD. All the groups were given their respective treatments for 23 days. Improvement in learning and memory was evaluated by using behavioral tests like open field test, elevated plus maze test, Morris water maze test and passive avoidance test. Furthermore, brain levels of biochemical markers of oxidative stress, neurotransmitters, β-amyloid and tau protein were also measured. Drotaverine showed statistically significant dose dependent improvement in behavioral and biochemical markers of AD: the maximum response was achieved at a dose level of 80 mg/kg. The Study concluded that drotaverine ameliorates cognitive impairment and as well as exhibited modulated the brain levels of neurotransmitters.

Exposure to excess levels of manganese (Mn) leads to neurotoxicity. Increasing evidence demonstrates that oxidative stress and neuroinflammation are important pathological causes of neurotoxicity. Resveratrol (Rsv), a sirtuin-1 (SIRT1) activator, plays an important role in neuroprotection. However, the molecular mechanisms of Rsv alleviating Mn-induced oxidative stress and neuroinflammation are not fully understood. To evaluate whether Rsv treatment relieves the oxidative stress and neuroinflammation in the hippocampus after Mn exposure through SIRT1 signaling, C57BL/6 adult mice were exposed to MnCl 2 (200 μmol/kg), Rsv (30 mg/kg), and EX527 (5 mg/kg). Our results showed that administering MnCl 2 for 6 weeks caused behavioral impairment and nerve cell injury in hippocampal tissue, which was related to oxidative stress and neuroinflammation. Activating Mn-induced JNK and inhibiting SIRT1 increased the phosphorylated and acetylated levels of NF-κB and STAT3, respectively. However, Rsv reduced the phosphorylated and acetylated levels of NF-κB and STAT3, and attenuated Mn-induced oxidative stress and inflammatory cytokines by activating SIRT1 signaling. Most importantly, EX527, a potent SIRT1 inhibitor, inactivated SIRT1, which prevented Rsv from exerting its beneficial effects. Taken together, our findings revealed that Rsv alleviated Mn-induced oxidative stress and neuroinflammation in adult mice by activating SIRT1., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is a worldwide problem and there are no effective drugs for AD treatment. Previous studies show that DL0410 is a multi-target, anti-AD agent. In this study, we investigated the therapeutic effect of DL0410 and its action mechanism in SAMP8 mice. DL0410 (1-10 mg·kg - 1 ·d - 1 ) was orally administered to 8-month-old SAMP mice (SAMP8) for 8 weeks. We showed that DL0410 administration effectively ameliorated the cognitive deficits in the Morris water maze test, novel object recognition test, and nest building test. We revealed that DL0410 dose-dependently increased the expression levels of the mitochondrial proteins (PGC-1α, Mitofusin 2, OPA1, and Drp1), and subsequently ameliorated the processes of mitochondrial biosynthesis, fusion, and fission in the cortex and hippocampus of SAMP8 mice. Furthermore, DL0410 administration promoted the expression of synaptic proteins (synaptophysin and PSD95) in the brain of SAMP8 mice, and upregulated the protein phosphorylation in NMDAR-CAMKII/CAMKIV-CREB pathway responsible for the synaptic plasticity. DL0410 administration dose-dependently increased the expression of BDNF and TrkB, and the neurotrophic effect was mediated via the ERK1/2 and PI3K-AKT-GSK-3β pathways. DL0410 administration upregulated Bcl-2, increased the Bcl-2/Bax ratio and the level of caspase 3 and PARP-1, alleviating neuronal apoptosis. We proposed that the NMDAR-CREB-BDNF pathway might establish a positive feedback loop between synaptic plasticity and neurotrophy, with CREB at the center. In summary, DL0410 promotes synaptic function and neuronal survival, thus ameliorating cognitive deficits in SAMP8 mice via improved mitochondrial dynamics and increased activity of the NMDAR-CREB-BDNF pathway. DL0410 is a promising candidate to treat aging-related AD, and deserves more research and development in future.

Diabetic neuropathy is one of the most common complications of diabetes mellitus. Excess glutamate release and oxidative stress are hypothesized to be involved in the pathophysiology of diabetes-induced neuropathy. This study was designed to investigate the effect of clavulanic acid (CLAV), a competitive beta-lactamase inhibitor, on the streptozocin (STZ)-induced neuropathic pain and possible mechanisms in the spinal cord of rats. Male Wistar rats were divided into naive group; control group which got a single dose of STZ (50 mg/kg, i.p.), as a model of diabetic neuropathic pain; prophylactic groups: animals received CLAV (10, 20 and 40 mg/kg, i.p.) 1 week after STZ for 10 days; and therapeutic group: animals received 20 mg/kg CLAV, 21 days after STZ for 10 days. Study of pain behaviors was started on days 0, 7, 14, 21, 28, 35 and 42 after STZ. The expression of the glutamate transport 1 (GLT1), genes of oxidative stress including inducible nitric oxide synthase (iNOS), proinflammatory cytokine, tumor necrosis factor alpha (TNF-α), as well as genes involved in the apoptosis including bcl2, bcl2-associated x (bax) were measured in the spinal cord tissue by Real Time PCR, on day 42. On day 21 post injection of STZ, diabetic animals showed significant mechanical allodynia, cold allodynia and thermal hyperalgesia. CLAV in all doses of 10, 20 and 40 mg/kg reduced symptoms of allodynia and hyperalgesia, in both prophylactic and therapeutic regimens. While iNOS, TNF-α, bax/bcl2 were found significantly overexpressed in spinal cord of diabetic animals, their expression in animals received CLAV had been reduced. In contrast, GLT1 that had decreased in the spinal cord of diabetic animals, significantly increased in those received CLAV. CLAV was found a promising candidate for reliving neuropathic pain in diabetes mellitus. Such beneficial effect of CLAV could be, in part, attributed to the increased expression of GLT 1, inhibition of nitrosative stress, anti-inflammation, and inhibition of some apoptotic mediators followed by administration into diabetic animals.

Proparacaine (PPC) is a previously discovered topical anesthetic for ophthalmic optometry and surgery by blocking the central Nav1.3. In this study, we found that proparacaine hydrochloride (PPC-HCl) exerted an acute robust antiepileptic effect in pilocarpine-induced epilepsy mice. More importantly, chronic treatment with PPC-HCl totally terminated spontaneous recurrent seizure occurrence without significant toxicity. Chronic treatment with PPC-HCl did not cause obvious cytotoxicity, neuropsychiatric adverse effects, hepatotoxicity, cardiotoxicity, and even genotoxicity that evaluated by whole genome-scale transcriptomic analyses. Only when in a high dose (50 mg/kg), the QRS interval measured by electrocardiography was slightly prolonged, which was similar to the impact of levetiracetam. Nevertheless, to overcome this potential issue, we adopt a liposome encapsulation strategy that could alleviate cardiotoxicity and prepared a type of hydrogel containing PPC-HCl for sustained release. Implantation of thermosensitive chitosan-based hydrogel containing liposomal PPC-HCl into the subcutaneous tissue exerted immediate and long-lasting remission from spontaneous recurrent seizure in epileptic mice without affecting QRS interval. Therefore, this new liposomal hydrogel formulation of proparacaine could be developed as a transdermal patch for treating epilepsy, avoiding the severe toxicity after chronic treatment with current antiepileptic drugs in clinic., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Like other drugs, ketamine is abused due to its ability to act as a positive reinforcer in the control of behavior, just as natural reinforcers do. Besides, through Pavlovian conditioning, tolerance to drug effects can become conditioned to specific contextual cues showing that environmental stimuli can act as powerful mediators of craving and relapse. In the present study, we shall investigate the effects of long-term ketamine administration and withdrawal on behavioral measures and emotionality, the drug-context-specific influence on the tolerance to the sedative effects of an anesthetic dose of ketamine, and the neuropharmacological events underlying this phenomenon, in rats conditioned with 10 mg/kg of ketamine and later challenged with a dose of ketamine of 80 mg/kg in a familiar and non-familiar environment. Variations in dopamine and serotonin efflux in the infralimbic cortex-nucleus accumbens shell circuitry (IL-NAcSh) was further recorded in the same conditions. Our results highlight that besides its well-known reinforcing properties, ketamine also shares the ability to induce behavioral and pharmacological conditioned tolerance, associated with increases in cortical (IL), and decreases in striatal (NAcSh) dopamine release. To our knowledge, we are presenting the first set of behavioral and neurochemical data showing that, like other drugs of abuse, ketamine can induce learned context-specific tolerance.

Background: Both animal and retrospective human studies have linked extended and repeated general anaesthesia during early development with cognitive and behavioural deficits later in life. However, the neuronal circuit mechanisms underlying this anaesthesia-induced behavioural impairment are poorly understood., Methods: Neonatal mice were administered one or three doses of propofol, a commonly used i.v. general anaesthetic, over Postnatal days 7-11. Control mice received Intralipid® vehicle injections. At 4 months of age, the mice were subjected to a series of behavioural tests, including motor learning. During the process of motor learning, calcium activity of pyramidal neurones and three classes of inhibitory interneurones in the primary motor cortex were examined in vivo using two-photon microscopy., Results: Repeated, but not a single, exposure of neonatal mice to propofol i.p. caused motor learning impairment in adulthood, which was accompanied by a reduction of pyramidal neurone number and activity in the motor cortex. The activity of local inhibitory interneurone networks was also altered: somatostatin-expressing and parvalbumin-expressing interneurones were hypoactive, whereas vasoactive intestinal peptide-expressing interneurones were hyperactive when the mice were performing a motor learning task. Administration of low-dose pentylenetetrazol to attenuate γ-aminobutyric acid A receptor-mediated inhibition or CX546 to potentiate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-subtype glutamate receptor function during emergence from anaesthesia ameliorated neuronal dysfunction in the cortex and prevented long-term behavioural deficits., Conclusions: Repeated exposure of neonatal mice to propofol anaesthesia during early development causes cortical circuit dysfunction and behavioural impairments in later life. Potentiation of neuronal activity during recovery from anaesthesia reduces these adverse effects of early-life anaesthesia., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Chronic manganese (Mn) exposure is related to elevated risks of neurodegenerative diseases, and mitochondrial dysfunction is considered a critical pathophysiological feature of Mn neurotoxicity. Although previous research has demonstrated Mn-induced alpha-synuclein (α-Syn) overexpression, the role of α-Syn in mitochondrial dysfunction remains unclear. Here, we used Wistar rats and human neuroblastoma cells (SH-SY5Y cells) to elucidate the molecular mechanisms underlying how α-Syn overexpression induced by different doses of Mn (15, 30, and 60 mg/kg) results in mitochondrial dysfunction. We found that Mn-induced neural cell injury was associated with mitochondrial damage. Furthermore, Mn upregulated α-Syn protein levels and increased the interaction between α-Syn and mitochondria. We then used a lentivirus vector containing α-Syn shRNA to examine the effect of Mn-induced α-Syn protein on PINK1/Parkin-mediated mitophagy in SH-SY5Y cells. Our data demonstrated that the knockdown of α-Syn decreased the interaction between α-Syn and PINK1. The enhanced level of phosphorylated Parkin (p-Parkin) was due to the decrease of the interaction between α-Syn and PINK1. Moreover, the knockdown of α-Syn increased recruitment of p-Parkin to mitochondria. Collectively, these observations revealed that Mn-induced α-Syn overexpression repressed PINK1/Parkin-mediated mitophagy and exacerbated mitochondrial damage., (Copyright © 2021 Elsevier Ltd. All rights reserved.)