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Snow mountain garlic (SMG) is a trans-Himalayan medicinal plant used in the traditional medicine system for several ailments, including inflammatory arthritis. Research studies are insufficient to validate its folk medicinal applications. In the present study, the comparative abundance of its key bioactive phytocompounds, viz., S-allyl-L-cysteine (SAC), alliin, and S-methyl-L-cysteine (SMC) against normal garlic were assessed using the LC–MS/MS-MRM method. In addition, the study also explored the antioxidant and anti-inflammatory potency of crude extract of SMG and purified signature phytocompounds (i.e., SMC, SAC, and alliin) in comparison with normal garlic and dexamethasone in LPS-stimulated RAW264.7 macrophage cells. The LC–MS/MS-MRM study revealed significant differences among SMG and normal garlic, viz., alliin 22.8-fold higher in SMG, and SMC could be detected only in SMG. In the bioassays, SMG extract and purified signature phytocompounds significantly downregulated oxidative damage in activated macrophages, boosting endogenous antioxidants' activity. SMG extract-treated macrophages significantly suppressed NF-κB expression and related inflammatory indicators such as cytokines, COX-2, iNOS, and NO. Notably, the observed anti-inflammatory and antioxidant bioactivities of SMG extract were comparable to signature phytocompounds and dexamethasone. In addition, SAC being uniformly found in SMG and normal garlic, its comparative pharmacokinetics was studied to validate the pharmacodynamic superiority of SMG over normal garlic. Significantly higher plasma concentrations (Cmax), half-life (t1/2), and area under curve (AUC) of SAC following SMG extract administration than normal garlic validated the proposed hypothesis. Thus, the abundance of bioactive phytocompounds and their better pharmacokinetics in SMG extract might be underlying its medicinal merits over normal garlic. [ABSTRACT FROM AUTHOR]

Vascular dementia (VD) is a degenerative cerebrovascular disorder associated with progressive cognitive decline. Previous reports have shown that 7,8-dihydroxyflavone (7,8-DHF), a well-known TrkB agonist, effectively ameliorates cognitive deficits in several disease models. Therefore, this study investigated the protective effects of 7,8-DHF against 2-VO-induced VD. VD was established in rats using the permanent bilateral carotid arteries occlusion (two-vessel occlusion, 2-VO) model. 7,8-DHF (5, 10, and 20 mg/kg) and Donepezil (10 mg/kg) were administered for 4 weeks. Memory function was assessed by the novel objective recognition task (NOR) and Morris water maze (MWM) tests. Inflammatory (TNF-α, IL-1β, and NF-kβ), oxidative stress, and apoptotic (BAX, BCL-2, caspase-3) markers, along with the activity of choline acetylcholinesterase (AChE) was assessed. p-AKT, p-CREB, BDNF, and neurotransmitter (NT) (GLU, GABA, and ACh) levels were also analyzed in the hippocampus of 2-VO rats. Our results show that 7,8-DHF effectively improved memory performance and cholinergic dysfunction in 2-VO model rats. Furthermore, 7,8-DHF treatment also increased p-AKT, p-CREB, and BDNF levels, suppressed oxidative, inflammatory, and apoptotic markers, and restored altered NT levels in the hippocampus. These findings imply that 7, 8-DHF may act via multiple mechanisms and as such serve as a promising neuroprotective agent in the context of VD. [ABSTRACT FROM AUTHOR]

This study was conducted to investigate the γ-aminobutyric acid (GABA) production ability of 20 Lactobacillus and 25 Bifidobacterium strains which were previously isolated in our laboratory. Effect of initial pH, incubation time, monosodium glutamate (MSG), and pyridoxal-5′-phosphate (PLP) concentration for highest GABA production by two potent bacterial strains, Levilactobacillus brevis LAB6 and Limosilactobacillus fermentum LAB19 were optimized in the MRS media. A threefold increase in GABA production at an initial pH 4.0, incubation time of 120 h in medium supplemented with 3% MSG and 400 μM of PLP for LAB6 and 300 μM for LAB19 lead to the production of 19.67 ± 0.28 and 20.77 ± 0.14 g/L of GABA, respectively. Coculturing both strains under optimized conditions led to a GABA yield of 20.02 ± 0.17 g/L. Owing to potent anti-inflammatory activity in-vitro, as reported previously, and highest GABA production ability of LAB6 (MTCC 25662), its whole-genome sequencing and bioinformatics analysis was carried out for mining genes related to GABA metabolism. LAB6 harbored a complete glutamate decarboxylase (GAD) gene system comprising gadA, gadB, and gadC as well as genes responsible for the beneficial probiotic traits, such as for acid and bile tolerance and host adhesion. Comparative genomic analysis of LAB6 with 28 completely sequenced Levilactobacillus brevis strains revealed the presence of 95 strain-specific genes-families that was significantly higher than most other L. brevis strains. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced cognitive impairment (CICI) is one of the major adverse effects of antineoplastic drugs, which decrease the quality of life in cancer survivors. Extensive experimental and clinical research suggests that chemotherapeutic drugs generate an enormous amount of reactive oxygen species (ROS), contributing to oxidative stress, neuroinflammation, blood-brain barrier (BBB) disruption, and neuronal death, eventually leading to CICI. Despite the progress in exploring different pathological mechanisms of CICI, effective treatment to prevent CICI progression has not been developed yet. Nrf2 is the principal transcription factor that regulates cellular redox balance and inflammation-related gene expression. Emerging evidence suggests that upregulation of Nrf2 and its target genes could suppress oxidative stress, and neuroinflammation, restore BBB integrity, and increase neurogenesis. This review discusses the role of Nrf2 in CICI, how it responds to oxidative stress, inflammation, neurotoxicity, and potential Nrf2 activators that could be used to enhance Nrf2 activation in CICI. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced cognitive impairment (CICI) is a common complication associated with the use of chemotherapeutics. Doxorubicin (DOX) is a reactive oxygen species (ROS) producing anticancer agent capable of causing potential neurotoxic effects via cytokine-induced oxidative and nitrosative damage to brain tissues. On the other hand, alpha-lipoic acid (ALA), a nutritional supplement, is reputable for its excellent antioxidant, anti-inflammatory, and anti-apoptotic activities. Consequently, the objective of the current investigation was to examine any potential neuroprotective and memory-improving benefits of ALA against DOX-induced behavioral and neurological anomalies. DOX (2 mg/kg/week, i.p.) was administrated for 4 weeks to Sprague–Dawley rats. ALA (50, 100, and 200 mg/kg) was administered for 4 weeks. The Morris water maze (MWM) and novel objective recognition task (NORT) tests were used to assess memory function. Biochemical assays with UV–visible spectrophotometry were used to analyze oxidative stress markers [malondialdehyde (MDA), protein carbonylation (PCO)], endogenous antioxidants [reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)] and acetylcholinesterase (AChE) activity in hippocampal tissue. Inflammatory markers [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and nuclear factor kappa B (NF-κB)], nuclear factor erythroid 2-related factor-2 (NRF-2) and hemeoxygenase-1 (HO-1) levels were estimated using enzyme-linked immunosorbent assay (ELISA). In addition, reactive oxygen species (ROS) levels were measured in hippocampus tissue using 2-7-dichlorofluorescein-diacetate (DCFH-DA) assay with fluorimetry. ALA treatment significantly protected against DOX-induced memory impairment. Furthermore, ALA restored hippocampal antioxidants, halted DOX-induced oxidative and inflammatory insults via upregulation of NRF-2/HO-1 levels, and alleviated the increase in NF-κB expression. These results indicate that ALA offers neuroprotection against DOX-induced cognitive impairment, which could be attributed to its antioxidant potential via the NRF-2/HO-1 signaling pathway. [ABSTRACT FROM AUTHOR]

Cognitive dysfunction is an important complication observed in type 2 diabetes mellitus (T2DM) patients. Tetramethylpyrazine (TMP) is known to exhibit anti-diabetic and neuroprotective properties. Therefore, the present study aimed to investigate the possible therapeutic effects of TMP against type 2 diabetes-associated cognitive impairment in rats. High-fat diet (HFD) followed by a low dose of streptozotocin (35 mg/kg) was used to induce diabetes in Sprague–Dawley rats. TMP (20, 40, and 80 mg/kg) and Pioglitazone (10 mg/kg) were administered for 4 weeks. The Morris water maze (MWM) and novel objective recognition task (NOR) tests were used to assess memory function. Fasting blood glucose (FBG), lipid profile, HOMA-IR, glycosylated hemoglobin (HbA1c), and glucose tolerance were measured. Acetylcholinesterase (AChE) and choline acetytransferase (ChAT) activity, acetylcholine (ACh) levels, oxidative stress, apoptotic (Bcl-2, Bax, caspase-3), and inflammatory markers (TNF-α, IL-1β, and NF-kβ) were assessed. BDNF, p-AKT, and p-CREB levels were also measured. In the present work, we observed that treatment of diabetic rats with TMP alleviated learning and memory deficits, improved insulin sensitivity, and attenuated hyperglycemia and dyslipidemia. Furthermore, treatment with TMP increased BDNF, p-Akt, and p-CREB levels, normalized cholinergic dysfunction, and suppressed oxidative, inflammatory, and apoptotic markers in the hippocampus. Collectively, our results suggest that the TMP may be an effective neuroprotective agent in alleviating type 2 diabetes-associated cognitive deficits. [ABSTRACT FROM AUTHOR]

Excessive generation of oxygen free radicals plays a pivotal role in destruction of biological molecules like DNA, proteins, lipids, carbohydrates and results in various pathologies including neuronal disorders. Antioxidant molecules from natural products are reported to have ability to mitigate their production or at least halt their progression and metastasis in the system. Different studies have been performed to spot antioxidants from natural sources and attempts have been made to integrate them in conventional therapy. In our present study, food grade Phycocyanin, a nutraceutical isolated from Spirulina platensis, has been evaluated for its in vitro and in vivo antioxidant potential using a battery of antioxidant assays viz. DPPH, TAC, FRAP, hydroxyl radical, hydrogen peroxide scavenging, SOD, GSH, and LPO assays. Reducing properties of Phycocyanin were also assessed by FRAC assay. For in vivo evaluation of antioxidant profile, animal model of intracerebroventricular administration of streptozotocin was employed. Levels of oxidative stress biomarkers were measured in cortex and hippocampal parts of brain. Results obtained depicted that Phycocyanin demonstrated a dose-dependent pattern in its efficacy, which indicates the presence of free radical scavenger moieties and possible role as a neuroprotective agent. [ABSTRACT FROM AUTHOR]

The night shift paradigm induces a state of chronic partial sleep deprivation (CPSD) and enhances the vulnerability to neuronal dysfunction. However, the specific neuronal impact of CPSD has not been thoroughly explored to date. In the current study, the night shift condition was mimicked in female Swiss albino mice. The classical sleep deprivation model, i.e., Modified Multiple Platform (MMP) method, was used for 8 h/day from Monday to Friday with Saturday and Sunday as a weekend off for nine weeks. Following nine weeks of night shift schedule, their neurobehavioral profile and physiological parameters were assessed along with the activity of the mitochondrial complexes, oxidative stress, serotonin levels, and inflammatory markers in the brain. Mice showed an overall hyperactive behavioral profile including hyperlocomotion, aggression, and stereotyped behavior accompanied by decreased activity of mitochondrial enzymes and serotonin levels, increased oxidative stress and inflammatory markers in whole brain homogenates. Collectively, the study points towards the occurrence of a hyperactive behavioral profile akin to mania and psychosis as a potential consequence of CPSD. [ABSTRACT FROM AUTHOR]

Growing experimental evidences have suggested the reciprocal correlation between sleep deprivation and pain. Inflammation and oxidative stress are among the key pathways underlying this correlation. Therefore, the present study was aimed to assess the effect of antioxidant and anti-inflammatory compound naringenin (NGN) against chronic sleep deprivation (CSD)-induced mechanical and thermal hyperalgesia in female Swiss albino mice. In this study, mice were chronically sleep-deprived for 8 h a day for five days a week with the weekend as a free sleep period and continued for nine weeks using a modified multiple platform method. The pain behavioral tests were conducted at the end of the fourth week to assess the development of hyperalgesia followed by the administration of NGN and a combination of NGN with Sirtinol (SIR, a sirtuin1 inhibitor) till the end of the study. After nine weeks, pain behavioral tests, along with oxidative stress and inflammatory parameters in cortex and striatum, were assessed. Results indicated that CSD-induced hyperalgesia in mice accompanied by increased oxidative stress and inflammatory markers in cortex and striatum of the brain. NGN combatted the hyperalgesic response and also decreased levels of oxidative stress and inflammatory markers. Furthermore, the pharmacological effect of NGN was mitigated with SIR. Thus, the findings of the present study reveal that NGN is acting via sirtuin1 to exert its antinociceptive activity against CSD-induced hyperalgesia. [ABSTRACT FROM AUTHOR]

Background: Chronic cerebral hypoperfusion (CCH) induced oxidative stress and inflammation is known to be implicated in the pathogenesis of vascular dementia. The nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a potential therapeutic target for neuroprotection. In the present study, we investigated the beneficial effects of dimethyl fumarate (DMF), an Nrf2 activator in an experimental model of vascular dementia. Methods: Permanent occlusion of the bilateral common carotid arteries (2-VO) was performed to induce CCH in adult male Sprague–Dawley rats. DMF (15, 30, and 60 mg/kg) was administered for 4 weeks. Cognitive performance was assessed using the Morris water maze (MWM) and novel object (NOR) tests. After behavior tests, various oxidative and inflammatory markers were assessed in the hippocampus. Results: The obtained results indicate that treatment with DMF significantly improved 2 VO-induced cognitive deficits. DMF decreased MDA (p < 0.001), protein carbonyl (PCO) contents (p < 0.001), and acetylcholinesterase (p < 0.01) activities, and inhibited inflammatory markers (TNF-α, IL-1β, NF-κβ, and COX-2) levels. Furthermore, our results showed that DMF augmented GSH (p < 0.001) levels and SOD (p < 0.05), CAT, and GSH-Px (p < 0.001) activities in the hippocampus. Nrf2 (p < 0.05) and its downstream targets HO-1 levels (p < 0.01) and NQO1 (p < 0.05) levels were also up-regulated after DMF treatment. Conclusion: Taken together, the results demonstrate that DMF could serve as a promising neuroprotective agent for treating vascular dementia. [ABSTRACT FROM AUTHOR]

Approximately one-third of the world population is suffering from MetS, and the same is expected to rise in the years to come. Worldwide, most of the staple diets contain high amounts of carbohydrates, fats and comparatively low quantities of proteins. The goal of this study was to evaluate the effect of high fat-low protein diet in the development of the metabolic syndrome and associated cognitive deficits in the female rats. The rats fed with high fat-low protein diet (HFLPD) and 15% oral fructose solution for 24 weeks. Body weight, food intake, water intake, fasting blood glucose, oral glucose tolerance, glycosylated hemoglobin (HbA1C), and serum lipid profile were measured after every 4 weeks. Serum insulin, HOMA-IR index, rectal temperature, and systolic blood pressure were measured to confirm the manifestation of the hallmarks of metabolic syndrome. Behavioral tests for locomotion, anxiety, learning, and spatial memory were performed from the 12th week to till the end of the study. At the 24th week, oxidative stress assays and histopathology of liver, kidney, brain, and WAT were also performed. HFLPD significantly altered the physiologic and metabolic parameters which contributed to the manifestation of MetS. HFLPD also impaired the cognitive functions along with significant structural changes in the liver, kidney, WAT, and brain. The findings of this study reveal that HFLPD has the potential to induce the physiological, metabolic and histological alterations in rats, which eventually led to the development of MetS and also disrupted the cognitive functions in female rats. [ABSTRACT FROM AUTHOR]

Purpose: Cranberries are a rich source of polyphenolic antioxidants. Purified sugars or artificial sweeteners are being added to cranberry-based food products to mask tartness. Refined sugar and artificial sweeteners intake modulate gut microbiota and result in metabolic complications. We evaluated effects of isomalto-oligosaccharides (IMOs; sweet tasting non-digestible oligosaccharides) with cranberry extract (CRX) on high fat diet (HFD)-induced metabolic alterations in mice.Methods: Male Swiss albino mice were fed normal chow or HFD (58% fat kcal), and were administered either CRX (200 mg/kg) alone or in combination with IMOs (1 g/kg). Cecal short-chain fatty acids, abundances of selected (1) butyrate producing, (2) metabolically beneficial, and (3) selective lipopolysaccharides producing gram negative gut bacteria were studied. Further, gut-related histological, biochemical, genomic changes along with circulating pro-/anti-inflammatory markers and systemic obesity-associated metabolic changes were studied.Results: Co-supplementation of CRX and IMOs significantly improved cecal SCFAs, especially butyrate levels, selected butyrate-producing bacteria (clostridial cluster XIVa bacteria) and butyrate kinase expression in HFD-fed mice. The combination also significantly improved gut beneficial bacterial abundance, gut histology and related changes (colon mucin production, gut permeability) as compared to individual agents. It also prevented HFD-induced systemic and tissue inflammation, glucose intolerance and systemic obesity-associated metabolic changes in adipose tissue and liver. The combination of CRX and IMOs appeared more effective in the prevention of HFD-induced gut derangements.Conclusion: Combination of CRX and IMOs could be advantageous for normalization of metabolic alterations seen in diet-induced obesity via beneficial modulation of gastrointestinal health. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by intracellular neurofibrillary tangles and extracellular Aβ deposition. Growing experimental evidence indicate diverse biological effects of vitamin D including antioxidant, neuroprotective, anti-inflammatory and cardiovascular benefits. However, the underlying neuroprotective mechanism of vitamin D is still largely elusive. Therefore, the present study was aimed to investigate the neuroprotective effects of vitamin D on ICV-STZ induced sporadic AD. Our study demonstrated that vitamin D3 pretreatment significantly improved spatial learning and memory functions and effectively mitigated ICV-STZ mediated neuronal oxidative stress, mitochondrial aberrations and improved cholinergic functions. Moreover, vitamin D attenuated hippocampal neuroinflammatory response and reduced neuronal death in cortex and hippocampus. Our findings indicated that prophylactic vitamin D supplementation ameliorated ICV-STZ mediated neurobehavioral alterations, oxidative stress and neuroinflammation thereby improving cholinergic functions and reversed degenerative changes in brain. Thus, our study further provides evidence for its therapeutic supplementation for various neurodegenerative disorders including AD. Graphical Abstract: [ABSTRACT FROM AUTHOR]

Mimosa pudica is used in traditional medicine for treating various disorders such as inflammatory conditions, diarrhoea, insomnia, alopecia, urogenital infections and wounds. The present study investigated the effect of M. pudica extract (MPE) on l-arginine-induced acute necrotising pancreatitis in rats. The ethanolic extract of M. pudica leaves was studied for the presence of quercetin and gallic acid using high-performance liquid chromatography. Four groups were employed-normal control rats, l-arginine control rats (two intraperitoneal [i.p.] injections of 2 g/kg at an interval of 1 h), MPE-treated rats (400 mg/kg orally) and melatonin-treated rats (positive control 10 mg/kg i.p.), which were further divided into subgroups according to time points (24 h, 3 days and 14 days). Serum amylase, lipase, tumour necrosis factor-α (TNF-α), pancreatic amylase, nucleic acid content, protein, transforming growth factor-β1 (TGF-β1), thiobarbituric reactive substances, glutathione, nitrite/nitrate, collagen content and histopathological examination were carried out. MPE significantly improved acute necrotising pancreatitis by modulating diagnostic markers of pancreatitis such as serum lipase and pancreatic amylase, inflammation (TNF-α), and oxidative and nitrosative stress. Moreover, MPE administration induced regenerative changes in the pancreas evidenced by increased levels of pancreatic proteins, nucleic acid content and histopathology report. In addition, MPE improved TGF-β1 and collagen levels thereby preventing fibrosis. The current investigation indicates the novel role of MPE in reducing the severity of acute necrotising pancreatitis by plausible mechanisms such as anti-inflammatory and anti-fibrotic activity and by promoting repair and regeneration of the pancreas. [ABSTRACT FROM AUTHOR]

Rationale: The therapeutic potential of berberine has been well documented in various neurological problems. However, the neurological mechanism of berberine remains untapped in the light of its P-glycoprotein (P-gp)-mediated gut efflux properties responsible for reduced bioavailability. Verapamil, a well known L-type calcium channel blocker, has additional inhibitory activity against P-gp efflux pump. Thus, there is a strong scientific rationale to explore the interaction of berberine with verapamil as a possible neuroprotective strategy. Objective: The present study was designed to evaluate the effect of berberine, verapamil, and their combination on behavioral alterations, oxidative stress, mitochondrial dysfunction, neuroinflammation, and histopathological modifications in intracerebroventricular streptozocin (ICV-STZ)-induced sporadic dementia of Alzheimer's type in rats. Methods: Single bilateral ICV-STZ (3 mg/kg) administration was used as an experimental model of sporadic dementia of Alzheimer's type. Results: Berberine (25, 50, and 100 mg/kg, oral gavage) or verapamil (2.5 and 5 mg/kg, intraperitoneally) were used as treatment drugs, and memantine (5 mg/kg, intraperitoneally) was used as a standard. Berberine and verapamil significantly attenuated behavioral, biochemical, cellular, and histological alterations, suggesting their neuroprotective potential. Further, treatment of berberine (25 and 50 mg/kg) with verapamil (2.5 and 5.0 mg/kg) combinations respectively significantly potentiated their neuroprotective effect which was significant as compared to their effect per se in ICV-STZ-treated animals. Conclusion: The augmentative outcome of verapamil on the neuroprotective effect of berberine can be speculated due to the inhibition of P-gp efflux mechanism and the prevention of calcium homeostasis alteration. Additionally, anti-inflammatory and antioxidant effects of both berberine and verapamil could also contribute in their protective effect. [ABSTRACT FROM AUTHOR]

Rationale: Clinical and experimental evidence have demonstrated that alcohol consumption during pregnancy can disrupt brain development, leading to a variety of behavioral alterations including hyperactivity, motor dysfunction, and cognitive deficits in offsprings. Alcohol-induced neurocognitive deficits are associated with activation of oxidative-inflammatory cascade coupled with extensive apoptotic neurodegeneration in different brain regions. Objectives: The present study was designed with an aim to investigate the protective effect of curcumin, a principal curcuminoid present in the Indian spice turmeric, against alcohol-induced cognitive deficits, neuroinflammation, and neuronal apoptosis in rat pups postnatally exposed to ethanol. Methods and results: Male Wistar rat pups were administered ethanol (5 g/kg, 12 % v/ v) by intragastric intubation on postnatal days (PD) 7, 8, and 9 and were treated with curcumin (30 and 60 mg/kg) from PD 6 to 28. Performance of ethanol-exposed pups that did not receive curcumin was significantly impaired as evaluated in both Morris water maze and elevated plus maze tasks recorded by using computer tracking. Cognitive deficit was associated with enhanced acetylcholinesterase activity, increased neuroinflammation (oxidative-nitrosative stress, TNF-α, IL-1β, and TGF-β1), and neuronal apoptosis (NF-κβ and caspase 3) in both cerebral cortex and hippocampus of ethanol-exposed pups. Chronic treatment with curcumin significantly ameliorated all the behavioral, biochemical, and molecular alterations in different brain regions of ethanol-exposed pups. Conclusions: The current study demonstrates the possible involvement of oxidative-inflammatory cascade-mediated apoptotic signaling in cognitive deficits associated with postnatal ethanol exposure and points towards the neuroprotective potential of curcumin in mitigating alcohol-induced behavioral, biochemical, and molecular deficits. [ABSTRACT FROM AUTHOR]

Long-term treatment with haloperidol is associated with a number of extrapyramidal side effects, particularly the irregular movements of chorionic type. This limitation presents a marked therapeutic challenge. The present study investigates the molecular etiology of haloperidol neurotoxicity and the role of curcumin, a well-known anti-oxidant, in ameliorating these adverse effects. The redox status of haloperidol-treated brains along with NO, TNF-α, NF-kappaB p65 subunit, caspase-3, and monoamine neurotransmitters were measured in the striatum of rat brain. Chronic treatment with haloperidol (5 mg/kg, i.p., 21 days) produced orofacial dyskinetic movements which were coupled with marked increase in oxidative stress parameters, TNF-α, caspase-3 activity in cytoplasmic lysate and active p65 sub unit of NF-kappaB in nuclear lysates of the striatum. Neurochemically, chronic administration of haloperidol resulted in a significant decrease in the levels of norepinephrine, dopamine, and serotonin. The prototype atypical anti-psychotic, clozapine (10 mg/kg, i.p., 21 days) produced mild oxidative stress but did not alter any other parameters. Interestingly, co-administration of curcumin (25 and 50 mg/kg, i.p., 21 days) dose-dependently prevented all the behavioral, cellular, and neurochemical changes associated with the chronic administration of haloperidol. Curcumin per se (50 mg/kg) did not show any side effects. Co-administration of piperine significantly enhanced the effect of curcumin (25 mg/kg) but not of curcumin (50 mg/kg). Collectively, the data indicated the potential of curcumin as an adjunct to haloperidol treatment and provided initial clues to the underlying molecular mechanisms in haloperidol neurotoxicity. This study also provides a rationale for the combination of piperine and curcumin. [ABSTRACT FROM AUTHOR]

Rationale: A complex relationship exists among stressful situations, body's reaction to stress, and the onset of clinical depression. Chronic unpredictable stressors can produce a situation similar to clinical depression, and such animal models can be used for the preclinical evaluation of antidepressants. Many findings have shown that the levels of proinflammatory cytokines (e.g., TNF-α) and oxidative stress (increased lipid peroxidation, decreased glutathione levels, and endogenous antioxidant enzyme activities) are increased in patients with depression. Sesamol, a phenolic derivative with a methylenedioxy group, is a potent inhibitor of cytokine production as well as an antioxidant. Objectives: The present study was designed to investigate the effect of sesamol on unpredictable chronic stress-induced behavioral and biochemical alterations in mice. Methods: Animals were subjected to different stress paradigms daily for a period of 21 days to induce depressive-like behavior. The sucrose preference, immobility period, locomotor activity, memory acquisition, and retention were evaluated. Results: Chronic treatment with sesamol significantly reversed the unpredictable chronic stress-induced behavioral (increased immobility period, reduced sucrose preference), biochemical (increased lipid peroxidation and nitrite levels; decreased glutathione levels, superoxide dismutase and catalase activities), and inflammation surge (serum TNF-α) in stressed mice. Conclusion: The study revealed that sesamol exerted antidepressant-like effects in behavioral despair paradigm in chronically stressed mice, specifically by modulating central oxidative-nitrosative stress and inflammation. [ABSTRACT FROM AUTHOR]

Emerging epidemiologic data indicates that diabetes is a potential predisposing factor for neuropsychiatric deficits as stroke, cerebrovascular diseases, diabetes-associated cognitive decline, depression and anxiety. Diabetes-associated cognitive decline, characterized by impaired cognitive functions and neurochemical and structural abnormalities, involves direct neuronal damage caused by intracellular glucose. The present study was designed to investigate the effect of sesamol (3,4-methylenedioxyphenol), a phenolic antioxidant and anti-inflammatory molecule, on cognitive functions, oxidative stress and inflammation in diabetic rats. Learning and memory behaviors were investigated using a spatial version of the Morris water maze test. Acetylcholinesterase activity, a marker of cholinergic dysfunction, was increased by 80% in the cerebral cortex of diabetic rats. There was 107 and 121% rise in thiobarbituric acid reactive substance levels in cerebral cortex and hippocampus of diabetic rats, respectively. Reduced glutathione levels and enzymatic activities of superoxide dismutase and catalase were decreased in both cerebral cortex and hippocampal regions of diabetic rat brain. Nitrite levels in cerebral cortex and hippocampus was increased by 138 and 109%, respectively. Serum tumor necrosis factor-alpha, a marker for inflammation, was found to increase by 1,100% in diabetic rats. Chronic treatment with sesamol (2, 4 and 8 mg/kg; p.o.) significantly and dose-dependently attenuated cognitive deficit, reduced acetylcholinesterase, oxidative stress and inflammation in diabetic rats. The results emphasize the involvement of oxidative stress and inflammation in the development of cognitive impairment in diabetic animals and point towards the therapeutic potential of sesamol in diabetes-associated cognitive decline. [ABSTRACT FROM AUTHOR]

Tardive dyskinesia is a syndrome of abnormal and involuntary movements which occurs as a complication of long-term neuroleptic therapy especially classical neuroleptics such as haloperidol and chlorpromazine. Dysfunction of GABA receptor mediated inhibition, and increased glutamatergic neurotransmission has been implicated in the development of orofacial dyskinesia in rats and tardive dyskinesia in humans. Neurosteroids modulate both GABAergic as well as glutamatergic neurotransmission in various brain areas. The objective of the present study was to elucidate the role of various neurosteroids in neuroleptic-induced vacuous chewing movements and related behaviors in rats by using behavioral, biochemical, and neurochemical parameters. Animals chronically treated with haloperidol (1 mg/kg i.p.) for a period of 21 days exhibited marked increase in vacuous chewing movements, tongue protrusions, and facial jerkings as compared to vehicle-treated controls. It also resulted in increased superoxide anion levels and lipid peroxidation, whereas decreased levels of endogenous antioxidant enzymes (catalase and superoxide dismutase) in rat brain striatum homogenates. Neurochemical studies revealed that chronic administration of haloperidol resulted in significant decrease in the levels of dopamine, serotonin, and norepinephrine in rat brain striatum homogenates, whereas urine biogenic amines metabolite levels were increased. In a series of experiments, rats co-administered with allopregnanolone (0.5, 1, and 2 mg/kg i.p.) and progesterone (5, 10, and 20 mg/kg i.p.), both positive GABA-modulating [negative N-methyl- d-aspartate (NMDA)-modulating] neurosteroids prevented, whereas pregnenolone (0.5, 1, and 2 mg/kg i.p.) and dihydroxyepiandrosterone sulfate (0.5, 1, and 2 mg/kg i.p.) both negative GABA-modulating (positive NMDA-modulating) neurosteroids aggravated all the behavioral, biochemical, and neurochemical parameters. These results suggest that neurosteroids may play a significant role in the pathophysiology of vacuous chewing movements and related behaviors by virtue of their action on either the GABA or NMDA modulation. Furthermore, neurosteroids showing selectivity for positive GABA modulation and/or negative NMDA modulation may be particularly efficacious as novel therapeutic agents for the treatment of tardive dyskinesia and deserve further evaluation. [ABSTRACT FROM AUTHOR]

The ability of an iron chelator, desferrioxamine, to inhibit the infarct size in in vivo rat heart was assessed. Anaesthetised rats were subjected to coronary artery ligation (CAL) for 72 hr and infarct size was measured macroscopically using TTC staining. Systolic blood pressure and ECG were monitored. Desferrioxamine (10 mg/kg and 20 mg/kg i.v.) administered half an hour after CAL markedly reduced the infarct size. However, drug treatment did not alter the systolic blood pressure of animals. In addition, desferrioxamine in vitro and in vivo demonstrated an inhibition of rat PMN-evoked and luminol-enhanced chemiluminiscence. The capacity of desferrioxamine to impair the generation or to scavenge directly oxygen free radicals may be responsible for its beneficial effect on myocardial infarct size in rats. [ABSTRACT FROM AUTHOR]