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Introduction: feeding rats with a corn-based diet (deficient in tryptophan, lysine and protein) before and during pregnancy has been associated with low brain serotonin synthesis and fewer cortical GABAergic neurons in offspring than in animals fed with normal Purina Chow (CTRL group), altering brain excitability. On the other hand, the systemic injection of a hyperosmolar solution of monosodium L-glutamate (MSG) to rats represents a valuable model of status epilepticus. Objective: this work was oriented to investigate whether cerebral changes induced by feeding rats a corn-based diet (prenatal and postnatally), might be associated with more susceptibility to MSG-induced seizures in a well-established model of status epilepticus. Materials and methods: chronic malnutrition was induced in adult female rats with a corn-based diet (CORN group) before and during pregnancy and the males from their offspring continued with the same diet until becoming 60-days old. The pattern and severity of convulsive phenomenon induced by various doses of MSG were evaluated in these animals. As the corn diet contains a low proportion of protein (8%), a group of animals under a hypoproteic diet was included as a matched control group (HYP), while a group of animals fed a normal Chow Purina diet was included as a normal control group (CTRL). Results: animals from CORN and HYP groups showed a greater susceptibility to convulsions than those fed a CTRL diet. The most severe effect was seen in rats from the CORN group. Conclusion: the results obtained are directly related to differences in the nutrient content of diets (especially TRY and protein), which are probably associated with alterations in the inhibitory neurotransmitter systems regulating brain excitability. [ABSTRACT FROM AUTHOR]

Pathological mechanism of mTLE-DR. Seizure activity propagation in the temporal cortex is related to the protein expression of Bcl-2, Caspase-3 and Caspase-9, which are involved in neuronal death, IL1-β, which is involved in the neuroinflammation response and decreased seizure threshold, increased release of P-glycoprotein, a drug transport protein, aberrant connection formation by NT-3 and SEMA-3a, and the relationship of their expression patterns with clinical data. These are key factors in recurrent epileptic seizures, and the increased expression of these intrinsic severity like factors allows the generation of hyperexcitable circuits in the temporal cortex that, in turn promote recurrent epileptic seizures and drug resistance progression. • The protein expression of neuronal death, neuroinflammation and aberrant connections in cerebral tempora cortex and their relation with intrinsic severity hypothesis in the mTLE-DR. • The protein expresion of Bcl-2, Caspase-3 and Caspase-9, P-glycoprotein and SEMA-3a with mTLE-DR clinical data. • Increased of Bcl-2, Caspase-9 and P-glycoprotein are associated with severity and recurrent seizures. Mesial temporal lobe epilepsy (mTLE) is the most common epilepsy induced by previous cerebral injury, and one out of three mTLE patients develops drug resistance (DR). To assess the expression of Bcl-2, Caspase-3, Caspase-9, IL1-β, SEMA-3a, NT-3 and P-glycoprotein in the temporal cortex and their relationship with the progression of mTLE-DR clinical features in patients with mTLE-DR. Tissue samples from 17 patients were evaluated for protein expression by Western blot and the relationships of the evaluated proteins with the clinical features of the mTLE were assessed through hierarchical cluster analysis. The mTLE-DR group showed significantly higher P-glycoprotein, Bcl-2 and Caspase-9 levels ***p < 0.0001, ****p < 0.0001 and ***p < 0.0002, respectively, than the autopsy control group. Four patient clusters were identified: Clusters 1 and 3 showed relationships among the age of mTLE onset, duration of mTLE-DR, average number of epileptic seizures per week, number of previous antiepileptic drugs (AEDs) and increased expression of Caspase-3, Caspase-9, Neurotrophin-3 and Semaphorin-3a. Clusters 2 and 4 showed relationships among the mTLE onset age, current age, average number of epileptic seizures per week, number of previous AEDs and increased expression of IL1-β, Bcl-2, P-glycoprotein, Caspase-3 and NT-3. The relationships among the clinical data the age of mTLE onset, DR duration, number of previous AEDs, and average number of seizures per week and the expression of proteins involved in neuronal death, neuroinflammation and aberrant connection formation, as which are biological markers in the cerebral temporal cortex, are important factors in the progression and severity of mTLE-DR and support the intrinsic severity hypothesis. [ABSTRACT FROM AUTHOR]

Inflammation and oxidative stress are critical events involved in neurodegeneration. In animal models, it has been shown that chronic consumption of a hypercaloric diet, which leads to inflammatory processes, affects the hippocampus, a brain region fundamental for learning and memory processes. In addition, advanced age and menopause are risk factors for neurodegeneration. Hormone replacement therapy (HRT) ameliorates menopause symptoms. Tibolone (TB), a synthetic hormone, exerts estrogenic, progestogenic and androgenic effects on different tissues. We aimed to determine the effect of short-term TB administration on oxidative stress and inflammation markers in the hippocampus of ovariectomized rats fed a high-fat-and-fructose diet (HFFD). Adult female rats were ovariectomized (OVX) and fed standard diet or HFFD-consisting of 10% lard supplemented chow and 20% high-fructose syrup in the drinking water-and administered vehicle or TB (1 mg/kg for seven days). Finally, we administered hormone receptor antagonists (MPP, RU486 or FLU) to each of the OVX + HFFD + TB groups. Bodyweight, triglycerides and cholesterol, oxidative stress and inflammation markers, and the activity and expression of antioxidant enzymes were quantified in the hippocampus of each experimental group. We observed that short-term TB administration significantly reduced body weight, AGEs, MDA levels, increased SOD and GPx activity, improved GSH/GSSG ratio, and reduced IL-6 and TNF-α. Our findings suggest that short-term administration of TB decreases oxidative stress and reduces inflammation caused by HFFD and early estrogenic decline. These effects occurred via estrogen receptor alpha.

Boron-containing compounds (BCC) exert effects on neurons. After the expanding of both the identification and synthesis of new BCC, novel effects in living systems have been reported, many of these involving neuronal action. In this review, the actions of BCC on neurons are described; the effects have been inferred by boron deprivation or addition. Also, the effects can be related to those mediated by interaction on ionic channels, G-protein coupled receptors, or other receptors exerting modification on neuronal behavior. Additionally, BCC have exhibited effects by the modulation of inflammation or oxidative processes. BCC are expanding as drugs. Deprivation of boron sources from the diet shows the role of some natural BCC. However, the observations of several new synthesized compounds suggest their ability to act with attractive potency, efficacy, and long-term action on neuronal receptors or processes related with the origin and evolution of neurodegenerative processes. The details of BCC-target interactions are currently being elucidated in progress, as those observed from BCC-protein crystal complexes. Taking all of the above into account, the expansion is presumably near to having studies on the application of BCC as drugs on specific targets for treating neurodegenerative diseases., Competing Interests: Declaration of Competing Interest The authors report there are no competing interest to declare., (Copyright © 2022. Published by Elsevier Inc.)

In basic research and clinical practice, the control of seizures has been the most important goal, but it should not be the only one. There are factors that remain poorly understood in the study of refractory epilepsy such as the age and gender of patients and the presence of psychiatric comorbidities. It is known that in patients with drug-resistant epilepsy (DRE), the comorbidities contribute to the deterioration of the quality of life, increase the severity, and worsen the prognosis of epilepsy. Some studies have demonstrated that patients diagnosed with a co-occurrence of epilepsy and psychiatric disorders are more likely to present refractory seizures and the probability of seizure remission after pharmacotherapy is reduced. The evidence of this association suggests the presence of shared pathogenic mechanisms that may include endocrine disorders, neuroinflammatory processes, disturbances of neurotransmitters, and mechanisms triggered by stress. Additionally, significant demographic, clinical, and electrographic differences have been observed between women and men with epilepsy. Epilepsy affects the female gender in a greater proportion, although there are no studies that report whether refractoriness affects more females. The reasons behind these sex differences are unclear; however, it is likely that sex hormones and sex brain differences related to chromosomal genes play an important role. On the other hand, it has been shown in industrialized countries that prevalence of DRE is higher in the elderly when compared to youngsters. Conversely, this phenomenon is not observed in developing regions, where more cases are found in children and young adults. The correct identification and management of these factors is crucial in order to improve the quality of life of the patients., (© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

More than one-third of people with epilepsy develop drug-resistant epilepsy (DRE). Different hypotheses have been proposed to explain the origin of DRE. Accumulating evidence suggests the contribution of neuroinflammation, modifications in the integrity of the blood-brain barrier (BBB), and altered immune responses in the pathophysiology of DRE. The inflammatory response is mainly due to the increase of cytokines and related molecules; these molecules have neuromodulatory effects that contribute to hyperexcitability in neural networks that cause seizure generation. Some patients with DRE display the presence of autoantibodies in the serum and mainly cerebrospinal fluid. These patients are refractory to the different treatments with standard antiseizure medications (ASMs), and they could be responding well to immunomodulatory therapies. This observation emphasizes that the etiopathogenesis of DRE is involved with immunology responses and associated long-term events and chronic inflammation processes. Furthermore, multiple studies have shown that functional polymorphisms as risk factors are involved in inflammation processes. Several relevant polymorphisms could be considered risk factors involved in inflammation-related DRE such as receptor for advanced glycation end products (RAGE) and interleukin 1β (IL-1β). All these evidences sustained the hypothesis that the chronic inflammation process is associated with the DRE. However, the effect of the chronic inflammation process should be investigated in further clinical studies to promote the development of novel therapeutics useful in treatment of DRE., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The CatSper channel localizes exclusively in the flagella of sperm cells. The Catsper1 protein, together with three pore units, is essential for the CatSper Channel formation, which produces flagellum hyperactivation and confers sperm fertility. Catsper1 expression is dependent on Sox transcription factors, which can recognize in vitro at least three Sox binding sites on the promoter. Sox transcription factors have calmodulin-binding domains for nuclear importation. Calmodulin (CaM) is affected by the specific inhibitor calmidazolium (CMZ), which prevents the nuclear transport of Sox factors. In this work, we assess the regulation of the Catsper1 promoter in vivo by Sox factors in the murine testis and evaluate the effects of the inhibitor calmidazolium on the expression of the Casper genes, and the motility and fertility of the sperm. Catsper1 promoter has significant transcriptional activity in vivo; on the contrary, three Sox site mutants in the Catsper1 promoter reduced transcriptional activity in the testis. CaM inhibition affects Sox factor nuclear transport and has notable implications in the expression and production of Catsper1 , as well as in the motility and fertility capability of sperm. The molecular mechanism described here might conform to the basis of a male contraceptive strategy acting at the transcriptional level by affecting the production of the CatSper channel, a fundamental piece of male fertility.

Frontal lobe epilepsy (FLE) is the second most frequent type of epilepsy and the surgical outcome depends on the etiology. For instance, patients with posttraumatic FLE (PTE) have a worse surgical outcome compared to patients with FLE related to a tumoral lesion (TL). The present study focuses to determine if the FLE etiology is associated with the P-glycoprotein (P-gp) expression, a condition associated with drug resistance. P-gp expression and cellular localization were determined by Western Blot and immunohistochemical experiments in cortical brain samples obtained from patients with PTE (n = 5), TL (n = 5), and autopsies (n = 5). The neuronal count was estimated by Nissl and stereology procedure. Results showed that the autopsies tissue showed a neuronal count of 3514 ± 304.2 neurons per mm 3 . The P-gp expression ratio was 0.33 ± 0.02. Its expression was found in endothelial cells. Negligible P-gp expression was detected in neurons and astrocytes. Compared to the autopsies group, the TL group showed no changes in the neuronal count but, there was a decreased P-gp expression ratio (46%, p < 0.05). P-gp was located mainly in neurons, slight in astroglial, and endothelial cells. The PTE group showed a similar P-gp expression ratio compared to the autopsies group. P-gp was expressed in neurons, astrocytes, and endothelial cells in these samples. However, experiments revealed a high P-gp expression in a lower neuronal count (38%, p < 0.05 vs autopsy group). The present study reveals that patients with PTE present neuronal P-gp overexpression. This finding could underlie their worst surgical outcome., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Alzheimer's disease (AD) affects women more than men and consequently has been associated with menopause. Tibolone (TIB) has been used as a hormone replacement therapy to alleviate climacteric symptoms. Neuroprotective effects of TIB have also been reported in some animal models., Objective: This study aimed to assess the effect of TIB on memory and Aβ peptides and tau protein content in the hippocampus and cerebellum of transgenic 3xTgAD ovariectomized mice., Methods: Three-month-old female mice were ovariectomized. Ten days after surgery, animals were divided into four groups: wild-type (WT)+vehicle; WT+TIB (1 mg/kg); 3xTgAD+vehicle; and 3xTgAD+TIB (1 mg/kg). TIB was administered for three months, and memory was evaluated using the object-in-context recognition task. Subsequently, animals were decapitated, and the hippocampus and cerebellum were dissected. Using commercial ELISA kits, these brain structures were homogenized in a PBS buffer for quantifying Aβ40 and Aβ42 and phosphorylated and total tau.ResultsA long-term memory deficit was observed in the 3xTgAD+vehicle group. In contrast, TIB treatment improved long-term memory in the 3xTgAD+TIB group than those treated with vehicle (p < 0.05). Furthermore, TIB treatment decreased Aβ and tau content in the hippocampus of 3xTgAD mice compared to vehicle-treated groups (p < 0.05). No significant changes were observed in the cerebellum., Conclusion: Chronic treatment with TIB showed neuroprotective effects and delayed AD neuropathology in the 3xTgAD mice. Our results support hormone replacement therapy with TIB in menopausal women for neuroprotection.

Epilepsy is the most common chronic neurological disease, affecting approximately 65 million people worldwide, with mesial temporal lobe epilepsy (mTLE) being the most common type, characterized by the presence of focal seizures that begin in the hippocampus, and subsequently generalize to structures such as the cerebral cortex. It is estimated that approximately 40% of patients with mTLE develop drug resistance (DR), whose pathophysiological mechanisms remain unclear. The neuronal network hypothesis is one attempt to understand the mechanisms underlying resistance to antiepileptic drugs (AEDs), since recurrent seizure activity generates excitotoxic damage and activation of neuronal death and survival pathways that, in turn, promote the formation of aberrant neuronal networks. This review addresses the mechanisms that are activated, perhaps as compensatory mechanisms in response to the neurological damage caused by epileptic seizures, but that affect the formation of aberrant connections that allow the establishment of inappropriate circuits. On the other hand, glia seems to have a relevant role in post-seizure plasticity, thus supporting the hypothesis of the neuronal network in drug-resistant epilepsy, which has been proposed for ELT., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Tryptophan hydroxylase type 2 (Tph2) is the rate-limiting enzyme for serotonin (5-HT) biosynthesis in the brain. Dysfunctional Tph2 alters 5-HT biosynthesis, leading to a deficiency of 5-HT, which could have repercussions on human behavior. In the last decade, several studies have associated polymorphisms of the TPH2 gene with suicidal behavior. Additionally, a 5-HT deficiency has been implicated in various psychiatric pathologies, including alcoholism, impulsive behavior, anxiety, and depression. Therefore, the TPH2 gene could be an ideal target for analyzing the effects of a 5-HT deficiency on brain function. The aim of this study was to use the construct pIRES-hrGFP-1a-Tph2-FLAG to treat CD1-male mice and to transfect HEK-293-cells and then to evaluate whether this treatment increases 5-HT production. 5-HT levels were enhanced 48 h post-transfection, in HEK-293 cells. Three days after the ocular administration of pIRES-hrGFP-1a-Tph2-FLAG to mice, putative 5-HT production was significantly higher than in the control in both hypothalamus and amygdala, but not in the brainstem. Further research will be needed on the possible application of this treatment for psychiatric diseases involving a Tph2 dysfunction or serotonin deficiency., (© 2021. The Author(s).)

Neuroinflammation is probably one of the factors involved in drug resistance in people with epilepsy. Finding peripheral markers reflecting the intensity of neuroinflammation could be of great help to decide for which patients anti-inflammatory treatment might be an option. In this context, peripheral cytokines levels and lymphocyte phenotypes were assessed by ELISA and flow cytometry in 3 groups of subjects: drug resistant patients with temporal lobe epilepsy (DR-TLE), non DR-TLE patients and healthy controls. The same parameters were assessed in brain tissue in the DR-TLE group. Differences in the peripheral immune-inflammatory status between the 3 groups of subjects, and correlations between the central and peripheral immune-inflammatory status in DR-TLE patients were evaluated. Forty-one patients with DR-TLE, ten with non-DR-TLE and twenty controls were included. In the periphery, decrease in regulatory cells were observed in DR-TLE patients compared to controls. In addition, significant increase of IL-6 and IL-5 was observed in patients with epilepsy (particularly DR-TLE patients). Two groups of DR-TLE patients with significant differences in several central inflammatory parameters were identified in a cluster analysis. The inflammatory cluster was associated with a peripheral increase of CD4+CD38+ cells and different significant correlations between central and systemic inflammatory parameters were observed. Although their interpretation is not immediate, they demonstrate a clear dialogue between central and peripheral inflammatory reactions. In conclusion, our results add new elements to better understand the interactions between the central and peripheral compartments in patients with DR-TLE, and to help better define treatment options in this group of patients., (Copyright © 2021 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the effects of cannabidiol alone or in combination with antiseizure drugs in the expression of recurrent generalized seizures in a rat model., Methods: Group A: Male Wistar rats received 3-mercaptopropionic acid (MP) every 12 h for 5 days to induce recurrent generalized seizures. Thereafter, the animals were submitted to a crossover protocol to receive different treatments with cannabidiol, phenytoin and phenobarbital, alone and in combination. Group B: Rats were manipulated as group A, but they received cannabidiol during the induction of recurrent seizures., Results: Minor and major seizures were induced after each MP administration. Status epilepticus (SE) detected during the last MP administrations was considered a sign of high seizure severity. Cannabidiol did not modify the expression of the MP induced seizures but reduced the prevalence of SE in both experimental groups. Phenytoin decreased the expression of major seizures but did not modify the prevalence of SE (groups A and B). Cannabidiol combined with phenytoin did not modify these effects. Phenobarbital diminished the expression of major seizures, an effect more evident when combined with cannabidiol (groups A and B). The combination of phenobarbital and cannabidiol reduced the expression of SE of group B. The mortality rate of groups A and B at the end of the crossover protocol was 30% and 9%, respectively (p=0.2)., Conclusion: CBD associated with appropriate antiseizure drugs reduces the severity and prevalence of generalized seizures. In contrast, CBD alone reduces the seizure severity, but does not avoid the expression of generalized seizures., (Copyright © 2021. Published by Elsevier Ltd.)

Epilepsy is a chronic neurobehavioral disorder whereby an imbalance between neurochemical excitation and inhibition at the synaptic level provokes seizures. Various experimental models have been used to study epilepsy, including that based on acute or chronic administration of Pentylenetetrazol (PTZ). In this study, a single PTZ dose (60 mg/kg) was administered to adult male rats and 30 min later, various neurobiological parameters were studied related to the transmission and modulation of excitatory impulses in pyramidal neurons of the hippocampal CA1 field. Rats experienced generalized seizures 1-3 min after PTZ administration, accompanied by elevated levels of Synaptophysin and Glutaminase. This response suggests presynaptic glutamate release is exacerbated to toxic levels, which eventually provokes neuronal death as witnessed by the higher levels of Caspase-3, TUNEL and GFAP. Similarly, the increase in PSD-95 suggests that viable dendritic spines are functional. Indeed, the increase in stubby and wide spines is likely related to de novo spinogenesis, and the regulation of neuronal excitability, which could represent a plastic response to the synaptic over-excitation. Furthermore, the increase in mushroom spines could be associated with the storage of cognitive information and the potentiation of thin spines until they are transformed into mushroom spines. However, the reduction in BDNF suggests that the activity of these spines would be down-regulated, may in part be responsible for the cognitive decline related to hippocampal function in patients with epilepsy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Transcranial focal stimulation (TFS) is a noninvasive neuromodulation strategy that reduces seizure activity in different experimental models. Nevertheless, there is no information about the effects of TFS in the drug-resistant phenotype associated with P-glycoprotein (Pgp) overexpression. The present study focused on determining the effects of TFS on Pgp expression after an acute seizure induced by 3-mercaptopropionic acid (MPA). P-glycoprotein expression was analyzed by western blot in the cerebral cortex and hippocampus of rats receiving 5 min of TFS (300 Hz, 50 mA, 200 μs, biphasic charge-balanced squared pulses) using a tripolar concentric ring electrode (TCRE) prior to administration of a single dose of MPA. An acute administration of MPA induced Pgp overexpression in cortex (68 ± 13.4%, p < 0.05 vs the control group) and hippocampus (48.5 ± 14%, p < 0.05, vs the control group). This effect was avoided when TFS was applied prior to MPA. We also investigated if TFS augments the effects of phenytoin in an experimental model of drug-resistant seizures induced by repetitive MPA administration. Animals with MPA-induced drug-resistant seizures received TFS alone or associated with phenytoin (75 mg/kg, i.p.). TFS alone did not modify the expression of the drug-resistant seizures. However, TFS combined with phenytoin reduced seizure intensity, an effect associated with a lower prevalence of major seizures (50%, p = 0.03 vs phenytoin alone). Our experiments demonstrated that TFS avoids the Pgp overexpression induced after an acute convulsive seizure. In addition, TFS augments the phenytoin effects in an experimental model of drug-resistant seizures. According with these results, it is indicated that TFS may represent a new neuromodulatory strategy to revert the drug-resistant phenotype., Competing Interests: Declaration of interest Dr. Besio is the CEO of CREmedical which develops concentric ring technologies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cannabinoid receptors 1 and 2 (CB1 and CB2, respectively) play an important role in maintaining the integrity of the blood-brain barrier (BBB). On the other hand, BBB dysfunction is a common feature in drug-resistant epilepsy. The focus of the present study was to characterize protein expression levels and Gαi/o protein-induced activation by CB1 and CB2 receptors in the microvascular endothelial cells (MECs) isolated from the brain of patients with drug-resistant mesial temporal lobe epilepsy (DR-MTLE). MECs were isolated from the hippocampus and temporal neocortex of 12 patients with DR-MTLE and 12 non-epileptic autopsies. Immunofluorescence experiments were carried out to determine the localization of CB1 and CB2 receptors in the different cell elements of MECs. Protein expression levels of CB1 and CB2 receptors were determined by Western blot experiments. [ 35 S]-GTPγS binding assay was used to evaluate the Gαi/o protein activation induced by specific agonists. Immunofluorescent double-labeling showed that CB1 and CB2 receptors colocalize with tight junction proteins (claudin-5, occludin, and zonula occludens-1), glial fibrillary acidic protein and platelet-derived growth factor receptor-β. These results support that CB1 and CB2 receptors are expressed in the human isolated microvessels fragments consisting of MECs, astrocyte end feet, and pericytes. The hippocampal microvasculature of patients with DR-MTLE presented lower protein expression of CB1 and CB2 receptors (66 and 43%, respectively; p < 0.001). However, its Gαi/o protein activation was with high efficiency (CB1, 251%, p < 0.0008; CB2, 255%, p < 0.0001). Microvasculature of temporal neocortex presented protein overexpression of CB1 and CB2 receptors (35 and 41%, respectively; p < 0.01). Their coupled Gαi/o protein activation was with higher efficiency for CB1 receptors (103%, p < 0.006), but lower potency ( p < 0.004) for CB2 receptors. The present study revealed opposite changes in the protein expression of CB1 and CB2 receptors when hippocampus (diminished expression of CB1 and CB2) and temporal neocortex (increased expression of CB1 and CB2) were compared. However, the exposure to specific CB1 and CB2 agonists results in high efficiency for activation of coupled Gαi/o proteins in the brain microvasculature of patients with DR-MTLE. CB1 and CB2 receptors with high efficiency could represent a therapeutic target to maintain the integrity of the BBB in patients with DR-MTLE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nuñez-Lumbreras, Castañeda-Cabral, Valle-Dorado, Sánchez-Valle, Orozco-Suárez, Guevara-Guzmán, Martínez-Juárez, Alonso-Vanegas, Walter, Deli, Carmona-Cruz and Rocha.)

Neural hyperexcitability in the event of damage during early life, such as hyperthermia, hypoxia, traumatic brain injury, status epilepticus, or a pre-existing neuroinflammatory condition, can promote the process of epileptogenesis, which is defined as the sequence of events that converts a normal circuit into a hyperexcitable circuit and represents the time that occurs between the damaging event and the development of spontaneous seizure activity or the establishment of epilepsy. Epilepsy is the most common neurological disease in the world, characterized by the presence of seizures recurring without apparent provocation. Cannabidiol (CBD), a phytocannabinoid derived from the subspecies Cannabis sativa ( CS ), is the most studied active ingredient and is currently studied as a therapeutic strategy: it is an anticonvulsant mainly used in children with catastrophic epileptic syndromes and has also been reported to have anti-inflammatory and antioxidant effects, supporting it as a therapeutic strategy with neuroprotective potential. However, the mechanisms by which CBD exerts these effects are not entirely known, and the few studies on acute and chronic models in immature animals have provided contradictory results. Thus, it is difficult to evaluate the therapeutic profile of CBD, as well as the involvement of the endocannabinoid system in epileptogenesis in the immature brain. Therefore, this review focuses on the collection of scientific data in animal models, as well as information from clinical studies on the effects of cannabinoids on epileptogenesis and their anticonvulsant and adverse effects in early life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vega-García, Feria-Romero, García-Juárez, Munguia-Madera, Montes-Aparicio, Zequeida-Muñoz, Garcia-Albavera and Orozco-Suárez.)

The blood-brain barrier (BBB) maintains the optimal microenvironment for brain function. Tight junctions (TJs) allow endothelial cells to adhere to each other, leading to the formation of a barrier that prevents the penetration of most molecules via transcellular routes. Evidence has indicated that seizure-induced vascular endothelial growth factor (VEGF) type 2 receptor (VEGFR-2) pathway activation weakens TJs, inducing vasodilatation and increasing vascular permeability and subsequent brain injury. The present study focused on investigating the expression levels of VEGF-related (VEGF-A and VEGFR-2) and TJ-related proteins (claudin-5, occludin and ZO-1) in the neocortical microvasculature of patients with drug-resistant temporal lobe epilepsy (TLE). The results obtained from hippocampal sclerosis TLE (HS-TLE) patients were compared with those obtained from patients with TLE secondary to lesions (lesion-TLE) and autopsy samples. The Western blotting and immunofluorescence results showed that VEGF-A and VEGFR-2 protein expression levels were increased in HS-TLE and lesion-TLE patients compared to autopsy group. On the other hand, claudin-5 expression was higher in HS-TLE patients and lesion-TLE patients than autopsies. The expression level of occludin and ZO-1 was decreased in HS-TLE patients. Our study described modifications to the integrity of the BBB that may contribute to the pathogenesis of TLE, in which the VEGF system may play an important role. We demonstrated that the same modifications were present in both HS-TLE and lesion-TLE patients, which suggests that seizures modify these systems and that they are not associated with the establishment of epilepsy., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Ketamine is an anesthetic agent that antagonizes N-methyl-d-aspartate receptors, inducing psychotic-like symptoms in healthy humans and animals. This agent has been used as a pharmacological tool for studying biochemical and physiological mechanisms underlying the clinical manifestations of schizophrenia. The main goal of this study was to evaluate the effect of repeated injections of ketamine (5 and 10 mg/kg, i.p., daily for 5 days) on recognition memory and neuronal morphology in ICR-CD1 mice. This treatment induced recognition memory impairment in the novel object recognition test and a decrease in dendritic spines density in both dorsal striatum and CA1-hippocampus. Sholl analysis showed that both ketamine doses decrease the dendritic arborization in ventromedial prefrontal cortex, dorsal striatum, and CA1-hippocampus. Finally, dendritic spines morphology was modified by both doses; that is, an increase of the filipodia-type spines (10 mg/kg) and a reduction of the mushroom-type spines (5 and 10 mg/kg) was observed in the ventromedial prefrontal cortex. In the dorsal striatum, the low dose of ketamine induced an increase in long thin spines and a decrease of mushroom spines. Interestingly, in CA1-hippocampus, there was an increase in the mushrooms type spines (5 mg/kg). Current findings suggest that the subchronic blockade of N-methyl-d-aspartate receptor changes the neuronal plasticity of several brain regions putatively related to recognition memory impairment.

Traumatic spinal cord injury (TSCI) can cause paralysis and permanent disability. Rehabilitation (RB) is currently the only accepted treatment, although its beneficial effect is limited. The development of biomaterials has provided therapeutic possibilities for TSCI, where our research group previously showed that the plasma-synthesized polypyrrole/iodine (PPy/I), a biopolymer with different physicochemical characteristics than those of the PPy synthesized by conventional methods, promotes recovery of motor function after TSCI. The present study evaluated if the plasma-synthesized PPy/I applied in combination with RB could increase its beneficial effects and the mechanisms involved. Adult rats with TSCI were divided into no treatment (control); biopolymer (PPy/I); mixed RB by swimming and enriched environment (SW/EE); and combined treatment (PPy/I + SW/EE) groups. Eight weeks after TSCI, the general health of the animals that received any of the treatments was better than the control animals. Functional recovery evaluated by two scales was better and was achieved in less time with the PPy/I + SW/EE combination. All treatments significantly increased βIII-tubulin (nerve plasticity) expression, but only PPy/I increased GAP-43 (nerve regeneration) and MBP (myelination) expression when were analyzed by immunohistochemistry. The expression of GFAP (glial scar) decreased in treated groups when determined by histochemistry, while morphometric analysis showed that tissue was better preserved when PPy/I and PPy/I + SW/EE were administered. The application of PPy/I + SW/EE, promotes the preservation of nervous tissue, and the expression of molecules related to plasticity as βIII-tubulin, reduces the glial scar, improves general health and allows the recovery of motor function after TSCI. The implant of the biomaterial polypyrrole/iodine (PPy/I) synthesized by plasma (an unconventional synthesis method), in combination with a mixed rehabilitation scheme with swimming and enriched environment applied after a traumatic spinal cord injury, promotes expression of GAP-43 and βIII-tubulin (molecules related to plasticity and nerve regeneration) and reduces the expression of GFAP (molecule related to the formation of the glial scar). Both effects together allow the formation of nerve fibers, the reconnection of the spinal cord in the area of injury and the recovery of lost motor function. The figure shows the colocalization (yellow) of βIII-tubilin (red) and GAP-43 (green) in fibers crossing the epicenter of the injury (arrowheads) that reconnect the rostral and caudal ends of the injured spinal cord and allowed recovery of motor function.

In the epilepsy spectrum, temporal lobe epilepsy (TLE) is the most common and devastating focal and symptomatic epilepsy form in adults, where more than 30% of patients develop pharmacoresistance. It is not fully understood how the gene expression contributes to establishing an epileptic phenotype. Cerebrovascular remodeling directed by VEGF (vascular endothelial growth factor) signaling might modulate the synaptic neurotransmission in the epileptic brain. To address this question, the gene expression was profiled in biopsies of the temporal cortex from diagnosed patients with pharmacoresistant TLE that underwent surgical resection to seizure control. One hundred sixty-eight genes related to VEGF signaling and GABA and glutamate neurotransmissions were evaluated. Genes related to downstream signaling -phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinases (MAPK), and Janus-activated kinase/signal transducer and activator of transcription (JAK/STAT) pathways- and neurotransmitters metabolism were evaluated too. Thirty-nine genes were upregulated. The genes encoding for G protein q polypeptide, serine racemase, gephyrin, and glutamate/cystine antiporter system xCT appeared as novel upregulated genes in the pharmacoresistant TLE. ClueGO, a Cytoscape plugin, was used to build a gene network associated using Gene Ontology (GO) terminology. Enrichment analysis by ClueGO retrieves that positive regulation of endothelial cell proliferation, nerve development, and neuronal apoptosis were over-represented categories. In conclusion, VEGF signaling is confirmed as a relevant mediator in the pharmacoresistant TLE. In addition, the enrichment analysis applied to differentially expressed genes suggests new pharmacological targets to be assessed in the treatment of pharmacoresistant TLE. Results make up an approximation to better understand the epileptic brain and complement the available data.

The regenerative capability of the central nervous system is limited after traumatic spinal cord injury (SCI) due to intrinsic and extrinsic factors that inhibit spinal cord regeneration, resulting in deficient functional recovery. It has been shown that strategies, such as pre-degenerated peripheral nerve (PPN) grafts or the use of bone marrow stromal cells (BMSCs) or exogenous molecules, such as chondroitinase ABC (ChABC) promote axonal growth and remyelination, resulting in an improvement in locomotor function. These treatments have been primarily assessed in acute injury models. The aim of the present study is to evaluate the ability of several single and combined treatments in order to modify the course of chronic complete SCI in rats. A complete cord transection was performed at the T9 level. One month later, animals were divided into five groups: original injury only (control group), and original injury plus spinal cord re-transection to create a gap to accommodate BMSCs, PPN, PPN + BMSCs, and PPN + BMSCs + ChABC. In comparison with control and single-treatment groups (PPN and BMSCs), combined treatment groups (PPN + BMSCs and PPN + BMSCs + ChABC) showed significative axonal regrowth, as revealed by an increase in GAP-43 and MAP-1B expression in axonal fibers, which correlated with an improvement in locomotor function. In conclusion, the combined therapies tested here improve locomotor function by enhancing axonal regeneration in rats with chronic SCI. Further studies are warranted to refine this promising line of research for clinical purposes., (Copyright © 2020 Buzoianu-Anguiano, Rivera-Osorio, Orozco-Suárez, Vega-García, García-Vences, Sánchez-Torres, Jiménez-Estrada, Guizar-Sahagún, Mondragon-Caso, Fernández-Valverde, Madrazo and Grijalva.)

Tryptophan hydroxylase-type 2 (Tph2) is the first rate-limiting step in the biosynthesis of serotonin (5-HT) in the brain. The ophthalmic administration (Op-Ad) is a non-invasive method that allows delivering genetic vehicles through the eye and reaches the brain. Here, the murine Tph2 gene was cloned in a non-viral vector (pIRES-hrGFP-1a), generating pIRES-hrGFP-1a-Tph2, plus the FLAG-tag. Recombinant Tph2-FLAG was detected and tested in vitro and in vivo, where 25 μg of pIRES-hrGFP-1a-Tph2-FLAG was Op-Ad to mice. The construct was capable of expressing and producing the recombinant Tph2-FLAG in vitro and in vivo. The in vivo assays showed that the construct efficiently crossed the Hemato-Ocular Barrier and the Blood-Brain Barrier, reached brain cells, passed the optical nerves, and transcribed mRNA-Tph2-FLAG in different brain areas. The recombinant Tph2-FLAG was observed in amygdala and brainstem, mainly in raphe dorsal and medial. Relative Tph2 expression of threefold over basal level was recorded three days after Op-Ad. These results demonstrated that pIRES-hrGFP-Tph2-FLAG, administrated through the eyes was capable of reaching the brain, transcribing, and translating Tph2. In conclusion, this study showed the feasibility of delivering therapeutic genes, such as the Tph2, the first enzyme, rate-limiting step in the 5-HT biosynthesis.

Prenatal stress modifies the serotonergic system by altering the synthesis, metabolism, receptors and serotonin content in the hippocampus. However, it is currently unknown whether serotonin release in the ventral hippocampus of prenatally stressed rats is altered. In this study, serotonin (5-HT) and its metabolite, 5‑hydroxyindoleacetic acid (5-HIAA) levels were analysed in dialysates (in vivo) and in homogenates (in vitro) of the ventral hippocampus. This was made after the sucrose preference test and after forced swim test (FST) in male adult progeny from mothers that were stressed by immersion in cold water during the last week of gestation. Serum concentration of corticosterone was also evaluated in control and in prenatally stressed males. Sucrose preference was differently affected in prenatally stressed males: 69% showed decreased sucrose consumption, and were considered anhedonic; 31% exhibited sucrose consumption similar to control and were considered non‑anhedonic. During the FST, increased immobility and decreased swimming were observed in prenatally stressed males. After sucrose test, content and release of 5‑HT in prenatally stressed rats were similar to those in the control group, with higher metabolite. After the FST, 5-HT content increased, but its release increased slightly in anhedonic rats and did not change in non-anhedonic rats, with lower metabolite. The response of the adrenal axis to the FST was larger in anhedonic prenatally stressed males, than in control and non‑anhedonic males. These data show that behavioural disruption caused by prenatal stress is related to low release and lower metabolism of serotonin in the ventral hippocampus in adult male offspring, as well as to hyperactivity and hyperreactivity of the adrenal axis.

Prenatal stress causes learning and spatial memory deficits in adulthood by modifying hippocampal function. The dorsal hippocampus contains serotonergic and noradrenergic neuron terminals, which are related to cognitive processes. It is currently unknown whether prenatal stress modifies serotonin (5-HT) and noradrenaline (NA) content and their release in the hippocampus during cognitive performance. Therefore, we measured these variables in the dorsal hippocampus of prenatally stressed males during spatial learning and memory tests. Cognitive tests were performed in 3-month-old control and prenatally stressed male rats in the Morris Water Maze (MWM). After cognitive tests, the dorsal hippocampus was dissected to quantify 5-HT and NA content. In other males, 5-HT and NA release in the dorsal hippocampus was assessed by microdialysis, before and after cognitive tests. Prenatally stressed males showed longer latencies to reach the platform, compared to control animals. Hippocampal 5-HT content decreased during learning and memory tasks in both groups, while NA content was not modified in prenatally stressed males neither before, nor after learning and memory tests. 5-HT and NA release were significantly lower in prenatally stressed animals during spatial learning and memory tasks. Corticosterone response was greater in prenatally stressed animals compared to controls. These results show that cognitive disruption caused by prenatal stress is related to decreased 5-HT and NA release, and to higher adrenal axis response in prenatally stressed animals.

Patients with spinal cord injury (SCI) face devastating health, social, and financial consequences, as well as their families and caregivers. Reducing the levels of reactive oxygen species (ROS) and oxidative stress are essential strategies for SCI treatment. Some compounds from traditional medicine could be useful to decrease ROS generated after SCI. This review is aimed at highlighting the importance of some natural compounds with antioxidant capacity used in traditional medicine to treat traumatic SCI. An electronic search of published articles describing animal models of SCI treated with natural compounds from traditional medicine was conducted using the following terms: Spinal Cord Injuries (MeSH terms) AND Models, Animal (MeSH terms) AND [Reactive Oxygen Species (MeSH terms) AND/OR Oxidative Stress (MeSH term)] AND Medicine, Traditional (MeSH terms). Articles reported from 2010 to 2018 were included. The results were further screened by title and abstract for studies performed in rats, mice, and nonhuman primates. The effects of these natural compounds are discussed, including their antioxidant, anti-inflammatory, and antiapoptotic properties. Moreover, the antioxidant properties of natural compounds were emphasized since oxidative stress has a fundamental role in the generation and progression of several pathologies of the nervous system. The use of these compounds diminishes toxic effects due to their high antioxidant capacity. These compounds have been tested in animal models with promising results; however, no clinical studies have been conducted in humans. Further research of these natural compounds is crucial to a better understanding of their effects in patients with SCI., Competing Interests: The authors declare no conflicts of interest regarding the publication of this paper., (Copyright © 2019 Angélica Coyoy-Salgado et al.)

In addition to oxidative stress due to the increase of free radicals, estrogen deficiency is associated with changes in enzymatic activity, glutathione redox ratio (GSH/GSSG), and the content of oxidative markers such as malondialdehyde. Tibolone, a synthetic steroid, has been used as an elective treatment for the relief of menopausal symptoms. However, the acute effects of hormonal therapy with tibolone on metabolic parameters and oxidative stress markers associated with the first stages of estrogen deficiency are still unknown. The study aimed to evaluate if the acute administration of tibolone reduces oxidative stress in ovariectomized rats fed high-fat-and-fructose diet. Rats were fed a standard diet or a diet consisting of 10% lard-supplemented chow and 20% high-fructose syrup in the drinking water plus tibolone or vehicle for seven days. Weight, cholesterol, triglycerides, and glucose levels, as well as antioxidant enzymes and oxidative stress markers were quantified in the serum of each experimental group. It was observed that seven days of diet and tibolone treatment in the ovariectomized group reduced weight, triglycerides, cholesterol, glucose levels and advanced glycation end products but did not change GSH/GSSG ratio nor the enzymatic activity of superoxide dismutase. Also, both glutathione peroxidase and glutathione reductase activity decreased, as well as malondialdehyde levels. These results suggest that the acute treatment with tibolone prevented the changes in the metabolic parameters analyzed as well as the increase in the levels of malondialdehyde and AGEs induced by ovariectomy and high-fat diet., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Aim: To evaluate the therapeutic potential of ligands of beta-adrenoceptors in cognitive disorders. Testosterone and adrenergic pathways are involved in hippocampal and emotional memory. Moreover, is strongly suggested that androgen diminishing in aging is involved in cognitive deficit, as well as beta-adrenoceptors, particularly beta2-adrenoceptor, participate in the adrenergic modulation of memory. In this regard, some animal models of memory disruption have shown improved performance after beta-drug administration., Material and Methods: In this work, we evaluated the effects of agonists (isoproterenol and salbutamol) and antagonists (propranolol and carvedilol) on beta-adrenoceptors in orchiectomized rats, as well as their effects in the performance on avoidance task and damage in hippocampal neurons by immunohistochemistry assays., Key Findings: Surprisingly, we found that both antagonists and salbutamol (but not isoproterenol) modulate the effects of hormone deprivation, improving memory and decreasing neuronal death and amyloid-beta related changes in some regions (particularly CA1-3 and dentate gyrus) of rat hippocampus., Significance: Two β-antagonists and one β2-agonist modulated the effects of hormone deprivation on memory and damage in brain. The mechanisms of signaling of these drugs for beneficial effects remain unclear, even if used β-ARs ligands share a weak activity on β-arrestin/ERK-pathway activation which can be involved in these effects as we proposed in this manuscript. Our observations could be useful for understanding effects suggested of adrenergic drugs to modulate emotional memory. But also, our results could be related to other pathologies involving neuronal death and Aβ accumulation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The Repressor Element-1 Silencing Transcription factor or Neuron-Restrictive Silencer Factor (REST/NRSF) is a zinc finger repressor transcription factor of the Kruppel family. Several studies in experimental models have shown that overexpression of REST/NRSF occurs after the induction of seizures. In the present study, the expression of REST/NRSF (messenger ribonucleic acid (mRNA) and protein) was evaluated in the hippocampus of 28 patients with drug-resistant mesial temporal lobe epilepsy (MTLE) and their correlation with clinical variables and comorbid anxiety and depression. The REST/NRSF protein expression was augmented in an age-dependent manner in the hippocampus of autopsied subjects. However, this condition was not observed in patients with MTLE, in whom overexpression of this transcription factor occurred at both the mRNA and protein levels. The correlations with clinical variables showed that the frequency of epileptic seizures was proportional to the protein expression of REST/NRSF. The results revealed that the overexpression of REST/NRSF was more evident in patients with MTLE without anxiety and depression. Our data indicate that the expression of REST/NRSF is modified in patients with MTLE. This condition has implications in the pathophysiology of this disorder, making it a potential candidate for the optimization of clinical treatments., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Epilepsy is associated with several epigenetic changes, such as DNA methylation, histone modification, and alterations in the synthesis and functioning of non-coding RNAs (ncRNAs). Paradoxically, antiepileptic drugs (AEDs) that are widely used to control epilepsy may also induce epigenetic modifications and alter the structure of chromatin. As a consequence, changes in the expression of various factors involved in the pathology of epilepsy may positively or negatively affect the course of the disease. It should be noted that while AEDs are widely used in the treatment of epilepsy and other neurological disorders, many of their epigenetic consequences are still unknown. Moreover, an improved understanding of AED-induced epigenetic alterations could provide new targets for future therapeutic interventions. In this review, we give a general overview of the current scientific evidence concerning the epigenetic effects of AEDs that are currently in clinic use and have been evaluated to date., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Gliomas are neoplasms with high recurrence and mortality. Due to the difficulty to apply the World Health Organization (2016) classification, developing countries continue to use histological evaluation to diagnose and classify these neoplasms., Objective: To develop a semi-quantitative scale to numerically grade gliomas by its morphological characteristics., Method: A cohort of patients with gliomas was assessed and followed for 36 months. Tumor tissue sections were analyzed and graded, including aspects such as cell line, cellularity, nuclear pleomorphism, mitosis, endothelial hyperplasia, hypoxic changes, apoptotic bodies, necrosis, hemorrhage and proliferation index., Results: 58 cases were analyzed. Low-grade gliomas median score was 12 points (9 and 13.5 for percentiles 25 and 75, respectively), whereas for high-grade gliomas it was 17 points (16 and 20.5 for percentiles 25 and 75, respectively) (p < 0.0001). Thirty-six-month survival of patients with low (13/17) and high grade gliomas (6/41) was also significantly different (p < 0.0001)., Conclusions: The semi-quantitative morphological scale allows an objective evaluation of gliomas, with an adequate correlation between the score, tumor grade and survival time., (Copyright: © 2019 Permanyer.)

Introduction: Gliomas are neoplasms with high recurrence and mortality. Due to the difficulty to apply the World Health Organization (2016) classification, developing countries continue to use histological evaluation to diagnose and classify these neoplasms., Objective: To develop a semi-quantitative scale to numerically grade gliomas morphological characteristics., Method: A cohort of patients with gliomas was assessed and followed for 36 months. Tumor tissue sections were analyzed and graded, including aspects such as cell line, cellularity, nuclear pleomorphism, mitosis, endothelial hyperplasia, hypoxic changes, apoptotic bodies, necrosis, hemorrhage and proliferation index., Results: 58 cases were analyzed. Low-grade gliomas median score was 12 points (9 and 13.5 for percentiles 25 and 75, respectively), whereas for high-grade gliomas it was 17 points (16 and 20.5 for percentiles 25 and 75, respectively) (p < 0.0001). Thirty-six-month survival of patients with low (13/17) and high grade gliomas (6/41) was also significantly different (p < 0.0001)., Conclusions: The semi-quantitative morphological scale allows an objective evaluation of gliomas, with an adequate correlation between the score, tumor grade and survival time., (Copyright: © 2019 Permanyer.)

After spinal cord injury (SCI), some self-destructive mechanisms start leading to irreversible neurological deficits. It is known that oxidative stress and apoptosis play a major role in increasing damage after SCI. Metallothioneins I and II (MT) are endogenous peptides with known antioxidant, neuroprotective capacities. Taking advantage of those capacities, we administered exogenous MT to rats after SCI in order to evaluate the protective effects of MT on the production of reactive oxygen species (ROS) and lipid peroxidation (LP), as markers of oxidative stress. The activities of caspases-9 and -3 and the number of annexin V and TUNEL-positive cells in the spinal cord tissue were also measured as markers of apoptosis. Rats were subjected to either sham surgery or SCI and received vehicle or two doses of MT (10  μ g per rat) at 2 and 8 h after surgical procedure. The results showed a significant increase in levels of MT protein by effect of SCI and SCI plus treatment at 12 h, while at 24 h an increase of MT was observed only in the injury plus treatment group ( p < 0.05). ROS production was decreased by effect of MT in lesioned tissue; likewise, we observed diminished LP levels by MT effect both in the sham group and in the group with SCI. Also, the results showed an increase in the activity of caspase-9 due to SCI, without changes by effect of MT, as compared to the sham group. Caspase-3 activity was increased by SCI, and again, MT treatment reduced this effect only at 24 h after injury. Finally, the results of the number of cells positive to annexin V and TUNEL showed a reduction due to MT treatment both at 24 and 72 h after the injury. With the findings of this work, we conclude that exogenously administered MT has antioxidant and antiapoptotic effects after SCI.

Status epilepticus (SE) is a neurological condition that frequently induces severe neuronal injury in the hippocampus, subsequent epileptogenesis and pharmacoresistant spontaneous recurrent seizures (SRS). The repeated administration of LEV (a broad-spectrum antiepileptic drug) during the post-SE period does not prevent the subsequent development of SRS. However, this treatment reduces SE-induced neurodegeneration in the hippocampus. Conversely, propylparaben (PPB) is a widely used antimicrobial that blocks voltage-dependent Na + channels, induces neuroprotection and reduces epileptiform activity in vitro. The present study attempted to determine if the neuroprotective effects induced by LEV are augmented when combined with a sub-effective dose of PPB. Long-term SE-induced consequences (hyperexcitability, high glutamate release, neuronal injury and volume loss) were evaluated in the hippocampus of rats. LEV alone, as well as combined with PPB, did not prevent the occurrence of SRS. However, animals treated with LEV plus PPB showed high prevalence of low frequency oscillations (0.1-4 Hz and 8-90 bands, p < 0.001) and low prevalence of high frequency activity (90-250 bands, p < 0.001) during the interictal period. In addition, these animals presented lower extracellular levels of glutamate, decreased rate of neurodegeneration and a similar hippocampal volume compared to the control conditions. This study's results suggest that LEV associated with PPB could represent a new therapeutic strategy to reduce long-term consequences induced by SE that facilitate pharmacoresistant SRS., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Epileptic seizures constitute an important problem in pediatric neurology during the developmental period. The frequency and nosological significance of seizures, as well as their association with epileptogenesis, may be related to underlying mechanisms such as neuroinflammation. Those mechanisms of response activate inflammatory molecules induced in the neurons, activated glial cells and endothelial cells via the key HMGB1/TLR4 pathway. In this study, the drug celecoxib (CCX) was used as a blocker of the cyclooxygenase 2 (COX-2) and HMGB1/TLR-4 pathways. The experimental model was implemented in 10-day-old neonatal Sprague Dawley rats to induce recurrent seizures with kainic acid (KA, 1.4 mg/kg). Data were evaluated at early (14 PND) and late (30 PND) time points. The results showed that the CCX and CCX + pentobarbital (PB) groups exhibited a protective effect by significantly increasing the time latency of seizures compared to the KA group at both early (p < 0.01) and late (p < 0.001) times. When the CCX group was compared to the KA group, there was also a significant decrease in the number of HMGB1 and TLR-4 transcripts (p < 0.05) and in COX-2 protein expression (p < 0.05) in the most important areas for seizure generation (the hippocampus and cortex) at both the early and late time points. These results demonstrated that CCX treatment after epileptic seizures has a neuroprotective effect due to the inhibition of proinflammatory proteins and associated signaling pathways and reduces seizure susceptibility. Additionally, the timely intervention of inflammatory pathways will reduce the risk of developing epilepsy in adulthood., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Oxidative stress (OS) has been implicated as a pathophysiological mechanism of drug-resistant epilepsy, but little is known about the relationship between OS markers and clinical parameters, such as the number of drugs, age onset of seizure and frequency of seizures per month. The current study&rsquo;s aim was to evaluate several oxidative stress markers and antioxidants in 18 drug-resistant partial complex seizure (DRPCS) patients compared to a control group (age and sex matched), and the results were related to clinical variables. We examined malondialdehyde (MDA), advanced oxidation protein products (AOPP), advanced glycation end products (AGEs), nitric oxide (NO), uric acid, superoxide dismutase (SOD), glutathione, vitamin C, 4-hydroxy-2-nonenal (4-HNE) and nitrotyrosine (3-NT). All markers except 4-HNE and 3-NT were studied by spectrophotometry. The expressions of 4-HNE and 3-NT were evaluated by Western blot analysis. MDA levels in patients were significantly increased ( p &le; 0.0001) while AOPP levels were similar to the control group. AGEs, NO and uric acid concentrations were significantly decreased ( p &le; 0.004, p &le; 0.005, p &le; 0.0001, respectively). Expressions of 3-NT and 4-HNE were increased ( p &le; 0.005) similarly to SOD activity ( p = 0.0001), whereas vitamin C was considerably diminished ( p = 0.0001). Glutathione levels were similar to the control group. There was a positive correlation between NO and MDA with the number of drugs. The expression of 3-NT was positively related with the frequency of seizures per month. There was a negative relationship between MDA and age at onset of seizures, as well as vitamin C with seizure frequency/month. We detected an imbalance in the redox state in patients with DRCPS, supporting oxidative stress as a relevant mechanism in this pathology. Thus, it is apparent that some oxidant and antioxidant parameters are closely linked with clinical variables.

Increasing amounts of evidence support the role of inflammation in epilepsy. This study was done to evaluate serum follow-up of IL-1β and IL-6 levels, as well as their concentration in the neocortex, and the relationship of central inflammation with NF-κB and annexin V in drug-resistant temporal lobe epileptic (DRTLE) patients submitted to surgical treatment. Peripheral and central levels of IL-1β and IL-6were measured by ELISA in 10 DRTLE patients. The sera from patients were taken before surgery, and 12 and 24 months after surgical treatment. The neocortical expression of NF-κB was evaluated by western blotting and annexin V co-localization with synaptophysin by immunohistochemistry. The neocortical tissues from five patients who died by non-neurological causes were used as control. Decreased serum levels of IL-1 and IL-6 were observed after surgery; at this time, 70% of patients were seizure-free. No values of IL-1 and IL-6 were detected in neocortical control tissue, whereas cytokine levels were evidenced in DRTLE. Increased NF-κB neocortex expression was found and the positive annexin V neurons were more obvious in the DRTLE tissue, correlating with IL-6 levels. The follow-up study confirmed that the inflammatory alterations disappeared one year after surgery, when the majority of patients were seizure-free, and the apoptotic death process correlated with inflammation., Competing Interests: The authors declare no conflict of interest.

Background: Intranasal administration (Int adm) has been well-studied and offers the possibility to deliver larger molecular weight biologics, such as proteins, viral vectors, nanoparticles, and naked plasmids to the brain and treat a variety of diseases in the central nervous system. The predominant challenge in this field is finding efficient vectors that are capable of crossing the blood-brain barrier (BBB)., Objectives: Here, we investigated whether a naked plasmid (pIRES-hrGFP-1a), could cross the BBB, reach brain cells and express green fluorescent protein (GFP) after int-adm and propose it as candidate for future gene therapy studies., Material and Methods: Thirty-six mice were divided into 2 groups. Eighteen animals were assigned to each cluster. Mice from experimental groups received 25 μg of pIRES-hrGFP-1a. The control groups received 25 μl of PBS. Plasmids were given intranasally by applying little drops in both nostrils. Twenty-four hours later, the mice were sacrificed, and their brains were removed. Later, PCR, RT-PCR, and immunohistochemical techniques were performed., Results: pIRES-hrGFP-1a crossed the BBB and was mainly detected in the olfactory nerves (20%) and hypothalamus (16%). In contrast, GFP/18S-expressing mRNAs were detected mostly in the olfactory bulbs (95%), frontal cortex (71%) and amygdala (60%). GFP was detected in the olfactory bulb, hippocampus, frontal cortex and brainstem at 24 h., Conclusions: pIRES-hrGFP-1a could be considered a good candidate for gene therapy studies. In the future could be cloned some therapeutic genes in the pIRES-hrGFP-1a and could transcribe and translates deficient proteins that are required to restore a function., (Copyright © 2018 IMSS. Published by Elsevier Inc. All rights reserved.)

Aging is a key risk factor for cognitive decline and age-related neurodegenerative disorders. Also, an age-related decrease in sex steroid hormones may have a negative impact on the formation of neurofibrillary tangles (NFTs); these hormones can regulate Tau phosphorylation and the principal kinase GSK3β involved in this process. Hormone replacement therapy decreases NFTs, but it increases the risk of some types of cancer. However, other synthetic hormones such as tibolone (TIB) have been used for hormone replacement therapy. The aim of this work was to evaluate the long-term effects of TIB (0.01 mg/kg and 1 mg/kg, intragastrically for 12 weeks) on the content of total and hyperphosphorylated Tau (PHF-1) proteins and the regulation of GSK3β/Akt/PI3K pathway and CDK5/p35/p25 complexes in the hippocampus of aged male mice. We observed that the content of PHF-1 decreased with TIB administration. In contrast, no changes were observed in the active form of GSK3β or PI3K. TIB decreased the expression of the total and phosphorylated form of Akt while increased that of p110 and p85. The content of CDK5 was differentially modified with TIB: it was increased at low doses and decreased at high doses. When we analyzed the content of CDK5 activators, an increase was found on p35; however, the content of p25 decreased with administration of low dose of TIB. Our results suggest a possible mechanism of action of TIB in the hippocampus of aged male mice. Through the regulation of Tau and GSK3β/Akt/PI3K pathway, and CDK5/p35/p25 complexes, TIB may modulate neuronal plasticity and regulate learning and memory processes., Competing Interests: Conflicts of interest: None declared.

Glutathione (GSH) deficiency has been identified as an early event in the progression of Parkinson's disease. However, the role of GSH in the etiology and pathogenesis of this neurodegenerative disorder is not well established. The aim of this study is to assess the effect of transient GSH depletion in the substantia nigra pars compacta (SNpc) on neuroinflammation after the injection of a single dose of l-buthionine sulfoximine (BSO) into the SNpc of male Sprague-Dawley rats. The results showed that BSO treatment stimulates microglia (p<0.01) and astroglial response (p<0.01), c-Jun N-terminal kinase and inducible nitric oxide synthase (iNOS) (p<0.001) in the SNpc, accompanied by dopaminergic dysfunction. In addition, high levels of tumor necrosis factor α (p<0.01), interleukins IL-1β p<0.01), IL-6 p<0.001) and nitric oxide p<0.01) were found in the treated animals compared to control groups, while no significant differences were found in IL-10 levels. These results suggest that transient GSH depletion can increase the susceptibility of SNpc to degeneration by promoting an inflammatory response and nitrosative stress, reinforcing the possible role of GSH unbalance, oxygen/nitrogen reactive species and neuroinflammation as causal factors on the degeneration of the SNpc., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)