Effect of Levetiracetam on Oxidant-Antioxidant Activity during Long-Term Temporal Lobe Epilepsy in Rats.

Epilepsy is a disorder characterized by a predisposition to generate seizures. Levetiracetam (LEV) is an antiseizure drug that has demonstrated oxidant-antioxidant effects during the early stages of epilepsy in several animal models. However, the effect of LEV on oxidant-antioxidant activity during long-term epilepsy has not been studied. Therefore, the objective of the present study was to determine the effects of LEV on the concentrations of five antioxidant enzymes and on the levels of four oxidant stress markers in the hippocampus of rats with temporal lobe epilepsy at 5.7 months after status epilepticus (SE). The results revealed that superoxide dismutase (SOD) activity was significantly greater in the epileptic group (EPI) than in the control (CTRL), CTRL + LEV and EPI + LEV groups. No significant differences were found among the groups' oxidant markers. However, the ratios of SOD/hydrogen peroxide (H2O2), SOD/glutathione peroxidase (GPx) and SOD/GPx + catalase (CAT) were greater in the EPI group than in the CTRL and EPI + LEV groups. Additionally, there was a positive correlation between SOD activity and GPx activity in the EPI + LEV group. LEV-mediated modulation of the antioxidant system appears to be time dependent; at 5.7 months after SE, the role of LEV may be as a stabilizer of the redox state.

Changes in the Dentate Gyrus Gene Expression Profile Induced by Levetiracetam Treatment in Rats with Mesial Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) is one of the most common forms of focal epilepsy. Levetiracetam (LEV) is an antiepileptic drug whose mechanism of action at the genetic level has not been fully described. Therefore, the aim of the present work was to evaluate the relevant gene expression changes in the dentate gyrus (DG) of LEV-treated rats with pilocarpine-induced TLE. Whole-transcriptome microarrays were used to obtain the differential genetic profiles of control (CTRL), epileptic (EPI), and EPI rats treated for one week with LEV (EPI + LEV). Quantitative RT-qPCR was used to evaluate the RNA levels of the genes of interest. According to the results of the EPI vs. CTRL analysis, 685 genes were differentially expressed, 355 of which were underexpressed and 330 of which were overexpressed. According to the analysis of the EPI + LEV vs. EPI groups, 675 genes were differentially expressed, 477 of which were downregulated and 198 of which were upregulated. A total of 94 genes whose expression was altered by epilepsy and modified by LEV were identified. The RT-qPCR confirmed that LEV treatment reversed the increased expression of Hgf mRNA and decreased the expression of the Efcab1, Adam8, Slc24a1, and Serpinb1a genes in the DG. These results indicate that LEV could be involved in nonclassical mechanisms involved in Ca2+ homeostasis and the regulation of the mTOR pathway through Efcab1, Hgf, SLC24a1, Adam8, and Serpinb1a, contributing to reduced hyperexcitability in TLE patients.

Antiangiogenic Effect of Dopamine and Dopaminergic Agonists as an Adjuvant Therapeutic Option in the Treatment of Cancer, Endometriosis, and Osteoarthritis.

Dopamine (DA) and dopamine agonists (DA-Ag) have shown antiangiogenic potential through the vascular endothelial growth factor (VEGF) pathway. They inhibit VEGF and VEGF receptor 2 (VEGFR 2) functions through the dopamine receptor D2 (D2R), preventing important angiogenesis-related processes such as proliferation, migration, and vascular permeability. However, few studies have demonstrated the antiangiogenic mechanism and efficacy of DA and DA-Ag in diseases such as cancer, endometriosis, and osteoarthritis (OA). Therefore, the objective of this review was to describe the mechanisms of the antiangiogenic action of the DA-D2R/VEGF-VEGFR 2 system and to compile related findings from experimental studies and clinical trials on cancer, endometriosis, and OA. Advanced searches were performed in PubMed, Web of Science, SciFinder, ProQuest, EBSCO, Scopus, Science Direct, Google Scholar, PubChem, NCBI Bookshelf, DrugBank, livertox, and Clinical Trials. Articles explaining the antiangiogenic effect of DA and DA-Ag in research articles, meta-analyses, books, reviews, databases, and clinical trials were considered. DA and DA-Ag have an antiangiogenic effect that could reinforce the treatment of diseases that do not yet have a fully curative treatment, such as cancer, endometriosis, and OA. In addition, DA and DA-Ag could present advantages over other angiogenic inhibitors, such as monoclonal antibodies.

Differential expression of synaptic vesicle protein 2A after status epilepticus and during epilepsy in a lithium-pilocarpine model.

Synaptic vesicle protein 2A (SV2A) has become an attractive target of investigation because of its role in the pathophysiology of epilepsy; SV2A is expressed ubiquitously throughout the brain in all nerve terminals independently of their neurotransmitter content and plays an important but poorly defined role in neurotransmission. Previous studies have shown that modifications in the SV2A protein expression could be a direct consequence of disease severity. Furthermore, these SV2A modifications may depend on specific changes in the nerve tissue following the induction of epilepsy and might be present in both excitatory and inhibitory terminals. Thus, we evaluated SV2A protein expression throughout the hippocampi of lithium-pilocarpine rats after status epilepticus (SE) and during early and late epilepsy. In addition, we determined the γ-aminobutyric acid (GABA)ergic or glutamatergic nature associated with SV2A modifications. Wistar rats were treated with lithium-pilocarpine to induce SE and subsequently were shown to present spontaneous recurrent seizures (SRS). Later, we conducted an exhaustive semi-quantitative analysis of SV2A optical density (OD) throughout the hippocampus by immunohistochemistry. Levels of the SV2A protein were substantially increased in layers formed by principal neurons after SE, mainly because of GABAergic activity. No changes were observed in the early stage of epilepsy. In the late stage of epilepsy, there were minor changes in SV2A OD compared with the robust modifications of SE; however, SV2A protein expression generally showed an increment reaching significant differences in two dendritic layers and hilus, without clear modifications of GABAergic or glutamatergic systems. Our results suggest that the SV2A variations may depend on several factors, such as neuronal activity, and might appear in both excitatory and inhibitory systems depending on the epilepsy stage.

Neurohabilitation of Cognitive Functions in Pediatric Epilepsy Patients through LEGO®-Based Therapy.

In the pediatric population, epilepsy is one of the most common neurological disorders that often results in cognitive dysfunction. It affects patients' life quality by limiting academic performance and self-esteem and increasing social rejection. There are several interventions for the neurohabilitation of cognitive impairment, including LEGO®-based therapy (LEGO® B-T), which promotes neuronal connectivity and cortical plasticity through the use of assembly sets and robotic programming. Therefore, the aim of this study was to analyze the effect of LEGO® B-T on cognitive processes in pediatric patients with epilepsy. Eligible patients were identified; in the treatment group, an initial evaluation was performed with the NEUROPSI and BANFE-2 neuropsychological tests. Then, the interventions were performed once a week, and a final test was performed. In the control group, after the initial evaluation, the final evaluation was performed. An overall improvement was observed in the LEGO® B-T patients, with a significant increase in BANFE-2 scores in the orbitomedial, anterior prefrontal, and dorsolateral areas. In addition, in the gain score analysis, the orbitomedial and memory scores were significantly different from the control group. LEGO® B-T neurohabilitation is a remarkable option for epilepsy patients, who are motivated when they observe improvements.

Effect of levetiracetam on DNA oxidation and glutathione content in a temporal lobe epilepsy model.

Levetiracetam (LEV) is a drug commonly used as an anticonvulsant. However, recent evidence points to a possible role as an antioxidant. We previously demonstrated the antioxidant properties of LEV by significantly increasing catalase and superoxide dismutase activities and decreasing the hydrogen peroxide (H2O2) levels in the hippocampus of rats with temporal lobe epilepsy (TLE) showing scavenging properties against the hydroxyl radical. The aim of the present work was to evaluate, the effect of LEV on DNA oxidation, by determining 8­hydroxy­2­deoxyguanosine (8­OHdG) levels, and glutathione content, through reduced (GSH) and oxidized (GSSG) glutathione levels, in the hippocampus of rats with TLE. Male Wistar rats were assigned to the control (CTRL), CTRL+LEV, epileptic (EPI) and EPI+LEV groups. TLE was induced using the lithium­pilocarpine model. Thirteen weeks after TLE induction, LEV was administered for one week through osmotic pumps implanted subcutaneously. The determination of 8­OHdG, GSH and GSSG levels were measured using spectrophotometric methods. We showed that LEV alone significantly increased 8­OHdG and GSSG levels in the hippocampus of control rats compared to those in epileptic condition. No significant differences in GSH levels were observed. LEV could induce changes in the hippocampus increasing DNA oxidation and GSSG levels under nonepileptic condition but not protecting against the mitochondrial dysfunction observed in TLE probably by mechanisms related to changes in chromatin structure, neuroinflammation and alterations in redox components.

Synaptic vesicle protein 2A: basic facts and role in synaptic function.

In recent years, there has been considerable interest in determining the function of synaptic vesicle protein 2A and its role as a target for antiepileptic drugs. Although it is known that synaptic vesicle protein 2A is involved in normal synaptic vesicle function, its participation in synaptic vesicle cycling and neurotransmitter release in normal and pathological conditions is unclear. However, the experimental evidence suggests that synaptic vesicle protein 2A could be a vesicular transporter, regulate synaptic exocytosis as a gel matrix, or modulate synaptotagmin-1 activity. This review describes and discusses the participation of synaptic vesicle protein 2A in synaptic modulation in normal and pathological conditions.

Therapeutic Potential of Dopamine and Related Drugs as Anti-Inflammatories and Antioxidants in Neuronal and Non-Neuronal Pathologies.

Dopamine (DA), its derivatives, and dopaminergic drugs are compounds widely used in the management of diseases related to the nervous system. However, DA receptors have been identified in nonneuronal tissues, which has been related to their therapeutic potential in pathologies such as sepsis or septic shock, blood pressure, renal failure, diabetes, and obesity, among others. In addition, DA and dopaminergic drugs have shown anti-inflammatory and antioxidant properties in different kinds of cells. AIM: To compile the mechanism of action of DA and the main dopaminergic drugs and show the findings that support the therapeutic potential of these molecules for the treatment of neurological and non-neurological diseases considering their antioxidant and anti-inflammatory actions. METHOD: We performed a review article. An exhaustive search for information was carried out in specialized databases such as PubMed, PubChem, ProQuest, EBSCO, Scopus, Science Direct, Web of Science, Bookshelf, DrugBank, Livertox, and Clinical Trials. RESULTS: We showed that DA and dopaminergic drugs have emerged for the management of neuronal and nonneuronal diseases with important therapeutic potential as anti-inflammatories and antioxidants. CONCLUSIONS: DA and DA derivatives can be an attractive treatment strategy and a promising approach to slowing the progression of disorders through repositioning.

Evaluation of the Antioxidant Activity of Levetiracetam in a Temporal Lobe Epilepsy Model.

Epilepsy is a neurological disorder in which it has been shown that the presence of oxidative stress (OS) is implicated in epileptogenesis. The literature has shown that some antiseizure drugs (ASD) have neuroprotective properties. Levetiracetam (LEV) is a drug commonly used as an ASD, and in some studies, it has been found to possess antioxidant properties. Because the antioxidant effects of LEV have not been demonstrated in the chronic phase of epilepsy, the objective of this study was to evaluate, for the first time, the effects of LEV on the oxidant-antioxidant status in the hippocampus of rats with temporal lobe epilepsy (TLE). The in vitro scavenging capacity of LEV was evaluated. LEV administration in rats with TLE significantly increased superoxide dismutase (SOD) activity, increased catalase (CAT) activity, but did not change glutathione peroxidase (GPx) activity, and significantly decreased glutathione reductase (GR) activity in comparison with epileptic rats. LEV administration in rats with TLE significantly reduced hydrogen peroxide (H2O2) levels but did not change lipoperoxidation and carbonylated protein levels in comparison with epileptic rats. In addition, LEV showed in vitro scavenging activity against hydroxyl radical (HO•). LEV showed significant antioxidant effects in relation to restoring the redox balance in the hippocampus of rats with TLE. In vitro, LEV demonstrated direct antioxidant activity against HO•.

Analysis of Adverse Drug Reactions in Pediatric Patients with Epilepsy: An Intensive Pharmacovigilance Study.

Epilepsy is a chronic neurological disease characterized by the presence of spontaneous seizures, with a higher incidence in the pediatric population. Anti-seizure medication (ASM) may produce adverse drug reactions (ADRs) with an elevated frequency and a high severity. Thus, the objective of the present study was to analyze, through intensive pharmacovigilance over 112 months, the ADRs produced by valproic acid (VPA), oxcarbazepine (OXC), phenytoin (PHT), and levetiracetam (LEV), among others, administered to monotherapy or polytherapy for Mexican hospitalized pediatric epilepsy patients. A total of 1034 patients were interviewed; 315 met the inclusion criteria, 211 patients presented ADRs, and 104 did not. A total of 548 ASM-ADRs were identified, and VPA, LEV, and PHT were the main culprit drugs. The most frequent ADRs were drowsiness, irritability, and thrombocytopenia, and the main systems affected were hematologic, nervous, and dermatologic. LEV and OXC caused more nonsevere ADRs, and PHT caused more severe ADRs. The risk analysis showed an association between belonging to the younger groups and polytherapy with ADR presence and between polytherapy and malnutrition with severe ADRs. In addition, most of the severe ADRs were preventable, and most of the nonsevere ADRs were nonpreventable.

Habilitation of Executive Functions in Pediatric Congenital Heart Disease Patients through LEGO®-Based Therapy: A Quasi-Experimental Study.

Congenital heart disease is defined as an abnormality in the cardiocirculatory structure or function. Various studies have shown that patients with this condition may present cognitive deficits. To compensate for this, several therapeutic strategies have been developed, among them, the LEGO® Education sets, which use the pedagogic enginery to modify cognitive function by didactic material based on mechanics and robotics principles. Accordingly, the goal of this study was to evaluate the effect of cognitive habilitation by using LEGO®-based therapy in pediatric congenital heart disease patients. This was a quasi-experimental study; eligible patients were identified, and their general data were obtained. In the treatment group, an initial evaluation with the neuropsychological BANFE-2 test was applied; then, once a week, the interventions were performed, with a final test at the end of the interventions. In the control group, after the initial evaluation, a second appointment was scheduled for the final evaluation. Our results show that >50% of children presented cognitive impairment; nevertheless, there was an overall improvement in treatment patients, showing a significant increase in BANFE scores in areas related to executive functions. LEGO®-based therapy may be useful to improve cognitive abilities; however, future research should be performed to strengthen the data.

The Proliferating Cell Nuclear Antigen (PCNA) Transcript Variants as Potential Relapse Markers in B-Cell Acute Lymphoblastic Leukemia.

Leukemia is the most common childhood malignancy in Mexico, representing more than 50% of all childhood cancers. Although treatment leads to a survival of up to 90% in developing countries, in our country, it is less than 65%. Additionally, ~30% of patients relapse with poor prognosis. Alternative splicing plays an important role in transcriptome diversity and cellular biology. This mechanism promotes an increase in the assortment of proteins with potentially distinct functions from a single gene. The proliferating cell nuclear antigen (PCNA) gene encodes two transcripts for the same protein of 261 amino acids, which is associated with several important cellular processes and with several types of cancer. However, the diversity of the transcript variants expressed in this condition is not clear. Then, we used microarray gene expression to identify changes in the exon expression level of PCNA. The data were validated using RT-PCR and Sanger sequencing, and three additional transcripts (PCNA_V3, PCNA_V4, and PCNA_V5) were identified. Computational analyses were used to determine the potential proteins resulting, their structure, and interactions with PCNA native protein and themselves. Additionally, the PCNA transcript variants were inhibited using specific siRNA, determining that their inhibition contributes to the malignant characteristics in vitro. Finally, we quantified the PCNA transcript variants in acute lymphoblastic leukemia samples and identified their expression in this disease. Based on the clinical characteristics, we determined that PCNA_V2 and PCNA_V4 are expressed at significantly low levels in relapsed B-ALL patients. We conclude that the low expression of PCNA_V2 and PCNA_V4 could be a potential molecular marker of relapse in acute lymphoblastic leukemia patients.

Levetiracetam Mechanisms of Action: From Molecules to Systems.

Epilepsy is a chronic disease that affects millions of people worldwide. Antiepileptic drugs (AEDs) are used to control seizures. Even though parts of their mechanisms of action are known, there are still components that need to be studied. Therefore, the search for novel drugs, new molecular targets, and a better understanding of the mechanisms of action of existing drugs is still crucial. Levetiracetam (LEV) is an AED that has been shown to be effective in seizure control and is well-tolerable, with a novel mechanism of action through an interaction with the synaptic vesicle protein 2A (SV2A). Moreover, LEV has other molecular targets that involve calcium homeostasis, the GABAergic system, and AMPA receptors among others, that might be integrated into a single mechanism of action that could explain the antiepileptogenic, anti-inflammatory, neuroprotective, and antioxidant properties of LEV. This puts it as a possible multitarget drug with clinical applications other than for epilepsy. According to the above, the objective of this work was to carry out a comprehensive and integrative review of LEV in relation to its clinical uses, structural properties, therapeutical targets, and different molecular, genetic, and systemic action mechanisms in order to consider LEV as a candidate for drug repurposing.

COVID-19 in G6PD-deficient Patients, Oxidative Stress, and Neuropathology.

Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme that regulates energy metabolism mainly through the pentose phosphate pathway (PPP). It is well known that this enzyme participates in the antioxidant/oxidant balance via the synthesis of energy-rich molecules: nicotinamide adenine dinucleotide phosphate reduced (NADPH), the reduced form of flavin adenine dinucleotide (FADH) and glutathione (GSH), controlling reactive oxygen species generation. Coronavirus disease 19 (COVID-19), induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a public health problem that has caused approximately 4.5 million deaths since December 2019. Concerning the role of G6PD in COVID-19 development, it is known from the existing literature that G6PD-deficient patients infected with SARS-CoV-2 are more susceptible to thrombosis and hemolysis, suggesting that G6PD deficiency facilitates infection by SARS-CoV-2. Concerning G6PD and neuropathology, it has been observed that deficiency of this enzyme is also present with an increase in oxidative markers. Concerning the role of G6PD and the neurological manifestations of COVID-19, it has been reported that the enzymatic deficiency in patients infected with SARSCoV- 2 exacerbates the disease, and, in some clinical reports, an increase in hemolysis and thrombosis was observed when patients were treated with hydroxychloroquine (OH-CQ), a drug with oxidative properties. In the present work, we summarize the evidence of the role of G6PD in COVID- 19 and its possible role in the generation of oxidative stress and glucose metabolism deficits, and inflammation present in this respiratory disease and its progression including neurological manifestations.

Late onset muscle plasticity in the whisker pad of enucleated rats.

Blindness leads to a major reorganization of neural pathways associated with touch. Because incoming somatosensory information influences motor output, it is plausible that motor plasticity occurs in the blind. In this work, we evaluated this issue at the peripheral level in enucleated rats. Whisker muscles in enucleated rats 160 days of age or older showed increased cytochrome oxidase activity, capillary density, motor plate size, and amplitude of evoked field potentials as compared with their control counterparts. Such differences were not observed at ages 10 and 60 days, the capillary density was the exception being greater in the enucleated rat at the latter age. Interestingly, there was a trend to increased neurotrophin-3 concentrations in the whisker pads of enucleated rats throughout postnatal development. Our results show that neonatal enucleation leads to late onset plasticity of the whisker's motor system.

Synaptic Vesicle Protein 2A Expression in Glutamatergic Terminals Is Associated with the Response to Levetiracetam Treatment.

Synaptic vesicle protein 2A (SV2A), the target of the antiepileptic drug levetiracetam (LEV), is expressed ubiquitously in all synaptic terminals. Its levels decrease in patients and animal models of epilepsy. Thus, changes in SV2A expression could be a critical factor in the response to LEV. Epilepsy is characterized by an imbalance between excitation and inhibition, hence SV2A levels in particular terminals could also influence the LEV response. SV2A expression was analyzed in the epileptic hippocampus of rats which responded or not to LEV, to clarify if changes in SV2A alone or together with glutamatergic or GABAergic markers may predict LEV resistance. Wistar rats were administered saline (control) or pilocarpine to induce epilepsy. These groups were subdivided into untreated or LEV-treated groups. All epileptic rats were video-monitored to assess their number of seizures. Epileptic rats with an important seizure reduction (>50%) were classified as responders. SV2A, vesicular γ-aminobutyric acid transporter and vesicular glutamate transporter (VGLUT) expression were assessed by immunostaining. SV2A expression was not modified during epilepsy. However, responders showed ≈55% SV2A-VGLUT co-expression in comparison with the non-responder group (≈40%). Thus, SV2A expression in glutamatergic terminals may be important for the response to LEV treatment.

Levetiracetam Reduced the Basal Excitability of the Dentate Gyrus without Restoring Impaired Synaptic Plasticity in Rats with Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE), the most common type of focal epilepsy, affects learning and memory; these effects are thought to emerge from changes in synaptic plasticity. Levetiracetam (LEV) is a widely used antiepileptic drug that is also associated with the reversal of cognitive dysfunction. The long-lasting effect of LEV treatment and its participation in synaptic plasticity have not been explored in early chronic epilepsy. Therefore, through the measurement of evoked field potentials, this study aimed to comprehensively identify the alterations in the excitability and the short-term (depression/facilitation) and long-term synaptic plasticity (long-term potentiation, LTP) of the dentate gyrus of the hippocampus in a lithium-pilocarpine rat model of TLE, as well as their possible restoration by LEV (1 week; 300 mg/kg/day). TLE increased the population spike (PS) amplitude (input/output curve); interestingly, LEV treatment partially reduced this hyperexcitability. Furthermore, TLE augmented synaptic depression, suppressed paired-pulse facilitation, and reduced PS-LTP; however, LEV did not alleviate such alterations. Conversely, the excitatory postsynaptic potential (EPSP)-LTP of TLE rats was comparable to that of control rats and was decreased by LEV. LEV caused a long-lasting attenuation of basal hyperexcitability but did not restore impaired synaptic plasticity in the early chronic phase of TLE.

Analysis of Differential Expression of Synaptic Vesicle Protein 2A in the Adult Rat Brain.

Synaptic vesicle protein 2A (SV2A), which plays an important role in the pathophysiology of epilepsy, is a unique vesicular protein recognized as a pharmacological target of anticonvulsant drugs. Furthermore, SV2A is a potential synaptic density marker, as it is ubiquitously expressed throughout the brain in all nerve terminals independently of their neurotransmitter content. Due to the growing interest in this protein, we thoroughly analyzed SV2A levels, expression patterns and colocalization in both excitatory and inhibitory synapses among different brain structures in healthy rats. In addition, we discuss the main semiquantitative methodologies used to study SV2A because these techniques might represent powerful tools for evaluating synaptic changes associated with brain disorders. Our results showed that the SV2A expression levels differed among the analyzed structures, and a positive correlation between the SV2A mRNA copy number and protein level was observed by Western blot. In addition, immunohistochemistry demonstrated slight but consistent asymmetrical SV2A levels in different laminated structures, and SV2A expression was increased by up to 40% in some specific layers compared to that in others. Finally, triple immunofluorescence revealed strong SV2A colocalization with GABAergic terminals, mainly around the principal cells, suggesting that SV2A primarily participates in this inhibitory system in different rat brain structures. Although the SV2A protein is considered a good candidate marker of synaptic density, our data show that changes in its expression in pathological processes must be viewed as not only increased or decreased synapse numbers but also in light of the type of neurotransmission being affected.

The rostral migratory stream is a neurogenic niche that predominantly engenders periglomerular cells: in vivo evidence in the adult rat brain.

In vitro studies support the existence of adult neural stem cells in the rostral migratory stream (RMS). The evidence supporting this possibility in vivo is scarce. We then explore this issue by taking advantage of a rat model in which a physical barrier implanted in the brain interrupted the migration of neuroblasts derived from the SVZ along the RMS at the level of its vertical limb. The presence of local stem cells and neurogenesis were then established by estimating the number of nuclei labeled with bromo-deoxyuridine (BrdU), the number of doublecortin-positive neuroblasts and the existence of cells displaying co-localization of BrdU and Sox-2 immunoreactivity along the RMS, at different time points following barrier implantation. Estimations of the number of the granular and periglomerular neurons integrated into the corresponding layers of the olfactory bulb of implanted rats established that stem cells in the RMS give rise predominantly to periglomerular neurons. Our results then support the notion that the RMS is indeed a region in which neurogenesis is taking place in the adult brain. They also support that the relative location of the neurogenic niche might imprint, at least in some degree, the identity and lineage of the neuroblasts arising from them.

Melatonin attenuates the decrement of dendritic protein MAP-2 immuno-staining in the hippocampal CA1 and CA3 fields of the aging male rat.

Neuronal death during brain aging results, at least in part, from the disruption of synaptic connectivity caused by oxidative stress. Synaptic elimination might be caused by increased instability of the neuronal processes. In vitro evidence shows that melatonin increases MAP-2 expression, a protein that improves the stability of the dendritic cytoskeleton, opening the possibility that melatonin could prevent synaptic elimination by increasing dendritic stability. One way to begin exploring this issue in vivo is to evaluate whether long-term melatonin treatment changes the intensity of MAP-2 immuno-staining in areas commonly afflicted by aging that are rich in dendritic processes. Accordingly, we evaluated the effects of administering melatonin for 6 or 12 months on the intensity of MAP-2 immuno-staining in the strata oriens and lucidum of the hippocampal CA1 and CA3 fields of aging male rats, through semi-quantitative densitometry. Melatonin treated rats showed a relative increment in the intensity of MAP-2 immuno-staining in both regions after 6 or 12 months of treatment, as compared with age matched control rats. Although melatonin untreated and treated rats showed a decrease of MAP-2 immuno-staining in the hippocampus with increasing age, such decrement was less pronounced following melatonin treatment. These findings were confirmed by qualitative Western blot analyses. The melatonin effect seems specific because MAP-2 staining in the primary somatosensory cortex was not affected by the treatment. Thus, chronic melatonin administration increases MAP-2 immuno-staining and attenuates its decay in the adult aging hippocampus. These results are compatible with the idea that melatonin could improve dendritic stability and thus diminish synaptic elimination in the aging brain.