Isradipine, an L-type calcium channel blocker, attenuates cocaine effects in mice by reducing central glutamate release.

Substance abuse disorder is a chronic condition for which pharmacological treatment options remain limited. L-type calcium channels (LTCC) have been implicated in drug-related plasticity and behavior. Specifically, dopaminergic neurons in the mesocorticolimbic pathway express Cav1.2 and Cav1.3 channels, which may regulate dopaminergic activity associated with reward behavior. Therefore, this study aimed to investigate the hypothesis that pre-administration of the LTCC blocker, isradipine can mitigate the effects of cocaine by modulating central glutamatergic transmission. For that, we administered isradipine at varying concentrations (1, 7.5, and 15 µg/µL) via intracerebroventricular injection in male Swiss mice. This pretreatment was carried out prior to subjecting animals to behavioral assessments to evaluate cocaine-induced locomotor sensitization and conditioned place preference (CPP). The results revealed that isradipine administered at a concentration of 1 µg/µL effectively attenuated both the sensitization and CPP induced by cocaine (15 mg/kg, via i. p.). Moreover, mice treated with 1 µg/µL of isradipine showed decreased presynaptic levels of glutamate and calcium in the cortex and hippocampus as compared to control mice following cocaine exposure. Notably, the gene expression of ionotropic glutamate receptors, AMPA, and NMDA, remained unchanged, as did the expression of Cav1.2 and Cav1.3 channels. Importantly, these findings suggest that LTCC blockage may inhibit behavioral responses to cocaine, most likely by decreasing glutamatergic input in areas related to addiction.

Chronic hyperpalatable diet induces impairment of hippocampal-dependent memories and alters glutamatergic and fractalkine axis signaling.

Chronic consumption of hyperpalatable and hypercaloric foods has been pointed out as a factor associated with cognitive decline and memory impairment in obesity. In this context, the integration between peripheral and central inflammation may play a significant role in the negative effects of an obesogenic environment on memory. However, little is known about how obesity-related peripheral inflammation affects specific neurotransmission systems involved with memory regulation. Here, we test the hypothesis that chronic exposure to a highly palatable diet may cause neuroinflammation, glutamatergic dysfunction, and memory impairment. For that, we exposed C57BL/6J mice to a high sugar and butter diet (HSB) for 12 weeks, and we investigated its effects on behavior, glial reactivity, blood-brain barrier permeability, pro-inflammatory features, glutamatergic alterations, plasticity, and fractalkine-CX3CR1 axis. Our results revealed that HSB diet induced a decrease in memory reconsolidation and extinction, as well as an increase in hippocampal glutamate levels. Although our data indicated a peripheral pro-inflammatory profile, we did not observe hippocampal neuroinflammatory features. Furthermore, we also observed that the HSB diet increased hippocampal fractalkine levels, a key chemokine associated with neuroprotection and inflammatory regulation. Then, we hypothesized that the elevation on glutamate levels may saturate synaptic communication, partially limiting plasticity, whereas fractalkine levels increase as a strategy to decrease glutamatergic damage.

Gut microbiota from patients with COVID-19 cause alterations in mice that resemble post-COVID symptoms.

Long-term sequelae of coronavirus disease (COVID)-19 are frequent and of major concern. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection affects the host gut microbiota, which is linked to disease severity in patients with COVID-19. Here, we report that the gut microbiota of post-COVID subjects had a remarkable predominance of Enterobacteriaceae strains with an antibiotic-resistant phenotype compared to healthy controls. Additionally, short-chain fatty acid (SCFA) levels were reduced in feces. Fecal transplantation from post-COVID subjects to germ-free mice led to lung inflammation and worse outcomes during pulmonary infection by multidrug-resistant Klebsiella pneumoniae. transplanted mice also exhibited poor cognitive performance. Overall, we show prolonged impacts of SARS-CoV-2 infection on the gut microbiota that persist after subjects have cleared the virus. Together, these data demonstrate that the gut microbiota can directly contribute to post-COVID sequelae, suggesting that it may be a potential therapeutic target.

Ion Channels-related Neuroprotection and Analgesia Mediated by Spider Venom Peptides.

Ion channels play critical roles in generating and propagating action potentials and in neurotransmitter release at a subset of excitatory and inhibitory synapses. Dysfunction of these channels has been linked to various health conditions, such as neurodegenerative diseases and chronic pain. Neurodegeneration is one of the underlying causes of a range of neurological pathologies, such as Alzheimer's disease (AD), Parkinson's disease (PD), cerebral ischemia, brain injury, and retinal ischemia. Pain is a symptom that can serve as an index of the severity and activity of a disease condition, a prognostic indicator, and a criterion of treatment efficacy. Neurological disorders and pain are conditions that undeniably impact a patient's survival, health, and quality of life, with possible financial consequences. Venoms are the best-known natural source of ion channel modulators. Venom peptides are increasingly recognized as potential therapeutic tools due to their high selectivity and potency gained through millions of years of evolutionary selection pressure. Spiders have been evolving complex and diverse repertoires of peptides in their venoms with vast pharmacological activities for more than 300 million years. These include peptides that potently and selectively modulate a range of targets, such as enzymes, receptors, and ion channels. Thus, components of spider venoms hold considerable capacity as drug candidates for alleviating or reducing neurodegeneration and pain. This review aims to summarize what is known about spider toxins acting upon ion channels, providing neuroprotective and analgesic effects.

Sex and the Estrous-Cycle Phase Influence the Expression of G Protein-Coupled Estrogen Receptor 1 (GPER) in Schizophrenia: Translational Evidence for a New Target.

Schizophrenia is a mental disorder with sex bias in disease onset and symptom severity. Recently, it was observed that females present more severe symptoms in the perimenstrual phase of the menstrual cycle. The administration of estrogen also alleviates schizophrenia symptoms. Despite this, little is known about symptom fluctuation over the menstrual cycle and the underlying mechanisms. To address this issue, we worked with the two-hit schizophrenia animal model induced by neonatal exposure to a virus-like particle, Poly I:C, associated with peripubertal unpredictable stress exposure. Prepulse inhibition of the startle reflex (PPI) in male and female mice was considered analogous to human schizophrenia-like behavior. Female mice were studied in the proestrus (high-estrogen estrous cycle phase) and diestrus (low-estrogen phase). Additionally, we evaluated the hippocampal mRNA expression of estrogen synthesis proteins; TSPO and aromatase; and estrogen receptors ERα, ERß, and GPER. We also collected peripheral blood mononuclear cells (PBMCs) from male and female patients with schizophrenia and converted them to induced microglia-like cells (iMGs) to evaluate the expression of GPER. We observed raised hippocampal expression of GPER in two-hit female mice at the proestrus phase without PPI deficits and higher levels of proteins related to estrogen synthesis, TSPO, and aromatase. In contrast, two-hit adult males with PPI deficits presented lower hippocampal mRNA expression of TSPO, aromatase, and GPER. iMGs from male and female patients with schizophrenia showed lower mRNA expression of GPER than controls. Therefore, our results suggest that GPER alterations constitute an underlying mechanism for sex influence in schizophrenia.

Molecular mechanisms underlying the neuroprotection of environmental enrichment in Parkinson's disease.

Parkinson's disease is the most common movement disorder, affecting about 1% of the population over the age of 60 years. Parkinson's disease is characterized clinically by resting tremor, bradykinesia, rigidity and postural instability, as a result of the progressive loss of nigrostriatal dopaminergic neurons. In addition to this neuronal cell loss, Parkinson's disease is characterized by the accumulation of intracellular protein aggregates, Lewy bodies and Lewy neurites, composed primarily of the protein α-synuclein. Although it was first described almost 200 years ago, there are no disease-modifying drugs to treat patients with Parkinson's disease. In addition to conventional therapies, non-pharmacological treatment strategies are under investigation in patients and animal models of neurodegenerative disorders. Among such strategies, environmental enrichment, comprising physical exercise, cognitive stimulus, and social interactions, has been assessed in preclinical models of Parkinson's disease. Environmental enrichment can cause structural and functional changes in the brain and promote neurogenesis and dendritic growth by modifying gene expression, enhancing the expression of neurotrophic factors and modulating neurotransmission. In this review article, we focus on the current knowledge about the molecular mechanisms underlying environmental enrichment neuroprotection in Parkinson's disease, highlighting its influence on the dopaminergic, cholinergic, glutamatergic and GABAergic systems, as well as the involvement of neurotrophic factors. We describe experimental pre-clinical data showing how environmental enrichment can act as a modulator in a neurochemical and behavioral context in different animal models of Parkinson's disease, highlighting the potential of environmental enrichment as an additional strategy in the management and prevention of this complex disease.

Implications of VIP and PACAP in Parkinson's Disease: What do we Know So Far?

BACKGROUND: Parkinson's disease is one of the most common neurodegenerative disorders and although its aetiology is not yet fully understood, neuroinflammation has been identified as a key factor in the progression of the disease. Vasoactive intestinal peptide and pituitary adenylate-cyclase activating polypeptide are two neuropeptides that exhibit anti-inflammatory and neuroprotective properties, modulating the production of cytokines and chemokines and the behaviour of immune cells. However, the role of chemokines and cytokines modulated by the endogenous receptors of the peptides varies according to the stage of the disease. METHODS: We present an overview of the relationship between some cytokines and chemokines with vasoactive intestinal peptide, pituitary adenylate cyclase activating polypeptide and their endogenous receptors in the context of Parkinson's disease neuroinflammation and oxidative stress, as well as the modulation of microglial cells by the peptides in this context. RESULTS: The two peptides exhibit neuroprotective and anti-inflammatory properties in models of Parkinson's disease, as they ameliorate cognitive functions, decrease the level of neuroinflammation and promote dopaminergic neuronal survival. The peptides have been tested in a variety of in vivo and in vitro models of Parkinson's disease, demonstrating the potential for therapeutic application. CONCLUSION: More studies are needed to establish the clinical use of vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide as safe candidates for treating Parkinson's disease, as the use of the peptides in different stages of the disease could produce different results concerning effectiveness.

Cannabidiol anticonvulsant effect is mediated by the PI3Kγ pathway.

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt)/mechanistic target of rapamycin (mTOR) signaling pathway has been associated with several pathologies in the central nervous system (CNS), including epilepsy. There is evidence supporting the hypothesis that the PI3Kγ signaling pathway may mediate the powerful anticonvulsant properties associated with the cannabinoidergic system. This work aims to investigate if the anticonvulsant and neuroprotective effects of cannabidiol (CBD) are mediated by PI3Kγ. In vitro and in vivo experiments were performed on C57Bl/6 wild-type (WT) and PI3Kγ-/- mice. Behavioral seizures were induced by bilateral intra-hippocampal pilocarpine microinjection. Twenty-four hours after the first behavioral seizure, animals were perfused and their brains removed and processed, for histological analysis of neurodegeneration, microgliosis and astrocytosis. Primary cultures of hippocampal neurons were used for glutamate-induced cell death assay. CDB increased latency and reduced the severity of pilocarpine-induced behavioral seizures, as well as prevented postictal changes, such as neurodegeneration, microgliosis and astrocytosis, in WT animals, but not in PI3Kγ-/-. CBD in vivo effects were abolished by pharmacological inhibition of cannabinoid receptor or mTOR. In vitro, PI3Kγ inhibition or deficiency also changed CBD protection observed in glutamate-induced cell death assay. Thus, we suggest that the modulation of PI3K/mTOR signaling pathway is involved in the anticonvulsant and neuroprotective effects of CBD. These findings are important not only for the elucidation of the mechanisms of action of CBD, which are currently poorly understood, but also to allow the prediction of therapeutic and side effects, ensuring efficacy and safety in the treatment of patients with epilepsy.

7-Deaza-7-fluoro-2'-C-methyladenosine inhibits Zika virus infection and viral-induced neuroinflammation.

Zika virus (ZIKV) has gained a lot of attention in the past few years due to its rapid spread worldwide and its close association to severe neurological outcomes, such as microcephaly and Guillain-Barre syndrome. In this study, the in vitro and in vivo anti-ZIKV activity of 7-deaza-7-fluoro-2'-C-methyl-adenosine (DFMA) was evaluated. In vitro, using primary mouse neuronal cells and human neural stem cells infected by ZIKV, treatment with DFMA resulted in impaired viral replication and protection against virus-induced cell death. In vivo, when administrated prior to infection, DFMA prevented lethality and markedly reduced viral loads and neuroinflammation, including microgliosis and overall brain damage. Additionally, as an early therapeutic treatment, DFMA increased survival rates in mice. Collectively, these findings demonstrate that the nucleoside analog DFMA inhibits ZIKV infection and viral-induced neuroinflammation in vitro and in vivo without apparent untoward effects, suggesting it may be useful in individuals infected with ZIKV.

Short and long TNF-alpha exposure recapitulates canonical astrogliosis events in human-induced pluripotent stem cells-derived astrocytes.

Astrogliosis comprises a variety of changes in astrocytes that occur in a context-specific manner, triggered by temporally diverse signaling events that vary with the nature and severity of brain insults. However, most mechanisms underlying astrogliosis were described using animals, which fail to reproduce some aspects of human astroglial signaling. Here, we report an in vitro model to study astrogliosis using human-induced pluripotent stem cells (iPSC)-derived astrocytes which replicate temporally intertwined aspects of reactive astrocytes in vivo. We analyzed the time course of astrogliosis by measuring nuclear translocation of NF-kB, production of cytokines, changes in morphology and function of iPSC-derived astrocytes exposed to TNF-α. We observed NF-kB p65 subunit nuclear translocation and increased gene expression of IL-1ß, IL-6, and TNF-α in the first hours following TNF-α stimulation. After 24 hr, conditioned media from iPSC-derived astrocytes exposed to TNF-α exhibited increased secretion of inflammation-related cytokines. After 5 days, TNF-α-stimulated cells presented a typical phenotype of astrogliosis such as increased immunolabeling of Vimentin and GFAP and nuclei with elongated shape and shrinkage. Moreover, ~50% decrease in aspartate uptake was observed during the time course of astrogliosis with no evident cell damage, suggesting astroglial dysfunction. Together, our results indicate that human iPSC-derived astrocytes reproduce canonical events associated with astrogliosis in a time dependent fashion. The approach described here may contribute to a better understanding of mechanisms governing human astrogliosis with potential applicability as a platform to uncover novel biomarkers and drug targets to prevent or mitigate astrogliosis associated with human brain disorders.

Phoneutria toxin PnTx3-5 inhibits TRPV1 channel with antinociceptive action in an orofacial pain model.

Capsaicin, an agonist of TRPV1, evokes intracellular [Ca2+] transients and glutamate release from perfused trigeminal ganglion. The spider toxin PnTx3-5, native or recombinant is more potent than the selective TRPV1 blocker SB-366791 with IC50 of 47 ±â€¯0.18 nM, 45 ±â€¯1.18 nM and 390 ±â€¯5.1 nM in the same experimental conditions. PnTx3-5 is thus more potent than the selective TRPV1 blocker SB-366791. PnTx3-5 (40 nM) and SB-366791 (3 µM) also inhibited the capsaicin-induced increase in intracellular Ca2+ in HEK293 cells transfected with TRPV1 by 75 ±â€¯16% and 84 ±â€¯3.2%, respectively. In HEK293 cells transfected with TRPA1, cinnamaldehyde (30 µM) generated an increase in intracellular Ca2+ that was blocked by the TRPA1 antagonist HC-030031 (10 µM, 89% inhibition), but not by PnTx3-5 (40 nM), indicating selectivity of the toxin for TRPV1. In whole-cell patch-clamp experiments on HEK293 cells transfected with TRPV1, capsaicin (10 µM) generated inward currents that were blocked by SB-366791 and by both native and recombinant PnTx3-5 by 47 ±â€¯1.4%; 54 ±â€¯7.8% and 56 ±â€¯9.0%, respectively. Intradermal injection of capsaicin into the rat left vibrissa induced nociceptive behavior that was blocked by pre-injection with either SB-366791 (3 nmol/site i.d., 83.3 ±â€¯7.2% inhibition) or PnTx3-5 (100 fmol/site, 89 ±â€¯8.4% inhibition). We conclude that both native and recombinant PnTx3-5 are potent TRPV1 receptor antagonists with antinociceptive action on pain behavior evoked by capsaicin.

NVP-BEZ235 (Dactolisib) Has Protective Effects in a Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease and the main cause of dementia. Its major symptom is memory loss, which is a result of neuronal cell death, which is accompanied by neuroinflammation. Some studies indicate the overactivation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway in this disease, being, thus, a potential target for pharmacological treatment. Here, we used a transgenic mouse model of AD that expresses a mutant amyloid-ß precursor protein (T41 mice) to investigate the effects of dactolisib (alternative name: NVP-BEZ235, abbreviation BEZ), a dual PI3K/mTOR inhibitor. Ten-months-old T41 animals were treated for 14 days with BEZ or vehicle via oral gavage and then submitted to social memory, open field and contextual conditioned fear tests. Hippocampal slices were prepared and Aß1-42 content, NeuN, Iba-1, CD68 and GFAP were evaluated. Tissues were further processed to evaluate cytokines levels through cytometric bead array. The treatment with BEZ (5 mg/kg) reduced social memory impairment in T41 mice. However, BEZ did not have any effect on altered Aß levels, NeuN, or GFAP staining. The drug reduced the CD68/Iba-1 ratio in CA3 region of hippocampus. Finally, BEZ diminished IL-10 levels in T41 mice. Thus, although its mechanisms are not clear, BEZ protects against memory impairment, reduces microglial activation and reestablishes IL-10 levels, revealing beneficial effects, which should be further investigated for the treatment of AD.

A positive allosteric modulator of mGluR5 promotes neuroprotective effects in mouse models of Alzheimer's disease.

Alzheimer's Disease (AD) is the most prevalent neurodegenerative disorder. Despite advances in the understanding of its pathophysiology, none of the available therapies prevents disease progression. Excess glutamate plays an important role in excitotoxicity by activating ionotropic receptors. However, the mechanisms modulating neuronal cell survival/death via metabotropic glutamate receptors (mGluRs) are not completely understood. Recent data indicates that CDPPB, a positive allosteric modulator of mGluR5, has neuroprotective effects. Thus, this work aimed to investigate CDPPB treatment effects on amyloid-ß (Aß) induced pathological alterations in vitro and in vivo and in a transgenic mouse model of AD (T41 mice). Aß induced cell death in primary cultures of hippocampal neurons, which was prevented by CDPPB. Male C57BL/6 mice underwent stereotaxic surgery for unilateral intra-hippocampal Aß injection, which induced memory deficits, neurodegeneration, neuronal viability reduction and decrease of doublecortin-positive cells, a marker of immature neurons and neuronal proliferation. Treatment with CDPPB for 8 days reversed neurodegeneration and doublecortin-positive cells loss and recovered memory function. Fourteen months old T41 mice presented cognitive deficits, neuronal viability reduction, gliosis and Aß accumulation. Treatment with CDPPB for 28 days increased neuronal viability (32.2% increase in NeuN+ cells) and reduced gliosis in CA1 region (Iba-1+ area by 31.3% and GFAP+ area by 37.5%) in transgenic animals, without inducing hepatotoxicity. However, it did not reverse cognitive deficit. Despite a four-week treatment did not prevent memory loss in aged transgenic mice, CDPPB is protective against Aß stimulus. Therefore, this drug represents a potential candidate for further investigations as AD treatment.

T-lymphocytes response persists following Plasmodium berghei strain Anka infection resolution and may contribute to later experimental cerebral malaria outcomes.

Several studies have proposed cerebral malaria (CM) as a CD4+ and CD8+ T lymphocyte-mediated disease. However, there are no data regarding the recruitment and/or persistence of these cells in the CNS following the phase of infection resolution. Glutamate-mediate excitotoxicity has also been implicated in CM. Blockade of glutamate NMDA receptors by its noncompetitive antagonist MK801 modulates cytokine and neurotrophic factors expression preventing cognitive and depressive-like behavior in experimental CM. Herein, we aim to investigate the role of T lymphocytes in later outcomes in CM, and whether the protective role of MK801 is associated with T lymphocytes response.

Consumption of Diet Containing Free Amino Acids Exacerbates Colitis in Mice.

Dietary proteins can influence the maturation of the immune system, particularly the gut-associated lymphoid tissue, when consumed from weaning to adulthood. Moreover, replacement of dietary proteins by amino acids at weaning has been shown to impair the generation of regulatory T cells in the gut as well as immune activities such as protective response to infection, induction of oral and nasal tolerance as well as allergic responses. Polymeric and elemental diets are used in the clinical practice, but the specific role of intact proteins and free amino acids during the intestinal inflammation are not known. It is plausible that these two dietary nitrogen sources would yield distinct immunological outcomes since proteins are recognized by the immune system as antigens and amino acids do not bind to antigen-recognition receptors but instead to intracellular receptors such as mammalian target of rapamycin (mTOR). In this study, our aim was to evaluate the effects of consumption of an amino acid-containing diet (AA diet) versus a control protein-containing diet in adult mice at steady state and during colitis development. We showed that consumption of a AA diet by adult mature mice lead to various immunological changes including decrease in the production of serum IgG as well as increase in the levels of IL-6, IL-17A, TGF-ß, and IL-10 in the small and large intestines. It also led to changes in the intestinal morphology, to increase in intestinal permeability, in the number of total and activated CD4+ T cells in the small intestine as well as in the frequency of proliferating cells in the colon. Moreover, consumption of AA diet during and prior to development of dextran sodium sulfate-induced colitis exacerbated gut inflammation. Administration of rapamycin during AA diet consumption prevented colitis exacerbation suggesting that mTOR activation was involved in the effects triggered by the AA diet. Therefore, our study suggests that different outcomes can result from the use of diets containing either intact proteins or free amino acids such as elemental, semielemental, and polymeric diets during intestinal inflammation. These results may contribute to the design of nutritional therapeutic intervention for inflammatory bowel diseases.

Antidepressant-like effect of valproic acid-Possible involvement of PI3K/Akt/mTOR pathway.

RATIONALE: Few studies suggest that antidepressants exert their effects by activating some signaling pathways, including the phosphatidylinositol 3-kinase (PI3K). Moreover, valproic acid (VPA) activates the PI3K pathway. Thus, here we investigated the antidepressant-like effect of VPA and if its effect is related to PI3K/Akt/mTOR activation. METHODS: C57Bl/6 (WT) and PI3Kγ-/- mice received VPA injections (30, 100 or 300mg/kg, i.p.) and 30min after they were submitted to the forced swimming (FS), tail suspension (TS) and open field (OF) tests. Another group was pretreated with rapamycin (5mg/kg, i.p.) 150min before VPA administration. Akt phosphorylation levels were measured by Western blotting. RESULTS: In WT mice, VPA (30mg/kg) reduced the immobility time in both FS and TS tests. However, VPA (300mg/kg) increased the immobility time in FS test. All doses of VPA did not alter locomotor activity. In PI3Kγ-/- mice, none of the doses revealed antidepressant-like effect. However, in the OF test, the lower dose of VPA increased the travelled distance in comparison with vehicle group. An increase in Akt phosphorylation levels was observed in WT, but not in PI3Kγ-/- mice. Finally, the pretreatment of WT mice with rapamycin abolished the antidepressant-like effect of VPA (30mg/kg) in FS test. CONCLUSION: These data suggest that the antidepressant-like effects of VPA might depend on PI3K and mTOR activation. Thus, more studies are necessary to investigate the mechanisms involved in the antidepressant-like effect induced by VPA in order to investigate novel therapeutic targets for the treatment of depression.

Muscle atrophy is associated with cervical spinal motoneuron loss in BACHD mouse model for Huntington's disease.

Involuntary choreiform movements are clinical hallmark of Huntington's disease, an autosomal dominant neurodegenerative disorder caused by an increased number of CAG trinucleotide repeats in the huntingtin gene. Involuntary movements start with an impairment of facial muscles and then affect trunk and limbs muscles. Huntington's disease symptoms are caused by changes in cortex and striatum neurons induced by mutated huntingtin protein. However, little is known about the impact of this abnormal protein in spinal cord motoneurons that control movement. Therefore, in this study we evaluated abnormalities in the motor unit (spinal cervical motoneurons, motor axons, neuromuscular junctions and muscle) in a mouse model for Huntington's disease (BACHD). Using light, fluorescence, confocal, and electron microscopy, we showed significant changes such as muscle fibers atrophy, fragmentation of neuromuscular junctions, axonal alterations, and motoneurons death in BACHD mice. Noteworthy, the surviving motoneurons from BACHD spinal cords were smaller than WT. We suggest that this loss of larger putative motoneurons is accompanied by a decrease in the expression of fast glycolytic muscle fibers in this model for Huntington's disease. These observations show spinal cord motoneurons loss in BACHD that might help to understand neuromuscular changes in Huntington's disease.

A Neuroprotective Effect of the Glutamate Receptor Antagonist MK801 on Long-Term Cognitive and Behavioral Outcomes Secondary to Experimental Cerebral Malaria.

Cerebral malaria (CM) is a life-threatening complication of Plasmodium falciparum infection, which can result in long-term cognitive and behavioral deficits despite successful anti-malarial therapy. Due to the substantial social and economic burden of CM, the development of adjuvant therapies is a scientific goal of highest priority. Apart from vascular and immune responses, changes in glutamate system have been reported in CM pathogenesis suggesting a potential therapeutic target. Based on that, we hypothesized that interventions in the glutamatergic system induced by blockage of N-methyl-D-aspartate (NMDA) receptors could attenuate experimental CM long-term cognitive and behavioral outcomes. Before the development of evident CM signs, susceptible mice infected with Plasmodium berghei ANKA (PbA) strain were initiated on treatment with dizocilpine maleate (MK801, 0.5 mg/kg), a noncompetitive NMDA receptor antagonist. On day 5 post-infection, mice were treated orally with a 10-day course chloroquine (CQ, 30 mg/kg). Control mice also received saline, CQ or MK801 + CQ therapy. After 10 days of cessation of CQ treatment, magnetic resonance images (MRI), behavioral and immunological assays were performed. Indeed, MK801 combined with CQ prevented long-term memory impairment and depressive-like behavior following successful PbA infection resolution. In addition, MK801 also modulated the immune system by promoting a balance of TH1/TH2 response and upregulating neurotrophic factors levels in the frontal cortex and hippocampus. Moreover, hippocampus abnormalities observed by MRI were partially prevented by MK801 treatment. Our results indicate that NMDA receptor antagonists can be neuroprotective in CM and could be a valuable adjuvant strategy for the management of the long-term impairment observed in CM.

Postictal alterations induced by intrahippocampal injection of pilocarpine in C57BL/6 mice.

Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults. The pilocarpine (PILO) experimental model of TLE portrays behavioral and pathophysiological changes in rodents that are very similar to those found in humans with TLE. However, this model is associated with an unfortunate high mortality rate. Studies have shown that intrahippocampal injection of PILO, while having a much smaller mortality rate, induces status epilepticus (SE) that secondarily leads to TLE. To the best of our knowledge, the present study was the first to evaluate the cognitive and histological alterations 72h after intrahippocampal microinjection of PILO in C57BL/6 mice. Seventy percent of mice developed status epilepticus (SE) after PILO administration, and all animals survived after SE. Seventy-two hours after SE, mice presented memory impairment in both Novel Object Recognition (recognition index - vehicle: 67.57±4.46% vs PILO: 52.33±3.29%) and Contextual Fear Conditioning (freezing time - vehicle: 203±20.43 vs PILO: 107.80±25.17s) tasks. Moreover, using Nissl and NeuN staining, we observed in PILO-treated mice a significant decrease in cell viability and an increase in neuronal loss in all three hippocampal regions analyzed, cornus ammonis (CA) 1, CA3, and dentate gyrus (DG), in comparison with the control group. Additionally, using Iba-1 staining, we observed in PILO-treated mice a significant increase in microglial proliferation in CA1, CA3, and DG of the hippocampus. Therefore, intrahippocampal PILO microinjection is an efficient route to induce SE and acute postictal epileptogenic-like alterations in C57BL/6 mice.