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Experimental autoimmune encephalomyelitis is a demyelinating disease that causes paralysis in laboratory rats. This condition lacks treatment that reverses damage to the myelin sheaths of neuronal cells. Therefore, in this study, treatment with EPO as a neuroprotective effect was established to evaluate the ERK 1/2 signaling pathway and its participation in the EAE model. EPO was administered in 5000 U/Kg Sprague Dawley rats. U0126 was used as an inhibitor of the ERK 1/2 pathway to demonstrate the possible activation of this pathway in the model. Spinal cord and optic nerve tissues were evaluated using staining techniques such as H&E and the Luxol Fast Blue myelin-specific technique, as well as immunohistochemistry of the ERK 1/2 protein. The EPO-treated groups showed a decrease in cellular sampling in the spinal cord tissues but mainly in the optic nerve, as well as an increase in the expression of the ERK 1/2 protein in both tissues. The findings of this study suggest that EPO treatment reduces cellular death in EAE-induced rats by regulating the ERK pathway.

Renin-Angiotensin System (RAS) is a peptidergic system, canonically known for its role in blood pressure regulation. Furthermore, a non-canonical RAS regulates pathophysiological phenomena, such as inflammation since it consists of two main axes: the pro-inflammatory renin/(pro)renin receptor ((P)RR) axis, and the anti-inflammatory angiotensin-converting enzyme 2 (ACE2)/Angiotensin-(1-7) (Ang-(1-7))/Mas Receptor (MasR) axis. Few phytochemicals have shown to exert angiotensinergic and anti-inflammatory effects through some of these axes; nevertheless, anti-inflammatory drugs, such as phytocannabinoids have not been studied regarding this subject. Among phytocannabinoids, β-Caryophyllene stands out as a dietary phytocannabinoid with antiphlogistic activity that possess a unique sesquiterpenoid structure. Although its cannabinergic effect has been studied, its angiotensinergic effect reminds underexplored. This study aims to explore the angiotensinergic effect of β-Caryophyllene on inflammation and stress at a systemic level. After intranasal Lipopolysaccharide (LPS) installation and oral treatment with β-Caryophyllene, the concentration and activity of key RAS elements in the serum, such as Renin, ACE2 and Ang-(1-7), along with the stress hormone corticosterone and pro/anti-inflammatory cytokines, were measured in mice serum. The results show that β-Caryophyllene treatment modified RAS levels by increasing Renin and Ang-(1-7), alongside the reduction of pro-inflammatory cytokines and corticosterone levels. These results indicate that β-Caryophyllene exhibits angiotensinergic activity in favor of anti-inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by alterations in motor capacity resulting from a decrease in the neurotransmitter dopamine due to the selective death of dopaminergic neurons of the nigrostriatal pathway. Unfortunately, conventional pharmacological treatments fail to halt disease progression; therefore, new therapeutic strategies are needed, and currently, some are being investigated. The endocannabinoid system (ECS), highly expressed in the basal ganglia (BG) circuit, undergoes alterations in response to dopaminergic depletion, potentially contributing to motor symptoms and the etiopathogenesis of PD. Substantial evidence supports the neuroprotective role of the ECS through various mechanisms, including anti-inflammatory, antioxidative, and antiapoptotic effects. Therefore, the ECS emerges as a promising target for PD treatment. This review provides a comprehensive summary of current clinical and preclinical evidence concerning ECS alterations in PD, along with potential pharmacological targets that may exert the protection of dopaminergic neurons., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2024 María Fernanda Urmeneta-Ortíz et al.)

Over time, several studies have been conducted to demonstrate the functions of the neurotransmitter 5-hydroxytryptamine (5-HT), better known as serotonin. This neurotransmitter is associated with the modulation of various social and physiological behaviors, and its dysregulation has consequences at the behavioral level, leading to various neurophysiological disorders. Disorders such as anxiety, depression, schizophrenia, epilepsy, sexual disorders, and eating disorders, have been closely linked to variations in 5-HT concentrations and modifications in brain structures, including the raphe nuclei (RN), prefrontal cortex, basal ganglia, hippocampus, and hypothalamus, among others. The involvement of β-arrestin proteins has been implicated in the modulation of the serotonergic receptor response, as well as the activation of different signaling pathways related to the serotonergic system, this is particularly relevant in depressive disorders. This review will cover the implications of alterations in 5-HT receptor expression in depressive disorders in one hand and how β-arrestin proteins modulate the response mediated by these receptors in the other hand., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Dysgeusia is characterized by a loss of taste perception, leading to malnutrition. This situation affects inflammatory conditions such as respiratory and neurological conditions, obesity, cancer, chemotherapy, aging, and many others. To date, there is not much information on the prevalence and risk of dysgeusia in an inflammatory condition; also, it is unclear which flavor is altered., Materials and Methods: We systematically searched three databases from January 2018 to January 2023. Participants were children, adults, or elderly persons with an inflammatory condition and evaluated taste loss. A random effects model was used for statistical analysis to calculate the pooled odds ratio with its corresponding 95.0% confidence interval to estimate the probability of taste alteration (dysgeusia) in an inflammatory condition., Results: The data allowed us to conduct a systematic review, including 63 original articles and 15 studies to perform the meta-analysis. The meta-analysis indicated a heterogenicity of 84.7% with an odds ratio of 3.25 (2.66-3.96), indicating a significant risk of Alzheimer's disease, SARS-CoV-2, chemotherapy, and rhinosinusitis., Conclusions: Inflammatory conditions and taste alterations are linked. Dysgeusia is associated with a higher risk of malnutrition and poorer general health status, especially in vulnerable populations.

Background: Cardiorenal syndrome (CRS) type 4 is prevalent among the chronic kidney disease (CKD) population, with many patients dying from cardiovascular complications. However, limited data regarding cardiac transcriptional changes induced early by CKD is available., Methods: We used a murine unilateral ureteral obstruction (UUO) model to evaluate renal damage, cardiac remodeling, and transcriptional regulation at 21 days post-surgery through histological analysis, RT-qPCR, RNA-seq, and bioinformatics., Results: UUO leads to significant kidney injury, low uremia, and pathological cardiac remodeling, evidenced by increased collagen deposition and smooth muscle alpha-actin 2 expression. RNA-seq analysis identified 76 differentially expressed genes (DEGs) in UUO hearts. Upregulated DEGs were significantly enriched in cell cycle and cell division pathways, immune responses, cardiac repair, inflammation, proliferation, oxidative stress, and apoptosis. Gene Set Enrichment Analysis further revealed mitochondrial oxidative bioenergetic pathways, autophagy, and peroxisomal pathways are downregulated in UUO hearts. Vimentin was also identified as an UUO-upregulated transcript., Conclusions: Our results emphasize the relevance of extensive transcriptional changes, mitochondrial dysfunction, homeostasis deregulation, fatty-acid metabolism alterations, and vimentin upregulation in CRS type 4 development., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Introduction: Parkinson's disease represents a neurodegenerative condition characterized by the progressive loss of dopaminergic neurons within the Substantia Nigra pars compacta (SNpc), resulting in diminished dopamine levels in the striatum (STR) and chronic neuroinflammation. Recent investigations have proposed the neuroprotective potential of the endocannabinoid system in neurodegenerative disorders. β-caryophyllene (BCP) is recognized for its antioxidant and anti-inflammatory properties, attributed to its activation of the type 2 cannabinoid receptor. This study aimed to assess the neuroprotective impact of BCP on dopaminergic neurons, with a particular focus on inhibiting the NLRP3 inflammasome., Methods: A model of hemiparkinsonism, induced by 6-hydroxydopamine (6-OHDA), served as the experimental framework. Motor function was evaluated using the cylinder test, and inflammasome inhibition was determined by assessing the expression of NLRP3, caspase-1, and the pro-inflammatory cytokine IL-1β in both the SNpc and STR through ELISA analysis. Furthermore, the evaluation of oxidative stress was facilitated by quantifying malondialdehyde (MDA) levels in the same regions., Results: BCP treatment demonstrated significant improvements in motor dysfunction, as assessed by the cylinder test (p=0.0011) and exhibited a neuroprotective effect on dopaminergic neurons within the SNpc (p=0.0017), as well as nerve fibers in the STR (p=0.0399). In terms of its ability to inhibit the inflammasome, BCP led to decreased expression levels of NLRP3 (p=0.0401 in STR and p = 0.0139 in SNpc), caspase-1 (p=0.0004 in STR), and MDA (p=0.0085 in STR and p=0.0414 in SNpc)., Conclusion: These results point to BCP's potential in mitigating the motor deficit, inhibiting NLRP3 inflammasome activation, and attenuating lipid peroxidation induced by 6-OHDA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

It has recently been shown that the administration of probiotics can modulate the microbiota-gut-brain axis and may have favorable effects in models of Parkinson's disease. In this study, we used a hemiparkinsonism model induced by the neurotoxin 6-OHDA to evaluate the efficacy of the administration of a four-week administration of a mixture containing the microorganisms Lactobacillus fermentum LH01, Lactobacillus reuteri LH03, and Lactobacillus plantarum LH05. The hemiparkinsonism model induced an increase in rotations in the apomorphine test, along with a decrease in the latency time to fall in the rotarod test on days 14 and 21 after surgery, respectively. The administration of probiotics was sufficient to improve this condition. The model also showed a decrease in tyrosine hydroxylase immunoreactivity in the striatum and the number of labeled cells in the substantia nigra, both of which were counteracted by the administration of probiotics. The permeability of the blood-brain barrier was increased in the model, but this effect was reversed by the probiotics for both brain regions. The gut barrier was permeated with the model, and this effect was reversed and dropped to lower levels than the control group after the administration of probiotics. Finally, lipid peroxidation showed a pattern of differences similar to that of permeabilities. The inhibition of the permeability of the blood-brain and gut barriers mediated by the administration of probiotics will likely provide protection by downregulating oxidative stress, thus affecting the rotarod test performance., Competing Interests: The authors declare no financial or competing interests., (Copyright © 2023 Angélica Y. Nápoles-Medina et al.)

Vascular endothelial growth factor (VEGF) exerts neuroprotective or proinflammatory effects, depending on what VEGF forms (A-E), receptor types (VEGFR1-3), and intracellular signaling pathways are involved. Neonatal monosodium glutamate (MSG) treatment triggers neuronal death by excitotoxicity, which is commonly involved in different neurological disorders, including neurodegenerative diseases. This study was designed to evaluate the effects of VEGFR-2 inhibition on neuronal damage triggered by excitotoxicity in the cerebral motor cortex (CMC) and hippocampus (Hp) after neonatal MSG treatment. MSG was administered at a dose of 4 g/kg of body weight (b.w.) subcutaneously on postnatal days (PD) 1, 3, 5, and 7, whereas the VEGFR-2 inhibitor SU5416 was administered at a dose of 10 mg/kg b.w. subcutaneously on PD 5 and 7, 30 min before the MSG treatment. Neuronal damage was assessed using hematoxylin and eosin staining, fluoro-Jade staining, and TUNEL assay. Additionally, western blot assays for some proteins of the VEGF-A/VEGFR-2 signaling pathway (VEGF-A, VEGFR-2, PI3K, Akt, and iNOS) were carried out. All assays were performed on PD 6, 8, 10, and 14. Inhibition of VEGFR-2 signaling by SU5416 increases the neuronal damage induced by neonatal MSG treatment in both the CMC and Hp. Moreover, neonatal MSG treatment increased the expression levels of the studied VEGF-A/VEGFR-2 signaling pathway proteins, particularly in the CMC. We conclude that VEGF-A/VEGFR-2 signaling pathway activation could be part of the neuroprotective mechanisms that attempt to compensate for neuronal damage induced by neonatal MSG treatment and possibly also in other conditions involving excitotoxicity., (© 2023 Wiley Periodicals LLC.)

Early life stress induced by maternal separation (MS) causes neuroendocrine, behavioral, and metabolic alterations that are related to gut dysbiosis. MS also increases microglial activation and decreases neurogenesis. Whether these long-term alterations are maintained or worsened in the absence of gut microbiota remains unknown. Hence, this study evaluated the effect of MS symptomatology after antibiotic-induced microbiota depletion (AIMD) in adult rats. Control and maternally separated (3 h per day from postnatal day one to 14, MS180) rats were subjected to AIMD for one month, then assessed for behavioral, metabolic, and neuroendocrine responses. Effects of MS180 and AIMD on gut microbiota were confirmed by qPCR. The data indicate that MS180 caused a passive coping strategy in the forced swimming test and decreased hippocampal neurogenesis. In addition, fasting glucose, cholesterol, and corticosterone levels increased, which correlated with a decrease in Lactobacillus spp counts in the caecum. AIMD also increased immobility in the forced swimming test, decreased hippocampal neurogenesis, and augmented corticosterone levels. However, it had no effects on glucose homeostasis or plasma lipid levels. Furthermore, the MS180-induced long-term effects on behavior and neurogenesis were not affected by microbiota depletion. Meanwhile, the metabolic imbalance was partially reversed in MS180 + AIMD rats. These results show that AIMD mimics the behavioral consequences of MS180 but may prevent metabolic imbalance, suggesting that gut dysbiosis could be part of the mechanisms involved in the maintenance of the long-term consequences of early life stress., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Landfill leachate is a complex mixture of organic and inorganic molecules, as well as environmental pollutants that can cause harm to ecosystems and living beings. The micronucleus test in peripheral blood erythrocytes was used to evaluate the genotoxic and cytotoxic effects of exposure to a landfill leachate from an outdoor solid waste storage system on Wistar strain rats at different developmental stages, pre-adolescents and young adults, and the heavy metal content of the leachate was determined by atomic absorption spectrometry. Contents of arsenic, cadmium, chromium, mercury, and lead in the landfill leachate were outside the allowable international standards, and the exposure to the landfill leachate caused genotoxic and cytotoxic effects on Wistar rats, where the pre-adolescent animals were more susceptible to the toxics contained in the landfill leachate than young adults. Heavy metals contained in landfill leachate, individually or synergically with other molecules can be responsible for clastogenic and cytotoxic effects that can be harmful to humans and ecosystems.

Symptoms of depressive disorders such as anhedonia and despair can be a product of an aberrant adaptation to stress conditions. Chronic unpredictable stress model (CUS) can generate an increase in the activity of the hypothalamic-pituitary-adrenal axis (HPA) and induce a reduction of neurotrophin signaling and the proliferation of neural progenitors in the adult dentate gyrus, together with increased oxidative stress. Levels of the endocannabinoid anandamide (AEA) seem to affect these depression-by-stress-related features and could be modulated by fatty acid amide hydrolase (FAAH). We aimed to evaluate the effects of FAAH inhibitor, URB597, on depressive-like behavior and neural proliferation of mice subjected to a model of CUS. URB597 was administered intraperitoneally at a dose of 0.2 mg/kg for 14 days after CUS. Depressive-like behaviors, anhedonia, and despair were evaluated in the splash and forced swimming tests, respectively. Alterations at the HPA axis level were analyzed using the relative weight of adrenal glands and serum corticosterone levels. Oxidative stress and brain-derived neurotrophic factor (BDNF) were also evaluated. Fluorescence immunohistochemistry tests were performed for the immunoreactivity of BrdU and Sox2 colabeling for comparison of neural precursors. The administration of URB597 was able to reverse the depressive-like behavior generated in mice after the model. Likewise, other physiological responses associated with CUS were reduced in the treated group, among them, increase in the relative weight of the adrenal glands, increased oxidative stress, and decreased BDNF and number of neural precursors. Most of these auspicious responses to enzyme inhibitor administration were blocked by employing a cannabinoid receptor antagonist. In conclusion, the chronic inhibition of FAAH generated an antidepressant effect, promoting neural progenitor proliferation and BDNF expression, while reducing adrenal gland weight and oxidative stress in mice under the CUS model., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 A. R. Tejeda-Martínez et al.)

Parkinson's disease (PD) is a neurodegenerative disorder, caused by the selective death of dopaminergic neurons in the substantia nigra pars compacta. β-caryophyllene (BCP) is a phytocannabinoid with several pharmacological properties, producing anti-inflammatory and antihypertensive effects. In addition, BCP protects dopaminergic neurons from neuronal death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), yet it remains unclear if this effect is due to its antioxidant activity. To assess whether this is the case, the effect of BCP on the expression and activity of NAD(P)H quinone oxidoreductase (NQO1) was evaluated in mice after the administration of MPTP. Male C57BL/6 J mice were divided into four groups, the first of which received saline solution i.p. in equivalent volume and served as a control group. The second group received MPTP. The second group received MPTP hydrochloride (5 mg/kg, i.p.) daily for seven consecutive days. The third group received BCP (10 mg/kg) for seven days, administered orally and finally, the fourth group received MPTP as described above and BCP for 7 days from the fourth day of MPTP administration. The results showed that BCP inhibits oxidative stress-induced cell death of dopaminergic neurons exposed to MPTP at the same time as it enhances the expression and enzymatic activity of NQO1. Also, the BCP treatment ameliorated motor dysfunction and protected the dopaminergic cells of the SNpc from damage induced by MPTP. Hence, BCP appears to achieve at least some of its antioxidant effects by augmenting NQO1 activity, which protects cells from MPTP toxicity. Accordingly, this phytocannabinoid may represent a promising pharmacological option to safeguard dopaminergic neurons and prevent the progression of PD., (Copyright © 2020. Published by Elsevier B.V.)

Aging is associated with detrimental cellular and cognitive changes, making it an important public health concern; yet, many of these changes may be influenced by nutritional interventions. The natural sesquiterpene β-caryophyllene (BCP) has anti-inflammatory and antioxidant effects that are mediated by cannabinoid type-2 receptor activation, and these actions promote neuroprotection in different animal models that involve a cognitive damage. Consequently, whether chronic administration of BCP might prevent the age-related cellular and cognitive damage in a model of aging induced by chronic d-galactose (GAL) consumption was assessed here. Male BALB/c mice were administered BCP (10 mg/kg, oral), GAL (300 mg/kg, intraperitoneal), or GAL+BCP, and long-term memory and cognitive flexibility were evaluated in the normal and the reverse phases of Morris water maze test. In addition, immunohistochemistry was performed on prefrontal and hippocampal brain slices to detect glial acidic fibrillary protein and DNA oxidation. Although GAL administration reduced cognitive flexibility ( P  = .0308), this functional damage was not reversed by administering BCP. However, GAL administration also elevated the total number of astrocytes and their interactions in the hippocampus, and increasing DNA oxidation in the prefrontal cortex. BCP administration impeded the rise in the total number of astrocytes ( P  = .0286) and the DNA oxidation ( P  = .0286) in mice that received GAL. Hence, although BCP did not improve cognitive flexibility, it did produce a neuroprotective effect at the molecular and cellular level in the GAL model of aging.

Neuropathic pain (NP) is associated with chronic hyperglycemia and emotional disorders such as depression in diabetic patients, complicating the course of treatment. Drugs currently used to treat NP have undesirable side effects, so research on other natural sources has been required. β -caryophyllene (BCP), a natural sesquiterpene found in some food condiments and considered an agonist to cannabinoid receptor type 2, could have potential therapeutic effects to treat conditions such as NP and emotional disorders. For this reason, we assessed whether BCP modulates nociception, anxiety, and depressive-like behavior in streptozotocin (STZ)-induced experimental diabetic BALB/c female mice. BCP was orally chronic administrated (10 mg/kg/60  μ L). Pain developed with STZ was evaluated with von Frey filament test, SMALGO ® , and hot plate test. Anxiety and depression-like behavior were assessed by marbles test, forced swim test, and tail suspension test. BCP significantly reduced glycemia in experimental diabetic mice. The pain was also mitigated by BCP administration. Depression-like behavior assessed with tail suspension test was attenuated with orally chronic BCP administration. Substance P and cytokines such as interleukin-1 β (IL-1 β ), tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) were also attenuated with BCP administration. NP was positively correlated with substance P and IL-6 and IL-1 β release. Our data using an orally chronic BCP administration in the STZ challenged mice to suggest that glycemia, diabetes-related NP, and depressive-like behavior could be prevented/reduced by dietary BCP.

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder characterised by balance problems, muscle rigidity, and slow movement due to low dopamine levels and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The endocannabinoid system is known to modulate the nigrostriatal pathway through endogenous ligands such as anandamide (AEA), which is hydrolysed by fatty acid amide hydrolase (FAAH). The purpose of this study was to increase AEA levels using FAAH inhibitor URB597 to evaluate the modulatory effect of AEA on dopaminergic neuronal death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)., Methods: Our study included 4 experimental groups (n = 6 mice per group): a control group receiving no treatment, a group receiving URB597 (0.2mg/kg) every 3 days for 30 days, a group treated with MPTP (30mg/kg) for 5 days, and a group receiving URB597 and subsequently MPTP injections. Three days after the last dose, we conducted a series of behavioural tests (beam test, pole test, and stride length test) to compare motor coordination between groups. We subsequently analysed immunoreactivity of dopaminergic cells and microglia in the SNpc and striatum., Results: Mice treated with URB597 plus MPTP were found to perform better on behavioural tests than mice receiving MPTP only. According to the immunohistochemistry study, mice receiving MPTP showed fewer dopaminergic cells and fibres in the SNpc and striatum. Animals treated with URB597 plus MPTP displayed increased tyrosine hydroxylase immunoreactivity compared to those treated with MPTP only. Regarding microglial immunoreactivity, the group receiving MPTP showed higher Iba1 immunoreactivity in the striatum and SNpc than did the group treated with URB597 plus MPTP., Conclusion: Our results show that URB597 exerts a protective effect since it inhibits dopaminergic neuronal death, decreases microglial immunoreactivity, and improves MPTP-induced motor alterations., (Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Different anandamide (AEA) transport inhibitors show antinociceptive and antiinflammatory effects in vivo , but due to their concomitant inhibition of fatty acid amide hydrolase (FAAH) and overall poor bioavailability, they cannot be used unequivocally to study the particular role of endocannabinoid (EC) transport in pathophysiological conditions in vivo . Here, the potent and selective endocannabinoid reuptake inhibitor WOBE437, which inhibits AEA and 2-arachidonoylglycerol (2-AG) transport, was tested for its oral bioavailability to the brain. WOBE437 is assumed to locally increase EC levels in tissues in which facilitated EC reuptake intermediates subsequent hydrolysis. Given the marked polypharmacology of ECs, we hypothesized to see differential effects on distinct EC receptors in animal models of acute and chronic pain/inflammation. In C57BL6/J male mice, WOBE437 was orally bioavailable with an estimated t max value of ≤20 min in plasma (C max ∼ 2000 pmol/mL after 50 mg/kg, p.o.) and brain (C max ∼ 500 pmol/g after 50 mg/kg, p.o.). WOBE437 was cleared from the brain after approximately 180 min. In addition, in BALB/c male mice, acute oral administration of WOBE437 (50 mg/kg) exhibited similar brain concentrations after 60 min and inhibited analgesia in the hot plate test in a cannabinoid CB1 receptor-dependent manner, without inducing catalepsy or affecting locomotion. WOBE437 significantly elevated AEA in the somatosensory cortex, while showing dose-dependent biphasic effects on 2-AG levels in plasma but no significant changes in N -acylethanolamines other than AEA in any of the tissues. In order to explore the presumed polypharmacology mediated via elevated EC levels, we tested this EC reuptake inhibitor in complete Freud's adjuvant induced monoarthritis in BALB/c mice as a model of chronic inflammation. Repetitive doses of WOBE437 (10 mg/kg, i.p.) attenuated allodynia and edema via cannabinoid CB2, CB1, and PPARγ receptors. The allodynia inhibition of WOBE437 treatment for 3 days was fully reversed by antagonists of any of the receptors. In the single dose treatment the CB2 and TRPV1 antagonists significantly blocked the effect of WOBE437. Overall, our results show the broad utility of WOBE437 for animal experimentation for both p.o. and i.p. administrations. Furthermore, the data indicate the possible involvement of EC reuptake/transport in pathophysiological processes related to pain and inflammation.

Guineensine is a dietary N-isobutylamide widely present in black and long pepper (Piper nigrum and Piper longum) previously shown to inhibit cellular endocannabinoid uptake. Given the role of endocannabinoids in inflammation and pain reduction, here we evaluated guineensine in mouse models of acute and inflammatory pain and endotoxemia. Significant dose-dependent anti-inflammatory effects (95.6 ± 3.1% inhibition of inflammatory pain at 2.5 mg/kg ip and 50.0 ± 15.9% inhibition of edema formation at 5 mg/kg ip) and acute analgesia (66.1 ± 28.1% inhibition at 5.0 mg/kg ip) were observed. Moreover, guineensine inhibited proinflammatory cytokine production in endotoxemia. Intriguingly, guineensine and LPS independently induced catalepsy, but in combination this effect was abolished. Both hypothermia and analgesia were blocked by the CB1 receptor inverse agonist rimonabant, but the pronounced hypolocomotion was CB1 receptor-independent. A subsequent screen of 45 CNS-related receptors, ion channels, and transporters revealed apparent interactions of guineensine with the dopamine transporter DAT, 5HT2A, and sigma receptors, uncovering its prospective polypharmacology. The described potent pharmacological effects of guineensine might relate to the reported anti-inflammatory effects of pepper.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Although the causes of PD are not understood, evidence suggests that its pathogenesis is associated with oxidative stress and inflammation. Recent studies have suggested a protective role of the cannabinoid signalling system in PD. β-caryophyllene (BCP) is a natural bicyclic sesquiterpene that is an agonist of the cannabinoid type 2 receptor (CB2R). Previous studies have suggested that BCP exerts prophylactic and/or curative effects against inflammatory bowel disease through its antioxidative and/or anti-inflammatory action. The present study describes the neuroprotective effects of BCP in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced murine model of PD, and we report the results of our investigation of its neuroprotective mechanism in neurons and glial cells. In the murine model, BCP pretreatment ameliorated motor dysfunction, protected against dopaminergic neuronal losses in the SN and striatum, and alleviated MPTP-induced glia activation. Additionally, BCP inhibited the levels of inflammatory cytokines in the nigrostriatal system. The observed neuroprotection and inhibited glia activation were reversed upon treatment with the CB2R selective antagonist AM630, confirming the involvement of the CB2R. These results indicate that BCP acts via multiple neuroprotective mechanisms in our murine model and suggest that BCP may be viewed as a potential treatment and/or preventative agent for PD., Competing Interests: The authors declare no conflict of interest.

Background: Estimation of the neurological prognosis of infants suffering from perinatal asphyxia and signs of hypoxic-ischemic encephalopathy is of great clinical importance; however, it remains difficult to satisfactorily assess these signs with current standard medical practices. Prognoses are typically based on data obtained from clinical examinations and neurological tests, such as electroencephalography (EEG) and neuroimaging, but their sensitivities and specificities are far from optimal, and they do not always reliably predict future neurological sequelae. In an attempt to improve prognostic estimates, neurological research envisaged various biochemical markers detectable in the umbilical cord blood of newborns (NB). Few studies examining these biochemical factors in the whole blood of newborns exist. Thus, the aim of this study was to determine the expression and concentrations of proinflammatory cytokines (TNF-α, IL-1β and IL-6) and specific CNS enzymes (S-100 and enolase) in infants with perinatal asphyxia. These data were compared between the affected infants and controls and were related to the degree of HIE to determine their utilities as biochemical markers for early diagnosis and prognosis., Methods: The levels of the proinflammatory cytokines and enzymes were measured by enzyme-linked immunosorbent assay (ELISA) and Reverse Transcription polymerase chain reaction (RT-PCR)., Results: The expression and serum levels of the proinflammatory cytokines, enolase and S-100 were significantly increased in the children with asphyxia compared with the controls., Conclusion: The role of cytokines after hypoxic-ischemic insult has been determined in studies of transgenic mice that support the use of these molecules as candidate biomarkers. Similarly, S-100 and enolase are considered promising candidates because these markers have been correlated with tissue damage in different experimental models., (Copyright © 2016. Published by Elsevier B.V.)

Purpose. The aim of this study was to assess the effect of melatonin in the proliferation of neural progenitors, melatonin concentration, and antiapoptotic proteins in the hippocampus of adult mice exposed to 96 h REM sleep deprivation (REMSD) prophylactic administration of melatonin for 14 days. Material and Methods. Five groups of Balb/C mice were used: (1) control, (2) REMSD, (3) melatonin (10 mg/kg) plus REMSD, (4) melatonin and intraperitoneal luzindole (once a day at 5 mg/kg) plus REMSD, and (5) luzindole plus REMSD. To measure melatonin content in hippocampal tissue we used HPLC. Bcl-2 and Bcl-xL proteins were measured by Western Blot and neurogenesis was determined by injecting 5-bromo-2-deoxyuridine (BrdU) and BrdU/nestin expressing cells in the subgranular zone of the dentate gyrus were quantified by epifluorescence. Results. The melatonin-treated REMSD group showed an increased neural precursor in 44% with respect to the REMSD group and in 28% when contrasted with the control group (P < 0.021). The melatonin-treated REMSD group also showed the highest expression of Bcl-2 and Bcl-xL as compared to the rest of the groups. Conclusion. The exogenous administration of melatonin restores the tissue levels of sleep-deprived group and appears to be an efficient neuroprotective agent against the deleterious effects of REMSD.

Excitotoxicity and neuroinflammation are strongly linked to the progressions of neurodegenerative diseases and acute injuries in the brain. Systematic administration of kainic acid (KA) in rodents causes severe limbic seizures, selective neuronal loss, and neuroinflammation in the hippocampus that are attributed to the excitotoxic process. Our previous report demonstrated the antioxidant and neuroprotective effects of pirfenidone (PFD) after the seizure onset induced by KA intraperitoneal injection. However, the aim of the present study is to analyze whether PFD has anti-inflammatory properties. Thus, pubescent male Wistar rats (30 days old) were exposed to 12 mg/Kg of KA, and the experimental group received KA and a single dose of 325 mg/Kg PFD in an orogastric tube at 90 min after KA exposure. The PFD treatment dramatically reduces the microglial activation observed by isolectin B4 staining and major histocompatibility complex II immunohistochemistry. We also determined that the messenger RNA of inducible nitric oxide synthase was downregulated by PFD treatment as measured 6 h after the KA injection. Our results indicate that the mechanism of neuroprotection after PFD treatment may include a decreased expression of the inducible nitric oxide synthase and reduced microglial activation. These findings suggest that PFD is a potentially useful strategy of the treatment for acute or chronic neurodegenerative diseases.

Systemic administration of kainic acid (KA) in rodents triggers limbic seizures following selective neuronal loss in the hippocampus attributed to the excitotoxic process. Lipid peroxidation products, such as 4-hydroxynonenal, are produced by oxidative stress and are present on the hippocampus, which contribute to neuronal death in the KA excitotoxicity model. Several antioxidants are neuroprotective agents. The aim of the present study was to analyse whether pirfenidone (PFD, 5-methyl-1-phenyl-2-(1H)-pyridone), an antioxidant drug, protects the neurons in the hippocampus of pubescent rats administered with KA. We evaluated the neuroprotective effect of PFD by quantifying the surviving neurons under hematoxilin-eosin staining after using three different doses of 100, 250, and 325 mg/kg administered via an orogastric tube 90 min after KA intraperitoneal injection (12 mg/kg). Only 325 mg/kg of PFD-attenuated neuronal loss in the hippocampal areas cornu ammonis field 1 (CA1) and cornu ammonis field 3 (CA3c) was observed; therefore, this dose was used in our subsequent studies. Later, we established that PFD reduces neuronal degeneration using Fluoro-Jade B stain in the CA3c but not in the CA1, and PFD reduces the presence of 4-hydroxynonenal, a lipid peroxidation product, in the CA3 by tissue immunohistochemistry. We concluded that only a single 325 mg/kg PFD dose had a neuroprotective effect after KA brain injury. This treatment may be advantageous because adequate pharmacological therapy with PFD can be developed to protect the neuron even after an acute neuronal disorder such as seizures or hypoxic/ischemic damage.

High-content screening led to the identification of the N-isobutylamide guineensine from Piper nigrum as novel nanomolar inhibitor (EC50=290nM) of cellular uptake of the endocannabinoid anandamide (AEA). Noteworthy, guineensine did not inhibit endocannabinoid degrading enzymes fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) nor interact with cannabinoid receptors or fatty acid binding protein 5 (FABP5), a major cytoplasmic AEA carrier. Activity-based protein profiling showed no inhibition of serine hydrolases. Guineensine also inhibited the cellular uptake of 2-arachidonoylglycerol (2-AG). Preliminary structure-activity relationships between natural guineensine analogs indicate the importance of the alkyl chain length interconnecting the pharmacophoric isobutylamide and benzodioxol moieties for AEA cellular uptake inhibition. Guineensine dose-dependently induced cannabimimetic effects in BALB/c mice shown by strong catalepsy, hypothermia, reduced locomotion and analgesia. The catalepsy and analgesia were blocked by the CB1 receptor antagonist rimonabant (SR141716A). Guineensine is a novel plant natural product which specifically inhibits endocannabinoid uptake in different cell lines independent of FAAH. Its scaffold may be useful to identify yet unknown targets involved in endocannabinoid transport., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction: Nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout several brain regions. Formation of the α4β2 and α7 subtypes in particular is involved in the organisation of different types of memory. Furthermore, due to their location, these receptors can control the release of various types of neurotransmitters and contribute to synaptic plasticity., Methods: Rats were divided into three groups, an experimental group (E), a sham-operated group, (S) and an intact group (T). In group E, stereotactic guidance was used to induce a chemical lesion with 1 μ/μL of 5,7-dihydroxytryptamine (5,7-DHT) in the anteroventral part of the dorsal raphe nucleus (DRN). In the sham-operated group (S), animals underwent surgery including delivery of the same excipient solution to the same site. The intact group (T) received no treatment whatsoever. Twenty days after surgery, animals in all groups were euthanised by decapitation to evaluate the expression of α4 and α7 nAChRs by means of molecular biology techniques., Results: 5-HT denervation of the rat PFC differentially modified the expression of α4 and α7 receptors: while α4 receptor expression increased, α7 expression decreased., Conclusion: Expression differences observed between the two subtypes may be due to their separate locations. The α4 subtype is found in postsynaptic locations and may be related to adaptive changes in postsynaptic cells, while the location of α7 is presynaptic. This explains why the lesion and the elimination of 5-HT fibres in the CPF would cause a decrease in α7 expression., (Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.)

Glutamic acid (Glu) is the major excitatory neurotransmitter in the central nervous system, and interacts with two classes of receptor: metabotropic and ionotropic receptors. Ionotropic receptors are divided according to the affinity of their specific agonists: Nmethyl- D-aspartate (NMDA), amino acid-3-hydroxy-5-methyl-4-isoxazole acid (AMPA) and kainic acid (KA). NMDA receptors (NMDA-R) are macromolecular structures that are formed by different combinations of subunits: NMDAR1 (NR1), NMDAR2 (NR2) and NMDAR3 (NR3). The study of this receptor has aroused great interest, partly due to its role in synaptic plasticity but mainly because of its permeability to the Ca(2+) ion. This review examines the molecular composition of NMDA-R and the variants of NR1 subunit editing in association with NR2 subunit dimers, which form the main components of this receptor. Their composition, structure, function and distinct temporal and spatial expression patterns demonstrate the versatility and diversity of functionally different isoforms of NR1 subunits and the various pharmacological properties of the NR2 subunit. Finally, the involvement of NMDA-R in the excitotoxicity phenomenon, as well as, its expression changes under these conditions as neuronal response are also discussed.

Cognitive impairment or its recovery has been associated with the absence or reestablishment of estrogenic actions in the central nervous system of female experimental animals or women. It has been proposed that these cognitive phenomena are related to estrogen-mediated modulatory activity of synaptic transmission in brain structures involved in cognitive functions. In the present work a morphological study was conducted in adult female ovariectomized rats to evaluate estradiol-dependent dendritic spine sprouting in hippocampal pyramidal neurons, and changes in the presynaptic marker synaptophysin. Three or ten days after estradiol treatment (10 μg/day, twice) in the ovariectomized rats, a significant increase of synaptophysin was observed, which was coincident with a significant higher numerical density of thin (22%), stubby (36%), mushroom (47%) and double spines (125%), at day 3, without significant changes of spine density at day 10, after treatment. These results may be interpreted as evidence of pre- and postsynaptic plastic events that may be involved in the modulation of cognitive-related behavioral performance after estrogen replacement therapy., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Introduction: In cirrhosis some toxic substances accumulate in brain and modify the expression of several neuronal receptors. Thus, the use of medicinal plants such as Rosmarinus officinalis L. has been proposed in several pathologies due to its hepatoprotective, antioxidant and neuroprotective activity. In this study we evaluated the expression of the subunits NR1, NR2A and NR2B of the glutamate receptor in rat prefrontal cortex in a model of hepatic damage induced with carbon tetrachloride after a treatment with Rosmarinus officinalis L., Methods: We used a total of 24 male Wistar rats weighing 80-90 g. body weight. We formed three study groups: control group (C) without a treatment, carbon tetrachloride group (CC14), and CC14 group plus Rosmarinus officinalis L (CCl4+ROM; 1.5 g/kg of extract orally)., Results: The expression of the NR1, NR2A and NR2B subunits in cirrhotic animals increased compared to the control group, however treatment with Rosmarinus officinalis L. was able to reduce this expression to normal levels compared with CC14 and CCl4+ROM groups. These results could be due to an improvement in hepatic function., Conclusion: Treatment with extract of Rosmarinus officinalis L. in cirrhotic animals modifies the expression of subunits of the NMDA receptor due to an improvement in hepatocellular function in the presence of antioxidant compounds and flavonoids., (Copyright © 2011 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.)

Introduction: To review the physiology of the glutamate receptor subunits such as N-methyl-D-aspartate (NMDA)., Development: Glutamic acid (Glu) is the major excitatory neurotransmitter in the central nervous system which interacts with two types classified into two types: metabotropic and ionotropic. Ionotropic receptors are classified according to the affinity of their specific agonists: N-methyl-D-aspartate (NMDA), α-amino acid-3-hydroxy-5-methyl-4-isoxazole (AMPA) and kainic acid (KA). NMDA receptors are macromolecular structures that are formed by different combinations of subunits, NMDAR1 (NR1), NMDAR2 (NR2) and NMDAR3 (NR3), Conclusions: The study of this receptor has been of great interest due to its role in synaptic plasticity, but mainly due to the permeability it has to Ca(++) ion. This review examines the molecular composition of NMDA receptor and the variants of NR1 subunit edition in association with NR2 subunit dimer, the main form of this receptor. The composition, structure and function and their distinct expression patterns in both time and space, has shown the versatility and diversity of functionally different isoforms of the NR1 subunit and various pharmacological properties of the NR2 subunit., (Copyright © 2011 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.)

Hypoxia-inducible factor-1 alpha (HIF-1α) is a master transcription factor that regulates the response to hypoxia and ischemia and induces the expression of various genes, including vascular endothelial growth factor (VEGF) and erythropoietin (EPO). This study shows the systemic response of increased HIF-1α, EPO, and VEGF mRNA and protein. In addition, VEGF expression was increased in neurons and over-expressed in glial cells in a model of neuroexcitotoxicity in the hippocampus, in which rats were neonatally exposed to high glutamate concentrations. Simultaneous increases in HIF-1α, EPO and VEGF mRNA in peritoneal macrophages were also observed. Our study is consistent with the hypothesis that these genes exert a protective effect in response to neurotoxicity., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objectives: HIF-1 alpha (hypoxia-inducible factor-1 alpha) mediates the responses of mammalian cells to hypoxia/ischemia by inducing the expression of adaptive gene products (e.g., vascular endothelial growth factor (VEGF) and erythropoietin (EPO)). Persistent pulmonary hypertension of the newborn (PPHN) and cyanotic congenital heart disease (CCHD) are common neonatal diseases considered as paradigms of hypoxemia. Since the expression HIF-1 alpha, VEGF and EPO in newborns diagnosed with these diseases has yet to be studied, we set out to define the expression of these genes in peripheral blood from newborn infants diagnosed with PPHN and CCHD., Design and Methods: The mRNA transcripts encoding HIF-1 alpha, VEGF and EPO were measured by RT-PCR in healthy newborn infants and infants diagnosed with PPHN and CCHD., Results: An important increase in HIF-1 alpha expression was observed in both pathological conditions, accompanied by significant increases in VEGF and EPO expression when compared to healthy infants., Conclusions: HIF-1 alpha mRNA expression increases in newborn infants with PPHN or CCHD, as does the expression of its target genes VEGF and EPO., ((c) 2009 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Monosodium glutamate (MSG) administered to neonatal rats during the first week of life induces a neurodegenerative process, which is represented by several neurochemical alterations of surviving neurons in the brain, where signalling mediated by GABA is essential for excitation threshold maintenance. GABA-positive cells, [(3)H]-GABA uptake, expression of mRNA for GABA transporters GAT-1 and GAT-3, and expression of mRNA and protein for two main GABA synthesizing enzymes, GAD(65) and GAD(67), were measured at postnatal day 60, after MSG neonatal treatment in two critical cerebral regions, cerebral cortex and hippocampus. GABA-positive cells, [(3)H]-GABA uptake, and mRNA for GAT-1, were significantly diminished in both cerebral regions. In the cerebral cortex, MSG neonatal treatment also decreased the mRNA for GAD(67) and protein for GAD(65) without significant changes in its corresponding protein and mRNA, respectively. Moreover in the hippocampus, mRNA and protein for GAD(65) were increased, whilst GAD(67) protein was elevated without significant changes in its mRNA. Clearly these results confirm the GABA cells loss after MSG neonatal treatment in both cerebral regions. As most of the GABAergic markers measured were reduced in the cerebral cortex, this region seems to be more sensitive than hippocampus, where interesting compensatory changes over GAD(65) and GAD(67) proteins were observed. However, it is possible that others neurotransmission systems are also compensating the GABA-positive cells loss in the cerebral cortex, and that elevations in two main forms of GAD in the hippocampus are not sufficient to maintain the neural excitation threshold for this region.

Overactivation of NMDA-Rs may mediate excitotoxic cell death associated with epileptic seizures, and hypoxic-ischemic conditions. We assessed whether repeated subcutaneous administration of l-glutamate to neonatal rats affects the subunit composition of NMDA-Rs. Accordingly, cortical and hippocampal tissue from 14-day-old rats was analyzed by Western blotting and RT-PCR to quantify the protein and mRNA expression of different NMDA-R subunits. In addition, tissue sections were Nissl stained to assess the cell damage in this tissue. Early exposure of neonatal rats to L-glutamate differentially affects the expression of mRNA transcripts for NMDA-R subunits in the cerebral cortex and hippocampus. In the cerebral cortex, a decrease in NR2B subunit mRNA expression was observed, as well as a loss of NR1 and NR2A protein. By contrast, neonatal L-glutamate administration augmented the transcripts encoding the NR1, NR2B, and NR2C subunits in the hippocampal formation. The expression of mRNA encoding the NR2A subunit was not affected by neonatal L-glutamate administration in either of the brain regions examined. This differential expression of NMDA-R subunits following neonatal exposure to L-glutamate may represent an adaptive response of the glutamate receptors to overactivation in order to reduce the effect of high L-glutamate during the early period of life when the animal is more vulnerable to excitotoxicity.

Pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6 rises significantly during neuronal damage and activate the signaling p38 MAPK pathway, which is involved in the apoptotic (AP) neuronal death. Systemic administration of glutamate as monosodium salt (MSG) to newborn animals induces neuronal death, however whether neurons die by AP or necrosis through MAPK p38 pathway activation it is unknown. In this study, TNF-alpha, IL-1beta and IL-6 expression levels, AP neuronal death and cellular type that produces TNF-alpha was also identified in the cerebral cortex (CC) and striatum (St) of rats at 8, 10, and 14 days of age after neonatal exposure to MSG. TNF-alpha production and AP neuronal death was significantly increased in the CC at PD8-10, and in the St in all ages studied by excitotoxicity effect induced with MSG. This effect was completely inhibited by SB203580 (p38 inhibitor) in both regions studied. TNF-alpha, IL-1beta and IL-6 RNAm increased after MSG administration, whereas SB203580 did not modify their expression. These data indicates that neuronal death induced by excitotoxicity appears to be mediated through p38 signaling pathway activated by TNF-alpha and their inhibition may have an important neuroprotective role as part of anti-inflammatory therapeutic strategy.

Vascular changes after acute spinal cord trauma are important factors that predispose quadriplegia, in most cases irreversible. Repair of the spinal blood flow helps the spinal cord recovery. The average time to arrive and perform surgery is 3 h in most cases. It is important to determine the critical ischemia time in order to offer better functional prognosis. A spinal cord section and vascular clamping of the spinal anterior artery at C5-C6 model was used to determine critical ischemia time. The objective was to establish a critical ischemia time in a model of acute spinal cord section. Four groups of dogs were used, anterior approach and vascular clamp of spinal anterior artery with 1, 2, 3, and 4 h of ischemia and posterior hemisection of spinal cord at C5-C6 was performed. Clinical evaluation was made during 12 weeks and morphological evaluation at the end of this period. We obtained a maximal neurological coordination at 23 days average. Two cases showed sequels of right upper limb paresis at 1 and 3 ischemia hours. There was nerve conduction delay of 56% at 3 h of ischemia. Morphological examination showed 25% of damaged area. The VIII and IX Rexed's laminae were the most affected. The critical ischemia time was 3 h. Dogs with 4 h did not exhibit any recovery.

Sparteine is a quinolizidine alkaloid (QA) produced by Lupine species that has generated much interest due to its anti-hypertensive, anti-pyretic, and anti-inflammatory properties. In the nervous system, sparteine has been shown to display anti-cholinergic and depressive activity, although how sparteine exerts its toxic effects in the brain remains unclear. We have addressed this issue by administering subcutaneous injections of sparteine (25 mg/kg of body weight) to rats on postnatal days 1 and 3, and then examining the expression of the muscarinic acetylcholine receptor (mAChR) subunits m1-m4 in the brains of the neonatal rats 14-60 days later. Administration of sparteine to neonatal rats caused neuronal damage in the cerebral motor cortex accompanied by transient changes in the expression of m1-m4 mAChR subunits as revealed by both RT-PCR and Western blotting. This effect could be prevented by pre-treatment with atropine (10 mg/kg) 1 h prior to the injection of sparteine, suggesting that the cytotoxic activity of sparteine is mediated through mAChRs.

Excitotoxic neuronal death occurs through the activation of NMDA and non-NMDA glutamatergic receptors in the CNS. Glutamate also induces strong activation of p38 and indeed, cell death can be prevented by inhibitors of the p38 pathway. Furthermore, intracellular signals generated by AMPA receptors activate the stress sensitive MAP kinases implicated in apoptotic neuronal death, such as JNK and p38. To investigate the relationship between these elements, we have used immunohistochemistry to analyze the expression of GluR2 in the cerebral cortex of postnatal rats (postnatal Day [PD] 8 and 14) after administering them with monosodium glutamate (MSG; 4 mg/g body weight on PD1, 3, 5, and 7). Similarly, the expression of REST, Fas-L and Bcl-2 mRNA transcripts in animals exposed to a p38 inhibitor, SB203580 (0.42 microg/g body weight, administered subcutaneously) was determined by reverse transcriptase-PCR. The enhanced GluR2-expression in the cerebral cortex at PD8 and the down regulation of this receptor at PD14 was correlated with neuronal damage induced by excitotoxicity. In addition, the enhanced expression of REST at PD8 and PD14 suggests that the induction of REST transcription contributes to glutamate-induced excitotoxic neurodegeneration, possibly by modulating GluR2 expression. Fas-L and Bcl-2 over expression at PD8 and their subsequent down regulation at PD14 also suggests that Fas-L could be the direct effector of apoptosis in the cerebral cortex. On the other hand, the presence of Bcl-2 at PD8 could attenuate certain survival signals in neurons under these neurotoxic conditions. Thus, a change in glutamate receptor composition, and enhanced Fas-L and Bcl-2 expression, coupled with activation of the p38/SAPK pathway appear to be events involved in the neuronal apoptosis induced under neurotoxic conditions.

This paper served to evaluate the expression levels of subunits NR1, NR2A and NR2C which are implicated in neuronal plasticity events. A 50% (right half) 4 mm longitudinal resection of the spinal cord was done at the C5-C6 level with preservation of the anterior spinal artery. This was effected in a dog model after either a homologous transplant or a pure spinal cord section. In this study we used two groups of dogs with four individuals each, as well as a control group. The transplant group (n=4) was analyzed at days 3 and 28 post surgery. The section group (n=4) was also analyzed at days 3 and 28 post op. All three groups (transplant, section and control) were evaluated as to the subunit expression in each of the segments corresponding to the transplanted or sectioned sites, the site contralateral to the transplanted or sectioned sites at levels half a centimeter both proximal and distal to the site of transplant and section. The results showed a variety of changes in each of the subunits depending on the group, the segment and the time of evaluation (acute versus chronic). This could be closely related to mechanisms which participate in regeneration and functional recuperation.

The proinflammatory cytokines TNF-alpha, IL-1beta, and IL-6 rise during neuronal damage and activate the apoptotic mitogen-activated protein kinase p38. We studied apoptosis, the levels of TNF-alpha, IL-1beta, and IL-6, and the cell type producing TNF-alpha in rats at 8, 10, and 14 days of age after neonatal exposure to glutamate, which induces neuronal damage. TNF-alpha production was significantly increased by glutamate, but inhibited by SB203580 (a p38 inhibitor). TNF-alpha, IL-1beta, and IL-6 mRNA levels increased, but SB203580 did not modify their expression. Thus, the p38 signaling pathway influences the expression of inflammatory genes and its inhibition may offer anti-inflammatory therapy.

Monosodium glutamate (MSG) was administered subcutaneously to male neonate rats, and the effects on N-methyl-D-asparatate (NMDA) subunit receptor types NR2C and NR2D from different brain regions were studied. A semi-quantitative reverse transcription-polymerase chain reaction was used to measure NR2C and NR2D expression levels in the cerebral cortex, hippocampus and striatum. MSG treatment (4 mg/g body weight, on postnatal days 1, 3, 5, and 7) produced an important increase of NR2C and NR2D subunit gene expression levels in the hippocampus and striatum of adults rats. No change was observed in the cerebral cortex. We propose that an early excessive activation of glutamate receptors could modify NMDA subunit expression and its structural composition on postnatal development. This, as part of a compensatory response by an altered neuronal circuitry, mainly in the hippocampus and striatum, suggests that the NMDA receptor could be a determinant factor to modulate the dendritic arrangement and the synaptogenesis.