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Background: COVID-19 vaccination has become a pivotal global strategy in managing the pandemic. Despite COVID-19 no longer being classified as a Public Health Emergency of International Concern, the virus continues affecting people worldwide. This study aimed to evaluate risk factors and vaccine effectiveness on COVID-19-related hospital admissions, intensive care unit (ICU) admission and mortality within the Andalusian population throughout the pandemic., Methods: From March 2020 to April 2022, 671,229 individuals, out of 9,283,485 with electronic health records in Andalusia, experienced SARS-CoV-2 infection and were included in the analysis. Data on demographics, medical history, vaccine administration, and hospitalization records were collected. Associations between medical history, COVID-19 vaccines, and COVID-19 outcomes were assessed., Results: Our study identified 48,196 hospital admissions, 5,057 ICU admissions, and 11,289 deaths linked to COVID-19. Age, male sex, and chronic diseases were identified as risk factors, while the COVID-19 vaccine demonstrated protective effects, although with reduced effectiveness during the omicron variant period. However, the risk for these outcomes increased over time after receiving the last vaccine dose, particularly after six months, especially among those aged 60 or older., Conclusion: The global health challenge of COVID-19 persists, marked by emerging variants with higher virulence and severity, particularly among the unvaccinated and those beyond six months post-vaccination, especially those aged 60 and above. These findings highlight the need for robust surveillance systems targeting new variants and administering booster doses, particularly for individuals aged 60 or older with underlying health conditions, to mitigate the global burden of COVID-19., Competing Interests: Declarations. Ethics Approval: The Clinical Research Ethics Committee of Andalusia (CCEIBA in Spanish) approved the research protocol for this study (010722 (Act 07/22), FPS-VAC-2022-01). This study was an epidemiological study including anonymized data, and the analysis was performed in Andalusian servers of the public healthcare system, and was not required to obtain informed consent from the patients. We conducted this study in accordance with the Declaration of Helsinki and the Spanish Law on the Protection of Personal Data and Guarantee of Digital Rights (3/2018 of December 5). Consent to Participate: Not applicable. Competing Interests: The authors have no competing interests to declare that are relevant to the content of this article., (© 2024. The Author(s).)

Glioblastoma (GBM) is an aggressive form of cancer affecting the Central Nervous System (CNS) of thousands of people every year. Redox alterations have been shown to play a key role in the development and progression of these tumors as Reactive Oxygen Species (ROS) formation is involved in the modulation of several signaling pathways, transcription factors, and cytokine formation. The second-generation oral alkylating agent temozolomide (TMZ) is the first-line chemotherapeutic drug used to treat of GBM, though patients often develop primary and secondary resistance, reducing its efficacy. Antioxidants represent promising and potential coadjutant agents as they can reduce excessive ROS formation derived from chemo- and radiotherapy, while decreasing pharmacological resistance. S-allyl-cysteine (SAC) has been shown to inhibit the proliferation of several types of cancer cells, though its precise antiproliferative mechanisms remain poorly investigated. To date, SAC effects have been poorly explored in GBM cells. Here, we investigated the effects of SAC in vitro, either alone or in combination with TMZ, on several toxic and modulatory endpoints-including oxidative stress markers and transcriptional regulation-in two glioblastoma cell lines from rats, RG2 and C6, to elucidate some of the biochemical and cellular mechanisms underlying its antiproliferative properties. SAC (1-750 µM) decreased cell viability in both cell lines in a concentration-dependent manner, although C6 cells were more resistant to SAC at several of the tested concentrations. TMZ also produced a concentration-dependent effect, decreasing cell viability of both cell lines. In combination, SAC (1 µM or 100 µM) and TMZ (500 µM) enhanced the effects of each other. SAC also augmented the lipoperoxidative effect of TMZ and reduced cell antioxidant resistance in both cell lines by decreasing the TMZ-induced increase in the GSH/GSSG ratio. In RG2 and C6 cells, SAC per se had no effect on Nrf2/ARE binding activity, while in RG2 cells TMZ and the combination of SAC + TMZ decreased this activity. Our results demonstrate that SAC, alone or in combination with TMZ, exerts antitumor effects mediated by regulatory mechanisms of redox activity responses. SAC is also a safe drug for testing in other models as it produces non-toxic effects in primary astrocytes. Combined, these effects suggest that SAC affords antioxidant properties and potential antitumor efficacy against GBM., (© 2024. The Author(s).)

Neurodegenerative disorders are chronic brain diseases that affect humans worldwide. Although many different factors are thought to be involved in the pathogenesis of these disorders, alterations in several key elements such as the ubiquitin-proteasome system (UPS), the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, and the endocannabinoid system (ECS or endocannabinoidome) have been implicated in their etiology. Impairment of these elements has been linked to the origin and progression of neurodegenerative disorders, while their potentiation is thought to promote neuronal survival and overall neuroprotection, as proved with several experimental models. These key neuroprotective pathways can interact and indirectly activate each other. In this review, we summarize the neuroprotective potential of the UPS, ECS, and Nrf2 signaling, both separately and combined, pinpointing their role as a potential therapeutic approach against several hallmarks of neurodegeneration., (© 2024. The Author(s).)

Inhibition of enzymes responsible for endocannabinoid hydrolysis represents an invaluable emerging tool for the potential treatment of neurodegenerative disorders. Monoacylglycerol lipase (MAGL) is the enzyme responsible for degrading 2-arachydonoylglycerol (2-AG), the most abundant endocannabinoid in the central nervous system (CNS). Here, we tested the effects of the selective MAGL inhibitor JZL184 on the 3-nitropropinic acid (3-NP)-induced short-term loss of mitochondrial reductive capacity/viability and oxidative damage in rat brain synaptosomal/mitochondrial fractions and cortical slices. In synaptosomes, while 3-NP decreased mitochondrial function and increased lipid peroxidation, JZL184 attenuated both markers. The protective effects evoked by JZL184 on the 3-NP-induced mitochondrial dysfunction were primarily mediated by activation of cannabinoid receptor 2 (CB2R), as evidenced by their inhibition by the selective CB2R inverse agonist JTE907. The cannabinoid receptor 1 (CB1R) also participated in this effect in a lesser extent, as evidenced by the CB1R antagonist/inverse agonist AM281. In contrast, activation of CB1R, but not CB2R, was responsible for the protective effects of JZL184 on the 3-NP-iduced lipid peroxidation. Protective effects of JZL184 were confirmed in other toxic models involving excitotoxicity and oxidative damage as internal controls. In cortical slices, JZL184 ameliorated the 3-NP-induced loss of mitochondrial function, the increase in lipid peroxidation, and the inhibition of succinate dehydrogenase (mitochondrial complex II) activity, and these effects were independent on CB1R and CB2R, as evidenced by the lack of effects of AM281 and JTE907, respectively. Our novel results provide experimental evidence that the differential protective effects exerted by JZL184 on the early toxic effects induced by 3-NP in brain synaptosomes and cortical slices involve MAGL inhibition, and possibly the subsequent accumulation of 2-AG. These effects involve pro-energetic and redox modulatory mechanisms that may be either dependent or independent of cannabinoid receptors' activation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The potential treatment of neurodegenerative disorders requires the development of novel pharmacological strategies at the experimental level, such as the endocannabinoid-based therapies. The effects of oleamide (OEA), a fatty acid primary amide with activity on cannabinoid receptors, was tested against mitochondrial toxicity induced by the electron transport chain complex II inhibitor, 3-nitropropionic acid (3-NP), in rat cortical slices. OEA prevented the 3-NP-induced loss of mitochondrial function/cell viability at a concentration range of 5 nM-25 µM, and this protective effect was observed only when the amide was administered as pretreatment, but not as post-treatment. The preservation of mitochondrial function/cell viability induced by OEA in the toxic model induced by 3-NP was lost when the slices were pre-incubated with the cannabinoid receptor 1 (CB1R) selective inhibitor, AM281, or the cannabinoid receptor 2 (CB2R) selective inhibitor, JTE-907. The 3-NP-induced inhibition of succinate dehydrogenase (mitochondrial Complex II) activity was recovered by 25 nM OEA. The amide also prevented the increased lipid peroxidation and the changes in reduced/oxidized glutathione (GSH/GSSG) ratio induced by 3-NP. The cell damage induced by 3-NP, assessed as incorporation of cellular propidium iodide, was mitigated by OEA. Our novel findings suggest that the neuroprotective properties displayed by OEA during the early stages of damage to cortical cells involve the converging activation of CB1R and CB2R and the increase in antioxidant activity, which combined may emerge from the preservation of the functional integrity of mitochondria., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Thallium (Tl + ) is a heavy metal that causes toxicity in several organs, including the brain. Its cytotoxic profile, combined with its affinity for tumor cells when used as a radioligand for labeling these cells, suggests its potential use as antitumor therapy. In this study, glioblastoma cell lines C6 (from rat) and U373 (from human) were exposed to increased concentrations of thallium(I) acetate (5, 10, 50, 100, or 200 µM) and several toxic endpoints were evaluated, including loss of confluence and morphological changes, loss of cell viability, changes in cell cycle, and apoptosis. Tl + was detected in cells exposed to thallium(I) acetate, demonstrating efficient uptake mechanism. Confluence in both cell lines decreased in a concentration-dependent manner (50-200 µM), while morphological changes (cell shrinkage and decreased cell volume) were more evident at exposures to higher Tl + concentrations. For both parameters, the effects of Tl + were more prominent in C6 cells compared to U373 cells. The same trend was observed for cell viability, with Tl + affecting this parameter in C6 cells at low concentrations, whereas U373 cells showed greater resistance, with significant changes observed only at the higher concentrations. C6 and U373 cells treated with Tl + also showed morphological characteristics corresponding to apoptosis. The cytotoxic effects of Tl + were also assessed in neural and astrocytic primary cultures from the whole rat brain. Primary neural and astrocytic cultures were less sensitive than C6 and U373 cells, showing changes in cell viability at 50 and 100 µM concentrations, respectively. Cell cycle in both brain tumor cell lines was altered by Tl + in G1/G2 and S phases. In addition, when combined with temozolamide (500 µM), Tl + elicited cell cycle alterations, increasing SubG1 population. Combined, our novel results characterize and validate the cytotoxic and antiproliferative effects of Tl + in glioblastoma cells., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The development, at the experimental level, of therapeutic strategies based on natural products to attenuate neurological alterations in degenerative disorders has gained attention. Antioxidant molecules exhibit both anti-inflammatory and neuroprotective properties. Alpha-mangostin (α-Man) is a natural xanthonoid isolated from the mangosteen tree with demonstrated antioxidant and cytoprotective properties. In this study, we investigated the antioxidant and protective properties of α-Man, both ex vivo and in vivo. We assessed the mitochondrial reductant capacity and oxidative damage to lipids in rat cortical slices, and several endpoints characteristic of physiological stress in the nematode, Caenorhabditis elegans (C. elegans), upon exposure to the parkinsonian neurotoxin, 6-hydroxydopamine (6-OHDA). In rat cortical slices, α-Man (25 and 50 µM) reduced the 6-OHDA (100 µM)-induced oxidative damage to lipid levels, but failed to reverse loss in cell viability. In wild-type (N2) C. elegans, α-Man (5-100 µM) protected against 6-OHDA (25 mM)-induced decrease in survival when administered either as pre- or post-treatment. Protective effects of α-Man were also observed on survival in the VC1772 strain (skn-1 KO - ) exposed to 6-OHDA, though the extent of the protection was lesser than in the wild-type N2 strain. However, α-Man (5-50 µM) failed to attenuate the 6-OHDA-induced motor alterations in the N2 strain. The loss of lifespan induced by 6-OHDA in the N2 strain was fully reversed by high concentrations of α-Man. In addition, while 6-OHDA decreased the expression of glutathione S-transferase in the CL2166 C. elegans strain, α-Man preserved and stimulated the expression of this protein. α-Man (25 µM) also prevented 6-OHDA-induced dopaminergic neurodegeneration in the BZ555 C. elegans strain. Altogether, our novel results suggest that α-Man affords partial protection against several, but not all, short-term toxic effects induced by 6-OHDA in cortical slices and in a skn-1-dependent manner in C. elegans., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuroprotective approaches comprising different mechanisms to counteract the noxious effects of excitotoxicity and oxidative stress need validation and detailed characterization. Although S-allylcysteine (SAC) is a natural compound exhibiting a broad spectrum of protective effects characterized by antioxidant, anti-inflammatory, and neuromodulatory actions, the mechanisms underlying its protective role on neuronal cell damage triggered by early excitotoxic insults remain elusive. In this study, we evaluated if the preconditioning or the post-treatment of isolated rat cortical slices with SAC (100 μM) can ameliorate the toxic effects induced by the excitotoxic metabolite quinolinic acid (QUIN, 100 μM), and whether this protective response involves the early display of specific antioxidant and neuroprotective signals. For this purpose, cell viability/mitochondrial reductive capacity, lipid peroxidation, levels of reduced and oxidized glutathione (GSH and GSSG, respectively), the rate of cell damage, the NF-E2-related factor 2/antioxidant response element (Nrf2/ARE) binding activity, heme oxygenase 1 (HO-1) regulation, extracellular signal-regulated kinase (ERK1/2) phosphorylation, and the levels of tumor necrosis factor-alpha (TNF-α) and the neurotrophin brain-derived neurotrophic factor (BDNF) were all estimated in tissue slices exposed to SAC and/or QUIN. The incubation of slices with QUIN augmented all toxic endpoints, whereas the addition of SAC prevented and/or recovered all toxic effects of QUIN, exhibiting better results when administered 60 min before the toxin and demonstrating protective and antioxidant properties. The early stimulation of Nrf2/ARE binding activity, the upregulation of HO-1, the ERK1/2 phosphorylation and the preservation of BDNF tissue levels by SAC demonstrate that this molecule displays a wide range of early protective signals by triggering orchestrated antioxidant responses and neuroprotective strategies. The relevance of the characterization of these mechanisms lies in the confirmation that the protective potential exerted by SAC begins at the early stages of excitotoxicity and neurodegeneration and supports the design of integral prophylactic/therapeutic strategies to reduce the deleterious effects observed in neurodegenerative disorders with inherent excitotoxic events.

Monovalent thallium (Tl + ) is a cation that can exert complex neurotoxic patterns in the brain by mechanisms that have yet to be completely characterized. To learn more about Tl + toxicity, it is necessary to investigate its major effects in vivo and its ability to trigger specific signaling pathways (such as the antioxidant SKN-1 pathway) in different biological models. Caenorhabditis elegans (C. elegans) is a nematode constituting a simple in vivo biological model with a well-characterized nervous system, and high genetic homology to mammalian systems. In this study, both wild-type (N2) and skn-1 knockout (KO) mutant C. elegans strains subjected to acute and chronic exposures to Tl + [2.5-35 μM] were evaluated for physiological stress (survival, longevity, and worm size), motor alterations (body bends), and biochemical changes (glutathione S-transferase regulation in a gst-4 fluorescence strain). While survival was affected by Tl + in N2 and skn-1 KO (worms lacking the orthologue of mammalian Nrf2) strains in a similar manner, the longevity was more prominently decreased in the skn-1 KO strain compared with the wild-type strain. Moreover, chronic exposure led to a greater compromise in the longevity in both strains compared with acute exposure. Tl + also induced motor alterations in both skn-1 KO and wild-type strains, as well as changes in worm size in wild-type worms. In addition, preconditioning nematodes with the well-known antioxidant S-allylcysteine (SAC) reversed the Tl + -induced decrease in survival in the N2 strain. GST fluorescent expression was also decreased by the metal in the nematode, and recovered by SAC. Our results describe and validate, for the first time, features of the toxic pattern induced by Tl + in an in vivo biological model established with C. elegans, supporting an altered redox component in Tl + toxicity, as previously described in mammal models. We demonstrate that the presence of the orthologous SKN-1 pathway is required for worms in evoking an efficient antioxidant defense. Therefore, the nematode represents an optimal model to reproduce mammalian Tl + toxicity, where toxic mechanisms and novel therapeutic approaches of clinical value may be successfully pursued.

One of the authors has incorrect family name spelling in the original article . Michael Ashner should read as Michael Aschner.

Caffeic acid (CA) is a hydroxycinnamic acid derivative and polyphenol with antioxidant and anti-inflammatory activities. The neuroprotective properties of CA still need detailed characterization in different biological models. Here, the antioxidant and neuroprotective effects of CA were compared in in vitro and in vivo neurotoxic models. Biochemical outcomes of cell dysfunction, oxidative damage, and transcriptional regulation were assessed in rat cortical slices, whereas endpoints of physiological stress and motor alterations were characterized in Caenorhabditis elegans (C. elegans). In rat cortical slices, CA (100 μM) prevented, in a differential manner, the loss of reductive capacity, the cell damage, and the oxidative damage induced by the excitotoxin quinolinic acid (QUIN, 100 μM), the pro-oxidant ferrous sulfate (FeSO 4 , 25 μM), and the dopaminergic toxin 6-hydroxydopamine (6-OHDA, 100 μM). CA also restored the levels of nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE; a master antioxidant regulatory pathway) binding activity affected by the three toxins. In wild-type (N2) of C. elegans, but not in the skn-1 KO mutant strain (worms lacking the orthologue of mammalian Nrf2), CA (25 mM) attenuated the loss of survival induced by QUIN (100 mM), FeSO 4 (15 mM), and 6-OHDA (25 mM). Motor alterations induced by the three toxic models in N2 and skn-1 KO strains were prevented by CA in a differential manner. Our results suggest that (1) CA affords partial protection against different toxic insults in mammalian brain tissue and in C. elegans specimens; (2) the Nrf2/ARE binding activity participates in the protective mechanisms evoked by CA in the mammalian cortical tissue; (3) the presence of the orthologous skn-1 pathway is required in the worms for CA to exert protective effects; and (4) CA exerts antioxidant and neuroprotective effects through homologous mechanisms in different species.

A number of physiological responses in the central nervous system (CNS) are regulated by the endocannabinoid system (ECS). Inhibition of neuronal excitability via activation of cannabinoid receptors (CBr) constitutes a potential protective response against neurotoxic insults. Oleamide (ODA) is a fatty acid amide with endocannabinoid profile exerting several effects in the CNS, though its neuroprotective properties remain unknown. The tryptophan metabolite quinolinic acid (QUIN) elicits toxic effects via overactivation of N-methyl-D-aspartate receptors (NMDAr) after its accumulation in the CNS under pathological conditions. Here, we investigated the protective properties of ODA against the excitotoxic damage induced by QUIN in rat brain synaptosomes and cortical slices, and whether these effects are linked to the stimulation of the endocannabinoid system via CB1 and/or CB2 receptor activation. ODA (1-50 μM) prevented the QUIN (100 μM)-induced loss of mitochondrial reductive capacity in synaptosomes in a mechanism partially mediated by CB1 receptor, as evidenced by the recovery of mitochondrial dysfunction induced by co-incubation with the CB1 receptor antagonist/inverse agonist AM281 (1 μM). In cortical slices, ODA prevented the short-term QUIN-induced loss of cell viability and the cell damage in a partial CB1 and CB2 receptor-dependent manner. Altogether, these findings demonstrate the neuroprotective and modulatory properties of ODA in biological brain preparations exposed to excitotoxic insults and the partial role that the stimulation of CB1 and CB2 receptors exerts in these effects.

Positive influence of yerba mate (Ilex paraguariensis) on human health issues has been attributed to its frequent consumption in South American countries and is assumed to be due to its high content of antioxidant compounds, including chlorogenic acid (CGA); however, hard evidence about its positive effects under chronic stress conditions is still required. In this study, the effects of yerba mate extracts (IpE), and its main compound chlorogenic acid (CGA), on behavioral and morphological endpoints of brain damage induced by chronic restraint stress (CRS) to rats were evaluated and compared. CRS sessions were performed during 21 days. IpE (200 mg/mL, p.o.) or CGA (2 mg/mL, p.o.) were administered daily 30 min before stress. Behavioral tests comprised motor skills and anxiety-like activity. Histological (H&E) and histochemical changes were explored in three brain regions: cortex (Cx), hippocampus (Hp), and striatum (S). Rats subjected to CRS exhibited hypoactive patterns of locomotor activity. Rats receiving IpE before CRS preserved the basal locomotor activity. Stressed animals also augmented the anxiety-like activity, whereas IpE normalized exploratory behavior. Stressed animals presented cell damage in all regions. Morphological damage was more effectively prevented by IpE than CGA. Stressed animals also augmented the expression/localization pattern of the tumor necrosis factor alpha in the striatum and the expression of the glial fibrillary acidic protein in the hippocampus (stratum moleculare) and cortex, whereas IpE and CGA reduced the expression of these molecules. In turn, CGA exhibited only moderate protective effects on all markers analyzed. Our findings support a protective role of IpE against CRS, which may be related to the antioxidant and anti-inflammatory properties of its compounds. Since CGA was unable to prevent all the alterations induced by CRS, it is concluded that the protective properties of the whole extract of Ilex paraguariensis are the result of the combined effects of all its natural antioxidant compounds, and not only of the properties of CGA.

Levetiracetam (LVT) is a relatively novel antiepileptic drug (AED) known to act through binding with the synaptic vesicular 2A (SV2A) protein, thus modulating the presynaptic neurotransmitter release. The tryptophan metabolite quinolinic acid (QUIN) acts as an excitotoxin when its brain concentrations reach toxic levels under pathological conditions. Since increased neuronal excitability induced by QUIN recruits degenerative events in the brain, and novel AED is also expected to exert neuroprotective effects in their pharmacological profiles, in this work the effect of LVT (54 mg/kg, i.p., administered for seven consecutive days) was tested as a pretreatment against the toxicity evoked by the bilateral intrastriatal injection of QUIN (60 nmol/μl) to adult rats. QUIN increased the striatal levels of peroxidized lipids and carbonylated proteins as indexes of oxidative damage 24 h after its infusion. In addition, in synaptosomal fractions isolated from QUIN-lesioned rats 24 h after the toxin infusion, γ-aminobutyric acid (GABA) release was decreased, whereas glutamate (Glu) release was increased. QUIN also decreased motor activity and augmented the rate of cell damage at 7 days post-lesion. All these alterations were significantly prevented by pretreatment of rats with LVT. The results of this study show a neuroprotective role and antioxidant action of LVT against the brain damage induced by excitotoxic events.

The mechanisms by which the heavy metal thallium (Tl + ) produces toxicity in the brain remain unclear. Herein, isolated synaptosomal/mitochondrial P2 crude fractions from adult rat brains were exposed to Tl + (5-250 μM) for 30 min. Three toxic endpoints were evaluated: mitochondrial dysfunction, lipid peroxidation, and Na + /K + -ATPase activity inhibition. Concentration-response curves for two of these endpoints revealed the optimum concentration of Tl + to induce damage in this preparation, 5 μM. Toxic markers were also estimated in preconditioned synaptosomes incubated in the presence of the N-methyl-D-aspartate receptor antagonist kynurenic acid (KYNA, 50 μM), the cannabinoid receptor agonist WIN 55,212-2 (1 μM), or the antioxidant S-allyl-L-cysteine (SAC, 100 μM). All these agents prevented Tl + toxicity, though SAC did it with lower efficacy. Our results suggest that energy depletion, oxidative damage, and Na + /K + -ATPase activity inhibition account for the toxic pattern elicited by Tl + in nerve terminals. In addition, the efficacy of the drugs employed against Tl + toxicity supports an active role of excitatory/cannabinoid and oxidative components in the toxic pattern elicited by the metal.

Several physiological events in the brain are regulated by the endocannabinoid system (ECS). While synthetic cannabinoid receptor (CBr) agonists such as WIN55,212-2 act directly on CBr, agents like URB597, a fatty acid amide hydrolase (FAAH) inhibitor, induce a more "physiological" activation of CBr by increasing the endogenous levels of the endocannabinoid anandamide (AEA). Herein, we compared the pre- and post-treatment efficacy of URB597 and WIN55,212-2 on different endpoints evaluated in the toxic model produced by the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. MPTP (40 mg/kg, s.c., single injection) decreased locomotor activity, depleted the striatal and nigral levels of dopamine (DA), augmented the levels of lipid peroxidation and protein carbonylation in both regions, decreased the striatal protein levels of tyrosine hydroxylase, and increased the striatal protein content of the subunit 1 (NR1) of the N-methyl-D-aspartate receptor (NMDAr). Both URB597 (0.3 mg/kg, i.p., once a day) and WIN55,212-2 (10 μg/kg, i.p., twice a day), administered for five consecutive days, either before or after the MPTP injection, prevented the alterations elicited by MPTP and downregulated NMDAr. Our results support a modulatory role of the ECS on the toxic profile exerted by MPTP in mice via the stimulation of antioxidant activity and the induction of NMDAr downregulation and hypofunction, and favor the stimulation of CBr as an effective experimental therapeutic strategy.