ABSTRACT
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.
ABSTRACT
Multiple sclerosis (MS) is a very complex and heterogeneous disease, with an unknown etiology and which, currently, remains incurable. For this reason, animal models are crucial to investigate this disease, which has increased in prevalence in recent years, affecting 2.8 million people worldwide, and is the leading cause of non-traumatic disability in young adults between the ages of 20-30years. Of all the models developed to replicate MS, experimental autoimmune encephalomyelitis (EAE) best reflects the autoimmune pathogenesis of MS. There are different methods to induce it, which will give rise to different types of EAE, which will vary in clinical presentation and severity. Of the EAE models, the most widespread and used is the one induced in rodents due to its advantages over other species. Likewise, EAE has become a widely used model in the development of therapies for the treatment of MS. Likewise, it is very useful to define the cellular and molecular mechanisms involved in the pathogenesis of MS and to establish therapeutic targets for this disease. For all these reasons, the EAE model plays a key role in improving the understanding of MS.
Subject(s)
Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , Encephalomyelitis, Autoimmune, Experimental/pathology , Animals , Multiple Sclerosis/pathology , Multiple Sclerosis/immunology , Mice , Humans , Rats , FemaleABSTRACT
Multiple sclerosis (MS) is characterized by a variety of symptoms that have a major impact on quality of life (QoL) even in early stages. In addition to individual motor, sensory, visual disturbances, and brainstem and sphincter disorders, which are expressed through the widely used Expanded Disability Status Scale (EDSS), other manifestations of MS have a detrimental effect on overall functioning and quality of life, such as cognitive impairment, depression, anxiety, fatigue, and pain. However, when talking about QoL, categorical definitions cannot be used because although the concept is generally understood, it is highly nuanced. Suffering from MS can significantly reduce QoL. Numerous research studies have focused on trying to identify and assess which are the elements that most affect the loss of QoL in MS people. However, in addition to the fact that the measurement of QoL can be subjective, it is very difficult to consider these elements in isolation, as they are interrelated. One such limiting factor of QoL that has been investigated is cognitive impairment (CI). This has been shown to have an impact on the lives of MS people, although the different approaches that have been taken to assess CI have evident limitations.
ABSTRACT
Mitochondrial dysfunction plays a key role in the development of neurodegenerative disorders. In contrast, the regulation of the endocannabinoid system has been shown to promote neuroprotection in different neurotoxic paradigms. The existence of an active form of the cannabinoid receptor 1 (CB1R) in mitochondrial membranes (mitCB1R), which might exert its effects through the same signaling mechanisms as the cell membrane CB1R, has been shown to regulate mitochondrial activity. Although there is evidence suggesting that some cannabinoids may induce protective effects on isolated mitochondria, substantial evidence on the role of cannabinoids in mitochondria remains to be explored. In this work, we developed a toxic model of mitochondrial dysfunction induced by exposure of brain mitochondria to the succinate dehydrogenase inhibitor 3-nitropropionic acid (3-NP). Mitochondria were also pre-incubated with the endogenous agonist anandamide (AEA) and the synthetic CB1R agonist WIN 55212-2 to evaluate their protective effects. Mitochondrial reduction capacity, reactive oxygen species (ROS) formation, and mitochondrial swelling were assessed as toxic markers. While 3-NP decreased the mitochondrial reduction capacity and augmented mitochondrial ROS formation and swelling, both AEA and WIN 55212-2 ameliorated these toxic effects. To explore the possible involvement of mitCB1R activation on the protective effects of AEA and WIN 55212-2, mitochondria were also pre-incubated in the presence of the selective CB1R antagonist AM281, which completely reverted the protective effects of the cannabinoids to levels similar to those evoked by 3-NP. These results show partial protective effects of cannabinoids, suggesting that mitCB1R activation may be involved in the recovery of compromised mitochondrial activity, related to reduction of ROS formation and further prevention of mitochondrial swelling.
ABSTRACT
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.
Subject(s)
Neurodegenerative Diseases , Proteasome Endopeptidase Complex , Humans , Proteasome Endopeptidase Complex/metabolism , Ubiquitin/metabolism , NF-E2-Related Factor 2/metabolism , Cytoplasm/metabolism , Neurodegenerative Diseases/metabolismABSTRACT
Multiple sclerosis (MS) is a chronic demyelinating disease, whose etiology is not yet fully understood, although there are several factors that can increase the chances of suffering from it. These factors include nutrition, which may be involved in the pathogenesis of the disease. In relation to nutrition, docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (n-3 PUFA), has emerged as an important player in the regulation of neuroinflammation, being considered a pleiotropic molecule. This study aimed to evaluate the effect of DHA supplementation on clinical state and oxidative stress produced by experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Twenty-five Dark Agouti rats which were used divided into Control Group, Control+Vehicle Group, Control+DHA Group, EAE Group, and EAE+DHA Group. DHA was administered for 51 days by intraperitoneal (i.p.) injection at a dose of 40 mg/kg, once a day, 5 days a week. DHA supplementation produced a decrease in oxidative stress, as well as an improvement in the clinical score of the disease. DHA could exert a beneficial effect on the clinic of MS, through the activation of the antioxidant factor Nrf2.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Fatty Acids, Omega-3 , Multiple Sclerosis , Rats , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Docosahexaenoic Acids/pharmacology , Docosahexaenoic Acids/therapeutic use , Multiple Sclerosis/drug therapy , Fatty Acids, Omega-3/pharmacology , Fatty Acids, Omega-3/therapeutic use , Models, TheoreticalABSTRACT
Objectives: The high-salt diet (HSD) has been associated with cognitive dysfunction by attacking the cerebral microvasculature, through an adaptive response, initiated in the intestine and mediated by Th17 cells. In the animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), it has been described that NaCl causes an increase in T cell infiltration in the central nervous system. NaCl also promotes macrophage response and Th17 cell differentiation, worsening the course of the disease. HSD may trigger an activation of the immune system and enhance inflammation. However, certain studies not only do not support this possibility, but support the opposite, as the effect of salt on immune cells may not necessarily be pathogenic. Therefore, this study aimed to evaluate the effect of an over intake of salt in rats with EAE, based on the clinical course, oxidative stress, markers of inflammation and the gut dysbiosis.Methods: 15 Dark Agouti rats were used, which were divided into control group, EAE group and EAE + NaCl group. Daily 0.027â g of NaCl dissolved in 300â µl of H2O was administered through a nasogastric tube for 51 days.Results: NaCl administration produced an improvement in clinical status and a decrease in biomarkers of oxidative stress, inflammation, and dysbiosis.Conclusion: The underlying mechanism by which NaCl causes these effects could involve the renin-angiotensin-aldosterone system (RAAS), which is blocked by high doses of salt.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , Rats , Animals , Mice , Multiple Sclerosis/complications , Sodium Chloride/adverse effects , Dysbiosis , Inflammation/complications , Oxidative Stress , Sodium Chloride, Dietary/adverse effects , Mice, Inbred C57BLABSTRACT
Oxidative stress is heavily involved in several pathological features of Multiple Sclerosis (MS), such as myelin destruction, axonal degeneration, and inflammation. Different therapies have been shown to reduce the oxidative stress that occurs in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). Some of these therapies are transcranial magnetic stimulation (TMS), extra virgin olive oil (EVOO) and S-allyl cysteine (SAC). This study aims to test the antioxidant effect of these three therapies, to compare the efficacy of SAC versus TMS and EVOO, and to analyze the effect of combining SAC + TMS and SAC and EVOO. Seventy Dark Agouti rats were used, which were divided into Control group; Vehicle group; Mock group; SAC; EVOO; TMS; SAC + EVOO; SAC + TMS; EAE; EAE + SAC; EAE + EVOO; EAE + TMS; EAE + SAC + EVOO; EAE + SAC + TMS. The TMS consisted of an oscillatory magnetic field in the form of a sine wave with a frequency of 60 Hz and an amplitude of 0.7mT (EL-EMF) applied for two hours in the morning, once a day, five days a week. SAC was administered at a dose of 50 mg/kg body weight, orally daily, five days a week. EVOO represented 10% of their calorie intake in the total standard daily diet of rats AIN-93G. All treatments were maintained for 51 days. TMS, EVOO and SAC, alone or in combination, reduce oxidative stress, increasing antioxidant defenses and also lowering the clinical score. Combination therapies do not appear to be more potent than individual therapies against the oxidative stress of EAE or its clinical symptoms.
ABSTRACT
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.
Subject(s)
Endocannabinoids , Synaptosomes , Rats , Animals , Synaptosomes/metabolism , Monoacylglycerol Lipases/metabolism , Receptors, Cannabinoid , Drug Inverse Agonism , Brain/metabolism , Oxidative Stress , Benzodioxoles/pharmacology , Receptor, Cannabinoid, CB1ABSTRACT
Thallium (Tl) is a toxic heavy metal responsible for noxious effects in living organisms. As a pollutant, Tl can be found in the environment at high concentrations, especially in industrial areas. Systemic toxicity induced by this toxic metal can affect cell metabolism, including redox alterations, mitochondrial dysfunction, and activation of apoptotic signaling pathways. Recent focus on Tl toxicity has been devoted to the characterization of its effects at the nuclear level, with emphasis on DNA, which, in turn, may be responsible for cytogenetic damage, mutations, and epigenetic changes. In this work, we review and discuss past and recent evidence on the toxic effects of Tl at the systemic level and its effects on DNA. We also address Tl's role in cancer and its control.
ABSTRACT
Alzheimer's disease (AD) is considered the most frequent neurodegenerative disorder worldwide, compromising cognitive function in patients, with an average incidence of 1-3% in the open population. Protein aggregation into amyloidogenic plaques and neurofibrillary tangles, as well as neurodegeneration in the hippocampal and cortical areas, represent the neuropathological hallmarks of this disorder. Mechanisms involved in neurodegeneration include protein misfolding, augmented apoptosis, disrupted molecular signaling pathways and axonal transport, oxidative stress, inflammation, and mitochondrial dysfunction, among others. It is precisely through a disrupted energy metabolism that neural cells trigger toxic mechanisms leading to cell death. In this regard, the study of mitochondrial dynamics constitutes a relevant topic to decipher the role of mitochondrial dysfunction in neurological disorders, especially when considering that amyloid-beta peptides can target mitochondria. Specifically, the amyloid beta (Aß) peptide, known to accumulate in the brain of AD patients, has been shown to disrupt overall mitochondrial metabolism by impairing energy production, mitochondrial redox activity, and calcium homeostasis, thus highlighting its key role in the AD pathogenesis. In this work, we review and discuss recent evidence supporting the concept that mitochondrial dysfunction mediated by amyloid peptides contributes to the development of AD.
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Mitochondrial Dynamics , Mitochondria/metabolismABSTRACT
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.
Subject(s)
Antioxidants , Neuroprotective Agents , Rats , Animals , Antioxidants/therapeutic use , Receptors, Cannabinoid/metabolism , Oxidative Stress , Glutathione/metabolism , Mitochondria , Amides/pharmacology , Amides/metabolism , Nitro Compounds/toxicity , Neuroprotective Agents/pharmacology , Neuroprotective Agents/metabolismABSTRACT
In this study, we investigated the effect of transcranial magnetic stimulation (TMS) on the ultrastructure of muscle fibers and satellite cells in rats with experimental autoimmune encephalomyelitis (EAE). EAE-induced animals were treated with TMS (60 Hz at 0.7 mT) for 2 hours in the morning, once a day, 5 days a week, for 3 weeks, starting on day 15 post-immunization. The rats were sacrificed on day 36 post-immunization, and the soleus muscles were evaluated by light microscopy and transmission electron microscopy. Findings were compared with a non-treated EAE group. Electron microscopy analysis showed the presence of degenerated mitochondria, autophagic vacuoles, and altered myofibrils in non-treated EAE group. This correlates with the presence of acid phosphatase activity in muscle fibers and core-targetoid lesions with desmin immunohistochemistry. Most myonuclei in the EAE group showed apoptotic features. In contrast, EAE induced-TMS treated animals had less ultrastructural changes in the mitochondria and the myofibrils, together with less frequent apoptotic nuclear features. Peripheral desmin+ protrusions, as a marker of active satellite cells, were significantly increased in TMS-treated group. This correlates ultrastructurally with the presence of active features in satellite cells in the TMS group. In conclusion, the attenuation of ultrastructural alterations in muscle fibers and activation response of satellite cells caused by EAE indicated that skeletal muscle had a regenerative response to TMS.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Acid Phosphatase , Animals , Desmin , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/therapy , Muscle Fibers, Skeletal/pathology , Muscle, Skeletal/ultrastructure , Rats , Transcranial Magnetic StimulationABSTRACT
The SARS-CoV-2 pandemic has raised particular concern for people with Multiple Sclerosis, as these people are believed to be at increased risk of infection, especially those being treated with disease-modifying therapies. Therefore, the objective of this review was to describe how COVID-19 affects people who suffer from Multiple Sclerosis, evaluating the risk they have of suffering an infection by this virus, according to the therapy to which they are subjected as well as the immune response of these patients both to infection and vaccines and the neurological consequences that the virus can have in the long term. The results regarding the increased risk of infection due to treatment are contradictory. B-cell depletion therapies may cause patients to have a lower probability of generating a detectable neutralizing antibody titer. However, more studies are needed to help understand how this virus works, paying special attention to long COVID and the neurological symptoms that it causes.
Subject(s)
COVID-19 , Multiple Sclerosis , Antibodies, Viral , COVID-19/complications , COVID-19 Vaccines/adverse effects , Humans , Multiple Sclerosis/complications , Multiple Sclerosis/therapy , SARS-CoV-2 , Post-Acute COVID-19 SyndromeABSTRACT
Many types of research have been carried out with the aim of combating the COVID-19 pandemic since the first outbreak was detected in Wuhan, China. Anticipating the evolution of an outbreak helps to devise suitable economic, social and health care strategies to mitigate the effects of the virus. For this reason, predicting the SARS-CoV-2 transmission rate has become one of the most important and challenging problems of the past months. In this paper, we apply a two-stage mid and long-term forecasting framework to the epidemic situation in eight districts of Andalusia, Spain. First, an analytical procedure is performed iteratively to fit polynomial curves to the cumulative curve of contagions. Then, the extracted information is used for estimating the parameters and structure of an evolutionary artificial neural network with hybrid architectures (i.e., with different basis functions for the hidden nodes) while considering single and simultaneous time horizon estimations. The results obtained demonstrate that including polynomial information extracted during the training stage significantly improves the mid- and long-term estimations in seven of the eight considered districts. The increase in average accuracy (for the joint mid- and long-term horizon forecasts) is 37.61% and 35.53% when considering the single and simultaneous forecast approaches, respectively.
ABSTRACT
BACKGROUND: Melatonin is an indole hormone secreted primarily by the pineal gland that showing anti-oxidant, anti-inflammatory and anti-apoptotic capacity. It can play an important role in the pathophysiological mechanisms of various diseases. In this regard, different studies have shown that there is a relationship between Melatonin and Multiple Sclerosis (MS). MS is a chronic immune-mediated disease of the Central Nervous System. AIM: The objective of this review was to evaluate the mechanisms of action of melatonin on oxidative stress, inflammation and intestinal dysbiosis caused by MS, as well as its interaction with different hormones and factors that can influence the pathophysiology of the disease. RESULTS: Melatonin causes a significant increase in the levels of catalase, superoxide dismutase, glutathione peroxidase, glutathione and can counteract and inhibit the effects of the NLRP3 inflammasome, which would also be beneficial during SARS-CoV-2 infection. In addition, melatonin increases antimicrobial peptides, especially Reg3ß, which could be useful in controlling the microbiota. CONCLUSION: Melatonin could exert a beneficial effect in people suffering from MS, running as a promising candidate for the treatment of this disease. However, more research in human is needed to help understand the possible interaction between melatonin and certain sex hormones, such as estrogens, to know the potential therapeutic efficacy in both men and women.
Subject(s)
COVID-19 , Melatonin , Multiple Sclerosis , Adjuvants, Immunologic , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antioxidants/pharmacology , Antioxidants/therapeutic use , Catalase/metabolism , Estrogens/pharmacology , Estrogens/therapeutic use , Female , Glutathione , Glutathione Peroxidase/metabolism , Humans , Inflammasomes , Male , Melatonin/pharmacology , Melatonin/therapeutic use , Multiple Sclerosis/drug therapy , NLR Family, Pyrin Domain-Containing 3 Protein , Oxidative Stress , SARS-CoV-2 , Superoxide Dismutase/metabolismABSTRACT
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.