RÉSUMÉ
Data on the participation of microbiota in the development of Parkinson's disease allow us to discuss the ability of bacterial preparations to influence the processes leading to neurodegeneration. We studied the effect of oral administration of Limosilactobacillus fermentum U-21 lyophilisate on a model of Parkinson's disease in rats induced by combined intranigral injection of LPS and systemic administration of paraquat. The toxins significantly increased the number of missteps in the "narrowing beam walking" test, but a tendency to a decrease in this parameter was shown after treatment with U-21. It should be noted that U-21 did not reduce the neuronal death in the substantia nigra, but mitigated the inflammatory glial response, decreased the accumulation of phosphorylated α-synuclein and complement protein C3. Our study demonstrated the efficiency of the combined model of parkinsonism and reduction of proinflammatory changes under the influence of pharmabiotic without changes in the nigral neuronal death and motor deficits.
Sujet(s)
Modèles animaux de maladie humaine , Lipopolysaccharides , Substantia nigra , alpha-Synucléine , Animaux , Rats , alpha-Synucléine/métabolisme , Mâle , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/métabolisme , Substantia nigra/anatomopathologie , Lipopolysaccharides/pharmacologie , Lipopolysaccharides/toxicité , Paraquat , Maladie de Parkinson/anatomopathologie , Maladie de Parkinson/traitement médicamenteux , Maladie de Parkinson/métabolisme , Rat Wistar , Complément C3/métabolisme , Maladies neuro-inflammatoires/anatomopathologie , Maladies neuro-inflammatoires/traitement médicamenteuxRÉSUMÉ
The pursuit of drugs and methods to safeguard dopaminergic neurons holds paramount importance in Parkinson's disease (PD) research. Benfotiamine (BFT) has demonstrated neuroprotective properties, yet its precise mechanisms in PD remain elusive. This study investigated BFT's potential protective effects against dopamine neuron damage in a PD animal model and the underlying mechanisms. The PD mouse model was induced by 5 consecutive MPTP injections, followed by BFT intervention for 28 days. Motor deficits were assessed via pole test, hang test, gait analysis, and open field test, while dopaminergic neuron damage was evaluated through Immunofluorescence, Nissl staining, and Western blot analysis of Tyrosine Hydroxylase (TH) in the substantia nigra and striatum. High Performance Liquid Chromatography quantified dopamine (DA) levels and its metabolites. Genetic pathways were explored using RNA-seq and bioinformatics analysis on substantia nigra tissues, confirmed by qPCR. Activation of the Nrf2 pathway was examined through nuclear translocation and expression of downstream antioxidant enzymes HO-1, GCLM, and NQO1 at mRNA and protein levels. Additionally, measurements of MDA content, GSH activity, and SOD activity were taken in the substantia nigra and striatum. BFT administration improved motor function and protected against dopaminergic neuron degeneration in MPTP mice, with partial recovery in TH expression and DA levels. RNA-seq analysis revealed distinct effects of BFT and the NLRP3 inhibitor MCC950 on Parkinson-related pathways and genes. Control of Nrf2 proved crucial for BFT, as it facilitated Nrf2 movement to the nucleus, upregulating antioxidant genes and enzymes while mitigating oxidative damage. This study elucidates BFT's neuroprotective effects in a PD mouse model via Nrf2-mediated antioxidant mechanisms and gene expression modulation, underscoring its potential as a therapeutic agent for PD.
Sujet(s)
Modèles animaux de maladie humaine , Facteur-2 apparenté à NF-E2 , Neuroprotecteurs , Transduction du signal , Animaux , Facteur-2 apparenté à NF-E2/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Souris , Mâle , Neuroprotecteurs/pharmacologie , Neuroprotecteurs/usage thérapeutique , Souris de lignée C57BL , Neurones dopaminergiques/effets des médicaments et des substances chimiques , Neurones dopaminergiques/métabolisme , Neurones dopaminergiques/anatomopathologie , Dopamine/métabolisme , 1-Méthyl-4-phényl-1,2,3,6-tétrahydropyridine , Substantia nigra/métabolisme , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/anatomopathologie , Maladie de Parkinson/métabolisme , Maladie de Parkinson/traitement médicamenteux , Maladie de Parkinson/étiologie , Stress oxydatif/effets des médicaments et des substances chimiques , Thiamine/analogues et dérivésRÉSUMÉ
Parkinson's disease (PD) is a debilitating neurodegenerative disease affecting millions of individuals worldwide. Hallmark features of PD pathology are the formation of Lewy bodies in neuromelanin-containing dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNpc), and the subsequent irreversible death of these neurons. Although genetic risk factors have been identified, around 90â¯% of PD cases are sporadic and likely caused by environmental exposures and gene-environment interaction. Mechanistic studies have identified a variety of chemical PD risk factors. PD neuropathology occurs throughout the brain and peripheral nervous system, but it is the loss of DAergic neurons in the SNpc that produce many of the cardinal motor symptoms. Toxicology studies have found specifically the DAergic neuron population of the SNpc exhibit heightened sensitivity to highly variable chemical insults (both in terms of chemical structure and mechanism of neurotoxic action). Thus, it has become clear that the inherent neurobiology of nigral DAergic neurons likely underlies much of this neurotoxic response to broad insults. This review focuses on inherent neurobiology of nigral DAergic neurons and how such neurobiology impacts the primary mechanism of neurotoxicity. While interactions with a variety of other cell types are important in disease pathogenesis, understanding how inherent DAergic biology contributes to selective sensitivity and primary mechanisms of neurotoxicity is critical to advancing the field. Specifically, key biological features of DAergic neurons that increase neurotoxicant susceptibility.
Sujet(s)
Neurones dopaminergiques , Humains , Animaux , Neurones dopaminergiques/effets des médicaments et des substances chimiques , Neurones dopaminergiques/anatomopathologie , Neurones dopaminergiques/métabolisme , Dopamine/métabolisme , Maladie de Parkinson/anatomopathologie , Maladie de Parkinson/métabolisme , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/anatomopathologie , Substantia nigra/métabolismeRÉSUMÉ
Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide. Current treatments for PD largely center around dopamine replacement therapies and fail to prevent the progression of pathology, underscoring the need for neuroprotective interventions. Approaches that target neuroinflammation, which occurs prior to dopaminergic neuron (DAn) loss in the substantia nigra (SN), represent a promising therapeutic strategy. The glucocorticoid receptor (GR) has been implicated in the neuropathology of PD and modulates numerous neuroinflammatory signaling pathways in the brain. Therefore, we investigated the neuroprotective effects of the novel GR modulator, PT150, in the rotenone mouse model of PD, postulating that inhibition of glial inflammation would protect DAn and reduce accumulation of neurotoxic misfolded âº-synuclein protein. C57Bl/6 mice were exposed to 2.5â¯mg/kg/day rotenone by intraperitoneal injection for 14 days. Upon completion of rotenone dosing, mice were orally treated at day 15 with 30â¯mg/kg/day or 100â¯mg/kg/day PT150 in the 14-day post-lesioning incubation period, during which the majority of DAn loss and α-synuclein (α-syn) accumulation occurs. Our results indicate that treatment with PT150 reduced both loss of DAn and microgliosis in the nigrostriatal pathway. Although morphologic features of astrogliosis were not attenuated, PT150 treatment promoted potentially neuroprotective activity in these cells, including increased phagocytosis of hyperphosphorylated α-syn. Ultimately, PT150 treatment reduced the loss of DAn cell bodies in the SN, but not the striatum, and prohibited intra-neuronal accumulation of α-syn. Together, these data indicate that PT150 effectively reduced SN pathology in the rotenone mouse model of PD.
Sujet(s)
Neurones dopaminergiques , Souris de lignée C57BL , Neuroprotecteurs , Récepteurs aux glucocorticoïdes , Roténone , alpha-Synucléine , Animaux , Roténone/toxicité , Neuroprotecteurs/pharmacologie , Souris , Mâle , Neurones dopaminergiques/effets des médicaments et des substances chimiques , Neurones dopaminergiques/anatomopathologie , Neurones dopaminergiques/métabolisme , Récepteurs aux glucocorticoïdes/métabolisme , alpha-Synucléine/métabolisme , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/anatomopathologie , Substantia nigra/métabolisme , Syndromes parkinsoniens/traitement médicamenteux , Syndromes parkinsoniens/induit chimiquement , Syndromes parkinsoniens/métabolisme , Syndromes parkinsoniens/anatomopathologie , Modèles animaux de maladie humaine , PhénanthrènesRÉSUMÉ
The effect of the modulators of the mitochondrial ATP-dependent potassium channel (mitoKATP) on the structural and biochemical alterations in the substantia nigra and brain tissues was studied in a rat model of Parkinson's disease induced by rotenone. It was found that, in experimental parkinsonism accompanied by characteristic motor deficits, both neurons and the myelin sheath of nerve fibers in the substantia nigra were affected. Changes in energy and ion exchange in brain mitochondria were also revealed. The nucleoside uridine, which is a source for the synthesis of the mitoKATP channel opener uridine diphosphate, was able to dose-dependently decrease behavioral disorders and prevent the death of animals, which occurred for about 50% of animals in the model. Uridine prevented disturbances in redox, energy, and ion exchanges in brain mitochondria, and eliminated alterations in their structure and the myelin sheath in the substantia nigra. Cytochemical examination showed that uridine restored the indicators of oxidative phosphorylation and glycolysis in peripheral blood lymphocytes. The specific blocker of the mitoKATP channel, 5-hydroxydecanoate, eliminated the positive effects of uridine, suggesting that this channel is involved in neuroprotection. Taken together, these findings indicate the promise of using the natural metabolite uridine as a new drug to prevent and, possibly, stop the progression of Parkinson's disease.
Sujet(s)
Mitochondries , Canaux potassiques , Roténone , Uridine , Animaux , Uridine/pharmacologie , Uridine/métabolisme , Rats , Canaux potassiques/métabolisme , Mitochondries/métabolisme , Mitochondries/effets des médicaments et des substances chimiques , Mâle , Modèles animaux de maladie humaine , Maladie de Parkinson/métabolisme , Maladie de Parkinson/traitement médicamenteux , Maladie de Parkinson/étiologie , Maladie de Parkinson/anatomopathologie , Substantia nigra/métabolisme , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/anatomopathologie , Neuroprotecteurs/pharmacologie , Phosphorylation oxydative/effets des médicaments et des substances chimiques , Rat Wistar , Acides capriques/pharmacologie , Hydroxyacides/pharmacologieRÉSUMÉ
Functional deficits in basal ganglia (BG) circuits contribute to cognitive and motor dysfunctions in alcohol use disorder. Chronic alcohol exposure alters synaptic function and neuronal excitability in the dorsal striatum, but it remains unclear how it affects BG output that is mediated by the substantia nigra pars reticulata (SNr). Here, we describe a neuronal subpopulation-specific synaptic organization of striatal and subthalamic (STN) inputs to the medial and lateral SNr. Chronic alcohol exposure (CIE) potentiated dorsolateral striatum (DLS) inputs but did not change dorsomedial striatum and STN inputs to the SNr. Chemogenetic inhibition of DLS direct pathway neurons revealed an enhanced role for DLS direct pathway neurons in execution of an instrumental lever-pressing task. Overall, we reveal a subregion-specific organization of striatal and subthalamic inputs onto the medial and lateral SNr and find that potentiated DLS-SNr inputs are accompanied by altered BG control of action execution following CIE.
Sujet(s)
Noyaux gris centraux , Corps strié , Éthanol , Plasticité neuronale , Substantia nigra , Animaux , Plasticité neuronale/effets des médicaments et des substances chimiques , Noyaux gris centraux/physiologie , Noyaux gris centraux/physiopathologie , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/physiologie , Éthanol/pharmacologie , Corps strié/physiologie , Mâle , Souris , Neurones/physiologie , Neurones/effets des médicaments et des substances chimiques , Alcoolisme/physiopathologie , Voies nerveusesRÉSUMÉ
Parkinson's disease (PD) is a chronic neurodegenerative disease with unclear pathogenesis that involves neuroinflammation and intestinal microbial dysbiosis. Intercellular adhesion molecule-1 (ICAM-1), an inflammatory marker, participates in neuroinflammation during dopaminergic neuronal damage. However, the explicit mechanisms of action of ICAM-1 in PD have not been elucidated. We established a subacute PD mouse model by the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and observed motor symptoms and gastrointestinal dysfunction in mice. Immunofluorescence was used to examine the survival of dopaminergic neurons, expression of microglial and astrocyte markers, and intestinal tight junction-associated proteins. Then, we use 16â¯S rRNA sequencing to identify alterations in the microbiota. Our findings revealed that ICAM-1-specific antibody (Ab) treatment relieved behavioural defects, gastrointestinal dysfunction, and dopaminergic neuronal death in MPTP-induced PD mice. Further mechanistic investigations indicated that ICAM-1Ab might suppress neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra and relieving colon barrier impairment and intestinal inflammation. Furthermore, 16â¯S rRNA sequencing revealed that the relative abundances of bacterial Firmicutes, Clostridia, and Lachnospiraceae were elevated in the PD mice. However, ICAM-1Ab treatment ameliorated the MPTP-induced disorders in the intestinal microbiota. Collectively, we concluded that the suppressing ICAM-1 might lead to the a significant decrease of inflammation and restore the gut microbial community, thus ameliorating the damage of DA neurons.
Sujet(s)
Neurones dopaminergiques , Molécule-1 d'adhérence intercellulaire , Souris de lignée C57BL , Animaux , Neurones dopaminergiques/métabolisme , Neurones dopaminergiques/anatomopathologie , Neurones dopaminergiques/effets des médicaments et des substances chimiques , Molécule-1 d'adhérence intercellulaire/métabolisme , Souris , Mâle , Modèles animaux de maladie humaine , Maladies neuro-inflammatoires/métabolisme , Microbiome gastro-intestinal/physiologie , Microbiome gastro-intestinal/effets des médicaments et des substances chimiques , 1-Méthyl-4-phényl-1,2,3,6-tétrahydropyridine/pharmacologie , Inflammation/métabolisme , Substantia nigra/métabolisme , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/anatomopathologie , Microglie/métabolisme , Astrocytes/métabolisme , Astrocytes/effets des médicaments et des substances chimiques , Syndromes parkinsoniens/métabolisme , Intoxication au MPTP/métabolisme , Intoxication au MPTP/anatomopathologieRÉSUMÉ
Neuroinflammation has been gaining attention as one of the potential causes of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis in recent years. The suppression of excessive proinflammatory responses is expected to be a target for the treatment and prevention of neurodegenerative diseases. Collapsin response mediator protein 4 (CRMP4) is involved in cytoskeleton-associated axonal guidance in the developing brain. Recently, the involvement of CRMP4 in several pathological conditions, including inflammation induced by lipopolysaccharide (LPS), a widely used inflammatory molecule, has been reported. However, the role of CRMP4 in LPS-induced inflammation in vivo remains largely unknown. In this study, we generated microglia-specific CRMP4 knockout mice for the first time and examined the role of CRMP4 in an LPS-induced brain inflammation model. We found that microglia after LPS injection in substantia nigra was significantly reduced in Crmp4-/- mice compared to Crmp4+/+mice. The increased expression of IL-10 in striatum samples was downregulated in Crmp4-/- mice. A significant reduction in Iba1 expression was also observed in microglia-specific Crmp4 knockout mice compared with that in control mice. In contrast, the expression of IL-10 did not change in these mice, whereas arginase 1 (Arg1) expression was significantly suppressed. These results demonstrate the involvement of CRMP4 in LPS-induced inflammation in vivo, that CRMP4 suppresses microglial proliferation in a cell-autonomous manner.
Sujet(s)
Lipopolysaccharides , Souris knockout , Microglie , Protéines de tissu nerveux , Maladies neuro-inflammatoires , Animaux , Lipopolysaccharides/pharmacologie , Microglie/métabolisme , Microglie/effets des médicaments et des substances chimiques , Protéines de tissu nerveux/métabolisme , Protéines de tissu nerveux/génétique , Souris , Maladies neuro-inflammatoires/métabolisme , Maladies neuro-inflammatoires/induit chimiquement , Inflammation/métabolisme , Inflammation/induit chimiquement , Interleukine-10/métabolisme , Substantia nigra/métabolisme , Substantia nigra/effets des médicaments et des substances chimiques , Souris de lignée C57BL , Corps strié/métabolisme , Corps strié/effets des médicaments et des substances chimiques , Mâle , Protéines des microfilaments/métabolisme , Arginase/métabolismeRÉSUMÉ
Parkinson's Disease is a progressive neurodegenerative disorder characterized by motor symptoms resulting from the loss of nigrostriatal dopaminergic neurons. Kisspeptins (KPs) are a family of neuropeptides that are encoded by the Kiss-1 gene, which exert their physiological effects through interaction with the GPR54 receptor. In the current investigation, we investigated the prospective protective effects of central KP-54 treatments on nigrostriatal dopaminergic neurons and consequent motor performance correlates in 6-hydroxydopamine (6-OHDA)-lesioned rats. Male adult Sprague Dawley rats underwent stereotaxic injection of 6-OHDA into the right medial forebrain bundle to induce hemiparkinsonism. Following surgery, rats received chronic central treatments of nasal or intracerebroventricular KP-54 (logarithmically increasing doses) for seven consecutive days. Motor performance was evaluated seven days post-surgery utilizing the open field test and catalepsy test. The levels of dopamine in the striatum were determined with mass spectrometry. Immunohistochemical analysis was conducted to assess the immunoreactivities of tyrosine hydroxylase (TH) and the GPR54 in the substantia nigra. The dose-response curve revealed a median effective dose value of ≈3 nmol/kg for both central injections. Due to its non-invasive and effective nature, nasal administration was utilized in the second phase of our study. Chronic administration of KP-54 (3nmol/kg, nasally) significantly protected 6-OHDA-induced motor deficits. Nasal KP-54 attenuated the loss of nigrostriatal dopaminergic neurons induced by 6-OHDA. Additionally, significant correlations were observed between motor performance and nigrostriatal dopamine levels. Immunohistochemical analysis demonstrated the localization of the GPR54 within TH-positive nigral cells. These findings suggest the potential efficacy of central KP-54 on motor impairments in hemiparkinsonism.
Sujet(s)
Administration par voie nasale , Corps strié , Dopamine , Neurones dopaminergiques , Kisspeptines , Oxidopamine , Syndromes parkinsoniens , Rat Sprague-Dawley , Substantia nigra , Animaux , Mâle , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/métabolisme , Dopamine/métabolisme , Oxidopamine/pharmacologie , Rats , Corps strié/effets des médicaments et des substances chimiques , Corps strié/métabolisme , Kisspeptines/administration et posologie , Kisspeptines/pharmacologie , Kisspeptines/métabolisme , Syndromes parkinsoniens/traitement médicamenteux , Syndromes parkinsoniens/métabolisme , Neurones dopaminergiques/effets des médicaments et des substances chimiques , Neurones dopaminergiques/métabolisme , Modèles animaux de maladie humaine , Activité motrice/effets des médicaments et des substances chimiques , Tyrosine 3-monooxygenase/métabolismeRÉSUMÉ
Adenosine A2A receptor (A2AR) antagonists are the leading nondopaminergic therapy to manage Parkinson's disease (PD) since they afford both motor benefits and neuroprotection. PD begins with a synaptic dysfunction and damage in the striatum evolving to an overt neuronal damage of dopaminergic neurons in the substantia nigra. We tested if A2AR antagonists are equally effective in controlling these two degenerative processes. We used a slow intracerebroventricular infusion of the toxin MPP+ in male rats for 15 days, which caused an initial loss of synaptic markers in the striatum within 10 days, followed by a neuronal loss in the substantia nigra within 30 days. Interestingly, the initial loss of striatal nerve terminals involved a loss of both dopaminergic and glutamatergic synaptic markers, while GABAergic markers were preserved. The daily administration of the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) in the first 10 days after MPP+ infusion markedly attenuated both the initial loss of striatal synaptic markers and the subsequent loss of nigra dopaminergic neurons. Strikingly, the administration of SCH58261 (0.1 mg/kg, i.p. for 10 days) starting 20 days after MPP+ infusion was less efficacious to attenuate the loss of nigra dopaminergic neurons. This prominent A2AR-mediated control of synaptotoxicity was directly confirmed by showing that the MPTP-induced dysfunction (MTT assay) and damage (lactate dehydrogenase release assay) of striatal synaptosomes were prevented by 50 nM SCH58261. This suggests that A2AR antagonists may be more effective to counteract the onset rather than the evolution of PD pathology.
Sujet(s)
Antagonistes des récepteurs A2 à l'adénosine , Corps strié , Maladie de Parkinson , Récepteur A2A à l'adénosine , Animaux , Rats , Antagonistes des récepteurs A2 à l'adénosine/pharmacologie , Antagonistes des récepteurs A2 à l'adénosine/usage thérapeutique , Corps strié/métabolisme , Corps strié/effets des médicaments et des substances chimiques , Corps strié/anatomopathologie , Modèles animaux de maladie humaine , Neurones dopaminergiques/effets des médicaments et des substances chimiques , Neurones dopaminergiques/métabolisme , Neurones dopaminergiques/anatomopathologie , Neuroprotecteurs/pharmacologie , Neuroprotecteurs/usage thérapeutique , Maladie de Parkinson/traitement médicamenteux , Maladie de Parkinson/métabolisme , Maladie de Parkinson/anatomopathologie , Pyrimidines/pharmacologie , Pyrimidines/usage thérapeutique , Rat Sprague-Dawley , Récepteur A2A à l'adénosine/métabolisme , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/métabolisme , Substantia nigra/anatomopathologie , Triazoles/pharmacologieRÉSUMÉ
Systemic manipulations that enhance dopamine (DA) transmission around the time of fear extinction can strengthen fear extinction and reduce conditioned fear relapse. Prior studies investigating the brain regions where DA augments fear extinction focus on targets of mesolimbic and mesocortical DA systems originating in the ventral tegmental area, given the role of these DA neurons in prediction error. The dorsal striatum (DS), a primary target of the nigrostriatal DA system originating in the substantia nigra (SN), is implicated in behaviors beyond its canonical role in movement, such as reward and punishment, goal-directed action, and stimulus-response associations, but whether DS DA contributes to fear extinction is unknown. We have observed that chemogenetic stimulation of SN DA neurons during fear extinction prevents the return of fear in contexts different from the extinction context, a form of relapse called renewal. This effect of SN DA stimulation is mimicked by a DA D1 receptor (D1R) agonist injected into the DS, thus implicating DS DA in fear extinction. Different DS subregions subserve unique functions of the DS, but it is unclear where in the DS D1R agonist acts during fear extinction to reduce renewal. Furthermore, although fear extinction increases neural activity in DS subregions, whether neural activity in DS subregions is causally involved in fear extinction is unknown. To explore the role of DS subregions in fear extinction, adult, male Long-Evans rats received microinjections of either the D1R agonist SKF38393 or a cocktail consisting of GABAA/GABAB receptor agonists muscimol/baclofen selectively into either dorsomedial (DMS) or dorsolateral (DLS) DS subregions immediately prior to fear extinction, and extinction retention and renewal were subsequently assessed drug-free. While increasing D1R signaling in the DMS during fear extinction did not impact fear extinction retention or renewal, DMS inactivation reduced later renewal. In contrast, DLS inactivation had no effect on fear extinction retention or renewal but increasing D1R signaling in the DLS during extinction reduced fear renewal. These data suggest that DMS and DLS activity during fear extinction can have opposing effects on later fear renewal, with the DMS promoting renewal and the DLS opposing renewal. Mechanisms through which the DS could influence the contextual gating of fear extinction are discussed.
Sujet(s)
Corps strié , Extinction (psychologie) , Peur , Récepteur dopamine D1 , Animaux , Peur/physiologie , Peur/effets des médicaments et des substances chimiques , Extinction (psychologie)/effets des médicaments et des substances chimiques , Extinction (psychologie)/physiologie , Mâle , Rats , Corps strié/effets des médicaments et des substances chimiques , Corps strié/physiologie , Corps strié/métabolisme , Récepteur dopamine D1/physiologie , Récepteur dopamine D1/métabolisme , Récepteur dopamine D1/antagonistes et inhibiteurs , Agonistes de la dopamine/pharmacologie , Conditionnement classique/effets des médicaments et des substances chimiques , Conditionnement classique/physiologie , Neurones dopaminergiques/effets des médicaments et des substances chimiques , Neurones dopaminergiques/physiologie , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/physiologie , Rat Long-Evans , Dopamine/métabolisme , Dopamine/physiologieRÉSUMÉ
Recent evidence has supported a pathogenic role for neuroinflammation in Parkinson's disease (PD). Inflammatory response has been associated with symptoms and subtypes of PD. However, it is unclear whether immune changes are involved in the initial pathogenesis of PD, leading to the non-motor symptoms (NMS) observed in its prodromal stage. The current study aimed to characterize the behavioral and cognitive changes in a toxin-induced model of prodromal PD-like syndrome. We also sought to investigate the role of neuroinflammation in prodromal PD-related NMS. Male mice were subjected to bilateral intranasal infusion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or saline (control group), followed by comprehensive behavioral, pathological and neurochemical analysis. Intranasal MPTP infusion was able to cause the loss of dopaminergic neurons in the substantia nigra (SN). In parallel, it induced impairment in olfactory discrimination and social memory consolidation, compulsive and anxiety-like behaviors, but did not influence motor performance. Iba-1 and GFAP expressions were increased in the SN, suggesting an activated state of microglia and astrocytes. Consistent with this, MPTP mice had increased levels of IL-10 and IL-17A, and decreased levels of BDNF and TrkA mRNA in the SN. The striatum showed increased IL-17A, BDNF, and NFG levels compared to control mice. In conclusion, neuroinflammation may play an important role in the early stage of experimental PD-like syndrome, leading to cognitive and behavioral changes. Our results also indicate that intranasal administration of MPTP may represent a valuable mouse model for prodromal PD.
Sujet(s)
Modèles animaux de maladie humaine , Souris de lignée C57BL , Symptômes prodromiques , Substantia nigra , Animaux , Mâle , Substantia nigra/métabolisme , Substantia nigra/anatomopathologie , Substantia nigra/effets des médicaments et des substances chimiques , Neurones dopaminergiques/anatomopathologie , Neurones dopaminergiques/métabolisme , Neurones dopaminergiques/effets des médicaments et des substances chimiques , Maladies neuro-inflammatoires/anatomopathologie , Corps strié/métabolisme , Corps strié/effets des médicaments et des substances chimiques , Corps strié/anatomopathologie , Souris , Microglie/métabolisme , Microglie/anatomopathologie , Inflammation/induit chimiquement , Inflammation/métabolisme , Inflammation/anatomopathologie , Facteur neurotrophique dérivé du cerveau/métabolisme , Anxiété/étiologie , 1-Méthyl-4-phényl-1,2,3,6-tétrahydropyridine/pharmacologieRÉSUMÉ
Chronic environmental exposure to toxic heavy metals, which often occurs as a mixture through occupational and industrial sources, has been implicated in various neurological disorders, including Parkinsonism. Vanadium pentoxide (V2O5) typically presents along with manganese (Mn), especially in welding rods and high-capacity batteries, including electric vehicle batteries; however, the neurotoxic effects of vanadium (V) and Mn co-exposure are largely unknown. In this study, we investigated the neurotoxic impact of MnCl2, V2O5, and MnCl2-V2O5 co-exposure in an animal model. C57BL/6 mice were intranasally administered either de-ionized water (vehicle), MnCl2 (252 µg) alone, V2O5 (182 µg) alone, or a mixture of MnCl2 (252 µg) and V2O5 (182 µg) three times a week for up to one month. Following exposure, we performed behavioral, neurochemical, and histological studies. Our results revealed dramatic decreases in olfactory bulb (OB) weight and levels of tyrosine hydroxylase, dopamine, and 3,4-dihydroxyphenylacetic acid in the treatment groups compared to the control group, with the Mn/V co-treatment group producing the most significant changes. Interestingly, increased levels of α-synuclein expression were observed in the substantia nigra (SN) of treated animals. Additionally, treatment groups exhibited locomotor deficits and olfactory dysfunction, with the co-treatment group producing the most severe deficits. The treatment groups exhibited increased levels of the oxidative stress marker 4-hydroxynonenal in the striatum and SN, as well as the upregulation of the pro-apoptotic protein PKCδ and accumulation of glomerular astroglia in the OB. The co-exposure of animals to Mn/V resulted in higher levels of these metals compared to other treatment groups. Taken together, our results suggest that co-exposure to Mn/V can adversely affect the olfactory and nigral systems. These results highlight the possible role of environmental metal mixtures in the etiology of Parkinsonism.
Sujet(s)
Composés du manganèse , Manganèse , Souris de lignée C57BL , Vanadium , Animaux , Souris , Manganèse/toxicité , Vanadium/toxicité , Mâle , Bulbe olfactif/métabolisme , Bulbe olfactif/effets des médicaments et des substances chimiques , Bulbe olfactif/anatomopathologie , Dopamine/métabolisme , Composés du vanadium , Stress oxydatif/effets des médicaments et des substances chimiques , Syndromes parkinsoniens/métabolisme , Syndromes parkinsoniens/induit chimiquement , alpha-Synucléine/métabolisme , Chlorures/toxicité , Chlorures/métabolisme , Tyrosine 3-monooxygenase/métabolisme , Aldéhydes/métabolisme , Substantia nigra/métabolisme , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/anatomopathologie , Modèles animaux de maladie humaine , Acide 3,4-dihydroxy-benzèneacétique/métabolismeRÉSUMÉ
This work aimed to study the effect of repeated exposure to low doses of ozone on alpha-synuclein and the inflammatory response in the substantia nigra, jejunum, and colon. Seventy-two male Wistar rats were divided into six groups. Each group received one of the following treatments: The control group was exposed to air. The ozone groups were exposed for 7, 15, 30, 60, and 90 days for 0.25 ppm for four hours daily. Afterward, they were anesthetized, and their tissues were extracted and processed using Western blotting, immunohistochemistry, and qPCR. The results indicated a significant increase in alpha-synuclein in the substantia nigra and jejunum from 7 to 60 days of exposure and an increase in NFκB from 7 to 90 days in the substantia nigra, while in the jejunum, a significant increase was observed at 7 and 15 days and a decrease at 60 and 90 days for the colon. Interleukin IL-17 showed an increase at 90 days in the substantia nigra in the jejunum and increases at 30 days and in the colon at 15 and 90 days. Exposure to ozone increases the presence of alpha-synuclein and induces the loss of regulation of the inflammatory response, which contributes significantly to degenerative processes.
Sujet(s)
Côlon , Jéjunum , Ozone , Substantia nigra , alpha-Synucléine , Animaux , Mâle , Rats , alpha-Synucléine/métabolisme , Côlon/métabolisme , Côlon/effets des médicaments et des substances chimiques , Côlon/anatomopathologie , Inflammation/métabolisme , Inflammation/induit chimiquement , Inflammation/anatomopathologie , Interleukine-17/métabolisme , Jéjunum/métabolisme , Jéjunum/effets des médicaments et des substances chimiques , Jéjunum/anatomopathologie , Facteur de transcription NF-kappa B/métabolisme , Ozone/toxicité , Rat Wistar , Substantia nigra/métabolisme , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/anatomopathologieRÉSUMÉ
INTRODUCTION: Studies have shown that dexmedetomidine (DEX, an a2-adrenoceptors agonist) provides a neuroprotective effect and influences blood glucose levels. Here, we evaluated the effect of prolonged treatment with low doses of DEX on the survival rate of dopaminergic (DAergic) neurons in the substantia nigra and also serum glucose levels in 6-hydroxydopamine (6-OHDA) - induced Parkinson's disease (PD) in the rat. MATERIAL AND METHODS: The neurotoxin of 6-OHDA was injected into the medial forebrain bundle by stereotaxic surgery. DEX (25 and 50 µg/kg, i.p) and yohimbine, an a2-adrenoceptor antagonist (1 mg/kg, i.p) were administered before the surgery to the 13 weeks afterward. Apomorphine-induced rotational tests and blood sampling were carried out before the surgery and multiple weeks after that. Thirteen weeks after the surgery, the rats' brain was transcardially perfused to assess the survival rate of DAergic neurons using the tyrosine hydroxylase (TH) immunohistochemistry. RESULTS: DEX remarkably attenuated the severity of rotational behavior and reversed the progress of the PD. It also increased the number of TH-labeled neurons by up to 60%. The serum glucose levels in 6-OHDA-received rats did not change in the third and seventh weeks after the surgery but decreased significantly in the thirteenth week. Treatment with DEX prevented this decrement in glucose levels. On the other hand, Treatment with yohimbine did not affect PD symptoms and glucose levels. CONCLUSION: Our data indicate that DEX through neuroprotective activity attenuates the severity of 6-OHDA-induced PD in rats. DEX might also prevent hypoglycemia during the progress of the PD.
Sujet(s)
Agonistes des récepteurs alpha-2 adrénergiques , Dexmédétomidine , Neurones dopaminergiques , Neuroprotecteurs , Oxidopamine , Substantia nigra , Animaux , Dexmédétomidine/pharmacologie , Neuroprotecteurs/pharmacologie , Mâle , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/métabolisme , Neurones dopaminergiques/effets des médicaments et des substances chimiques , Neurones dopaminergiques/métabolisme , Agonistes des récepteurs alpha-2 adrénergiques/pharmacologie , Rats , Glycémie/effets des médicaments et des substances chimiques , Glycémie/métabolisme , Modèles animaux de maladie humaine , Syndromes parkinsoniens/traitement médicamenteux , Syndromes parkinsoniens/métabolisme , Syndromes parkinsoniens/induit chimiquement , Glucose/métabolisme , Rat Sprague-Dawley , Rat Wistar , Tyrosine 3-monooxygenase/métabolismeRÉSUMÉ
In recent years, accumulating evidence supports that occupational exposure to solvents is associated with an increased incidence of Parkinson's disease (PD) among workers. The neurotoxic effects of 1-bromopropane (1-BP), a widely used new-type solvent, are well-established, yet data on its relationship with the etiology of PD remain limited. Simultaneously, high-fat consumption in modern society is recognized as a significant risk factor for PD. However, whether there is a synergistic effect between a high-fat diet and 1-BP exposure remains unclear. In this study, adult C57BL/6 mice were fed either a chow or a high-fat diet for 18 weeks prior to 12-week 1-BP treatment. Subsequent neurobehavioral and neuropathological examinations were conducted to assess the effects of 1-BP exposure on parkinsonian pathology. The results demonstrated that 1-BP exposure produced obvious neurobehavioral abnormalities and dopaminergic degeneration in the nigral region of mice. Importantly, a high-fat diet further exacerbated the impact of 1-BP on motor and cognitive abnormalities in mice. Mechanistic investigation revealed that mitochondrial damage and mtDNA release induced by 1-BP and high-fat diet activate NLRP3 and cGAS-STING pathway- mediated neuroinflammatory response, and ultimately lead to necroptosis of dopaminergic neurons. In summary, our study unveils a potential link between chronic 1-BP exposure and PD-like pathology with motor and no-motor defects in experimental animals, and long-term high-fat diet can further promote 1-BP neurotoxicity, which underscores the pivotal role of environmental factors in the etiology of PD.
Sujet(s)
Alimentation riche en graisse , Neurones dopaminergiques , Hydrocarbures bromés , Souris de lignée C57BL , Mitochondries , Substantia nigra , Animaux , Hydrocarbures bromés/toxicité , Neurones dopaminergiques/effets des médicaments et des substances chimiques , Neurones dopaminergiques/anatomopathologie , Souris , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/anatomopathologie , Substantia nigra/métabolisme , Mâle , Mitochondries/effets des médicaments et des substances chimiques , Mitochondries/anatomopathologie , Solvants/toxicitéRÉSUMÉ
BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by the presence of proteinaceous alpha-synuclein (α-syn) inclusions (Lewy bodies), markers of neuroinflammation and the progressive loss of nigrostriatal dopamine (DA) neurons. These pathological features can be recapitulated in vivo using the α-syn preformed fibril (PFF) model of synucleinopathy. We have previously determined that microglia proximal to PFF-induced nigral α-syn inclusions increase in soma size, upregulate major-histocompatibility complex-II (MHC-II) expression, and increase expression of a suite of inflammation-associated transcripts. This microglial response is observed months prior to degeneration, suggesting that microglia reacting to α-syn inclusion may contribute to neurodegeneration and could represent a potential target for novel therapeutics. The goal of this study was to determine whether colony stimulating factor-1 receptor (CSF1R)-mediated microglial depletion impacts the magnitude of α-syn aggregation, nigrostriatal degeneration, or the response of microglial in the context of the α-syn PFF model. METHODS: Male Fischer 344 rats were injected intrastriatally with either α-syn PFFs or saline. Rats were continuously administered Pexidartinib (PLX3397B, 600 mg/kg), a CSF1R inhibitor, to deplete microglia for a period of either 2 or 6 months. RESULTS: CSF1R inhibition resulted in significant depletion (~ 43%) of ionized calcium-binding adapter molecule 1 immunoreactive (Iba-1ir) microglia within the SNpc. However, CSF1R inhibition did not impact the increase in microglial number, soma size, number of MHC-II immunoreactive microglia or microglial expression of Cd74, Cxcl10, Rt-1a2, Grn, Csf1r, Tyrobp, and Fcer1g associated with phosphorylated α-syn (pSyn) nigral inclusions. Further, accumulation of pSyn and degeneration of nigral neurons was not impacted by CSF1R inhibition. Paradoxically, long term CSF1R inhibition resulted in increased soma size of remaining Iba-1ir microglia in both control and PFF rats, as well as expression of MHC-II in extranigral regions. CONCLUSIONS: Collectively, our results suggest that CSF1R inhibition does not impact the microglial response to nigral pSyn inclusions and that CSF1R inhibition is not a viable disease-modifying strategy for PD.
Sujet(s)
Microglie , Rats de lignée F344 , Récepteur de facteur de croissance granulocyte-macrophage , alpha-Synucléine , Animaux , Microglie/métabolisme , Microglie/effets des médicaments et des substances chimiques , alpha-Synucléine/métabolisme , Rats , Mâle , Récepteur de facteur de croissance granulocyte-macrophage/antagonistes et inhibiteurs , Récepteur de facteur de croissance granulocyte-macrophage/métabolisme , Pyrroles/pharmacologie , Aminopyridines/pharmacologie , Corps d'inclusion/métabolisme , Corps d'inclusion/anatomopathologie , Substantia nigra/métabolisme , Substantia nigra/anatomopathologie , Substantia nigra/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaineRÉSUMÉ
The spontaneous firing activity of nigral dopaminergic neurons is associated with some important roles including modulation of dopamine release, expression of tyrosine hydroxylase (TH), as well as neuronal survival. The decreased neuroactivity of nigral dopaminergic neurons has been revealed in Parkinson's disease. Central glucagon-like peptide-1 (GLP-1) functions as a neurotransmitter or neuromodulator to exert multiple brain functions. Although morphological studies revealed the expression of GLP-1 receptors (GLP-1Rs) in the substantia nigra pars compacta, the possible modulation of GLP-1 on spontaneous firing activity of nigral dopaminergic neurons is unknown. The present extracellular in vivo single unit recordings revealed that GLP-1R agonist exendin-4 significantly increased the spontaneous firing rate and decreased the firing regularity of partial nigral dopaminergic neurons of adult male C57BL/6 mice. Blockade of GLP-1Rs by exendin (9-39) decreased the firing rate of nigral dopaminergic neurons suggesting the involvement of endogenous GLP-1 in the modulation of firing activity. Furthermore, the PKA and the transient receptor potential canonical (TRPC) 4/5 channels are involved in activation of GLP-1Rs-induced excitatory effects of nigral dopaminergic neurons. Under parkinsonian state, both the exogenous and endogenous GLP-1 could still induce excitatory effects on the surviving nigral dopaminergic neurons. As the mild excitatory stimuli exert neuroprotective effects on nigral dopaminergic neurons, the present GLP-1-induced excitatory effects may partially contribute to its antiparkinsonian effects.
Sujet(s)
Potentiels d'action , Neurones dopaminergiques , Exénatide , Glucagon-like peptide 1 , Récepteur du peptide-1 similaire au glucagon , Souris de lignée C57BL , Substantia nigra , Animaux , Mâle , Neurones dopaminergiques/effets des médicaments et des substances chimiques , Neurones dopaminergiques/métabolisme , Glucagon-like peptide 1/métabolisme , Glucagon-like peptide 1/pharmacologie , Exénatide/pharmacologie , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/métabolisme , Récepteur du peptide-1 similaire au glucagon/métabolisme , Récepteur du peptide-1 similaire au glucagon/agonistes , Potentiels d'action/effets des médicaments et des substances chimiques , Potentiels d'action/physiologie , Souris , Venins/pharmacologie , Peptides/pharmacologie , Syndromes parkinsoniens/métabolisme , Syndromes parkinsoniens/physiopathologie , Fragments peptidiques/pharmacologie , Cyclic AMP-Dependent Protein Kinases/métabolismeRÉSUMÉ
Parkinson's disease (PD) is a neurodegenerative disease characterized by dopaminergic neuron death and neuroinflammation. Emerging evidence points to the involvement of the transient receptor potential melastatin 2 (TRPM2) channel in neuron death and glial activation in several neurodegenerative diseases. However, the involvement of TRPM2 in PD and specifically its relation to the neuroinflammation aspect of the disease remains poorly understood. Here, we hypothesized that AG490, a TRPM2 inhibitor, can be used as a treatment in a mouse model of PD. Mice underwent stereotaxic surgery for 6-hydroxydopamine (6-OHDA) administration in the right striatum. Motor behavioral tests (apomorphine, cylinder, and rotarod) were performed on day 3 post-injection to confirm the PD model induction. AG490 was then daily injected i.p. between days 3 to 6 after surgery. On day 6, motor behavior was assessed again. Substantia nigra (SNc) and striatum (CPu) were collected for immunohistochemistry, immunoblotting, and RT-qPCR analysis on day 7. Our results revealed that AG490 post-treatment reduced motor behavior impairment and nigrostriatal neurodegeneration. In addition, the compound prevented TRPM2 upregulation and changes of the Akt/GSK-3ß/caspase-3 signaling pathway. The TRPM2 inhibition also avoids the glial morphology changes observed in the PD group. Remarkably, the morphometrical analysis revealed that the ameboid-shaped microglia, found in 6-OHDA-injected animals, were no longer present in the AG490-treated group. These results indicate that AG490 treatment can reduce dopaminergic neuronal death and suppress neuroinflammation in a PD mouse model. Inhibition of TRPM2 by AG490 could then represent a potential therapeutical strategy to be evaluated for PD treatment.
Sujet(s)
Souris de lignée C57BL , Névroglie , Canaux cationiques TRPM , Tyrphostines , Animaux , Canaux cationiques TRPM/antagonistes et inhibiteurs , Canaux cationiques TRPM/métabolisme , Souris , Mâle , Névroglie/effets des médicaments et des substances chimiques , Névroglie/métabolisme , Névroglie/anatomopathologie , Tyrphostines/pharmacologie , Tyrphostines/usage thérapeutique , Évolution de la maladie , Oxidopamine/toxicité , Modèles animaux de maladie humaine , Dégénérescence nerveuse/anatomopathologie , Dégénérescence nerveuse/traitement médicamenteux , Syndromes parkinsoniens/anatomopathologie , Syndromes parkinsoniens/métabolisme , Syndromes parkinsoniens/prévention et contrôle , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/anatomopathologie , Substantia nigra/métabolisme , Maladie de Parkinson/anatomopathologie , Maladie de Parkinson/métabolisme , Maladie de Parkinson/traitement médicamenteuxRÉSUMÉ
BACKGROUND: Parkinson's disease (PD) is a prevailing neurodegenerative disorder increasingly affecting the elderly population. The involvement of microRNAs (miRNAs) in PD has been confirmed. We sought to explore the molecular mechanism of miR-20a-5p in PD. METHODS: Lipopolysaccharide (LPS)-induced BV2 cell model and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP-HCl)-induced PD mouse model were established. miR-20a-5p, inducible nitric oxide synthase (iNOS), interleukin (IL)-6, tumour necrosis factor (TNF)-α, transforming growth factor (TGF)-ß1, and IL-10 expression in BV2 cells was examined by reverse transcription - quantitative polymerase chain reaction. Cell viability was assessed by MTT assay. The apoptotic rate and levels of Bcl-2, Bax, cleaved caspase-3, and signal transducer and activator of transmission (STAT)3 were examined by flow cytometry and Western blot. Bioinformatics software predicted the potential binding sites of miR-20a-5p and STAT3. Dual-luciferase experiment verified the binding relationship. Iba1-positive and tyrosine hydroxylase (TH)-positive cell numbers in substantia nigra pars compacta were detected by immunohistochemistry. The effect of miR-20a-5p on motor function in MPTP-induced PD mice was detected by Rota-rod test, Pole test, Traction test and Beam-crossing task. RESULTS: miR-20a-5p was under-expressed in LPS-induced BV2 cells. Overexpression of miR-20a-5p increased the viability of LPS-induced BV2 cells and reduced apoptosis rates. Moreover, overexpression of miR-20a-5p reduced cleaved caspase-3, Bax, iNOS, IL-6, and TNF-α and increased Bcl-2 and TGF-ß1, and IL-10. miR-20a-5p targeted STAT3. STAT3 overexpression partially reversed miR-20a-5p overexpression-mediated effects on LPS-induced BV2 cell viability, apoptosis, and inflammatory responses. miR-20a-5p overexpression inhibited MPTP-induced STAT3 and α-synuclein levels, microglia activation, and inflammatory response, and reduced the loss of TH-positive cells in mice. miR-20a-5p overexpression ameliorated MPTP-induced dyskinesia in PD model mice. CONCLUSION: miR-20a-5p alleviates neuronal damage and suppresses inflammation by targeting STAT3 in PD.