RESUMEN
Ferroptosis is an iron-dependent cell death form characterized by reactive oxygen species (ROS) overgeneration and lipid peroxidation. Myricetin, a flavonoid that exists in numerous plants, exhibits potent antioxidant capacity. Given that iron accumulation and ROS-provoked dopaminergic neuron death are the two main pathological hallmarks of Parkinson's disease (PD), we aimed to investigate whether myricetin decreases neuronal death through suppressing ferroptosis. The PD models were established by intraperitoneally injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into rats and by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+), respectively. Ferroptosis was identified by assessing the levels of Fe2+, ROS, malondialdehyde (MDA), and glutathione (GSH). The results demonstrated that myricetin treatment effectively mitigated MPTP-triggered motor impairment, dopamine neuronal death, and α-synuclein (α-Syn) accumulation in PD models. Myricetin also alleviated MPTP-induced ferroptosis, as evidenced by decreased levels of Fe2+, ROS, and MDA and increased levels of GSH in the substantia nigra (SN) and serum in PD models. All these changes were reversed by erastin, a ferroptosis activator. In vitro, myricetin treatment restored SH-SY5Y cell viability and alleviated MPP+-induced SH-SY5Y cell ferroptosis. Mechanistically, myricetin accelerated nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and subsequent glutathione peroxidase 4 (Gpx4) expression in MPP+-treated SH-SY5Y cells, two critical inhibitors of ferroptosis. Collectively, these data demonstrate that myricetin may be a potential agent for decreasing dopaminergic neuron death by inhibiting ferroptosis in PD.
Asunto(s)
Modelos Animales de Enfermedad , Neuronas Dopaminérgicas , Ferroptosis , Flavonoides , Especies Reactivas de Oxígeno , Ferroptosis/efectos de los fármacos , Animales , Flavonoides/farmacología , Ratas , Masculino , Especies Reactivas de Oxígeno/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Humanos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Línea Celular Tumoral , Hierro/metabolismo , alfa-Sinucleína/metabolismo , Ratas Sprague-Dawley , Glutatión/metabolismo , Peroxidación de Lípido/efectos de los fármacos , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Factor 2 Relacionado con NF-E2/metabolismoRESUMEN
Parkinson's disease (PD) is a prevalent progressive and multifactorial neurodegenerative disorder. Cordycepin is known to exhibit antitumor, anti-inflammatory, antioxidative stress, and neuroprotective effects; however, few studies have explored the neuroprotective mechanism of cordycepin in PD. Using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model, we investigated the impact of cordycepin on PD and its underlying molecular mechanisms. The findings indicated that cordycepin significantly mitigated MPTP-induced behavior disorder and neuroapoptosis, diminished the loss of dopaminergic neurons in the striatum-substantia nigra pathway, elevated striatal monoamine levels and its metabolites, and inhibited the polarization of microglia and the expression of pro-inflammatory factors. Subsequent proteomic and phosphoproteomic analyses revealed the involvement of the MAPK, mTOR, and PI3K/AKT signaling pathways in the protective mechanism of cordycepin. Cordycepin treatment inhibited the activation of the PI3K/AKT/mTOR signaling pathway and enhanced the expression of autophagy proteins in the striatum and substantia nigra. We also demonstrated the in vivo inhibition of the ERK/JNK signaling pathway by cordycepin treatment. In summary, our investigation reveals that cordycepin exerts neuroprotective effects against PD by promoting autophagy and suppressing neuroinflammation and neuronal apoptosis by inhibiting the PI3K/AKT/mTOR and ERK/JNK signaling pathways. This finding highlights the favorable characteristics of cordycepin in neuroprotection and provides novel molecular insights into the neuroprotective role of natural products in PD.
Asunto(s)
Desoxiadenosinas , Fármacos Neuroprotectores , Enfermedad de Parkinson , Ratones , Animales , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Fármacos Neuroprotectores/farmacología , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Enfermedades Neuroinflamatorias , Proteómica , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Ratones Endogámicos C57BL , Neuronas Dopaminérgicas/metabolismo , Modelos Animales de Enfermedad , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversosRESUMEN
Parkinson's disease (PD) is marked by the degeneration of dopaminergic neurons of the substantia nigra (SN), with neuroinflammation and mitochondrial dysfunction being key contributors. The neuroprotective potential of folic acid (FA) in the dopaminergic system of PD was assessed in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model. MPTP (20 mg/kg of body weight) was administered to C57BL/6J mice to simulate PD symptoms followed by FA treatment (5 mg/kg of body weight). Behavioral tests, pole, rotarod, and open-field tests, evaluated motor function, while immunohistochemistry, ELISA, RT-qPCR, and Western blotting quantified neuroinflammation, oxidative stress markers, and mitochondrial function. FA supplementation considerably improved motor performance, reduced homocysteine levels and mitigated oxidative damage in the SN. The FA-attenuated activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome lessened glial cell activity and reduced neuroinflammation. At the molecular level, FA reduced DNA damage, downregulated phosphorylated p53, and induced the expression of peroxisome proliferator-activated receptor α coactivator 1α (PGC-1α), enhancing mitochondrial function. Therefore, FA exerts neuroprotection in MPTP-induced PD by inhibiting neuroinflammation via NLRP3 inflammasome suppression and promoting mitochondrial integrity through the p53-PGC-1α pathway. Notable limitations of our study include its reliance on a single animal model and the incompletely elucidated mechanisms underlying the impact of FA on mitochondrial dynamics. Future investigations will explore the clinical utility of FA and its molecular mechanisms, further advancing it as a potential therapeutic for managing and delaying the progression of PD.
Asunto(s)
Intoxicación por MPTP , Fármacos Neuroprotectores , Enfermedad de Parkinson , Ratones , Animales , Inflamasomas/genética , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Neuronas Dopaminérgicas , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/metabolismo , Enfermedades Neuroinflamatorias , Proteína p53 Supresora de Tumor/metabolismo , Ratones Endogámicos C57BL , Enfermedad de Parkinson/genética , Mitocondrias/metabolismo , Peso Corporal , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacologíaRESUMEN
Parkinson's disease (PD), a neurodegenerative disease, is the leading cause of movement disorders. Neuroinflammation plays a critical role in PD pathogenesis. Neohesperidin (Neo), a natural flavonoid extracted from citric fruits exhibits anti-inflammatory effects. However, the effect of Neo on PD progression is unclear. This study aimed to investigate the effects of Neo on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice and its underlying mechanism. Our results indicated that Neo administration ameliorated motor impairment and neural damage in MPTP-injected mice, by inhibiting neuroinflammation and regulating gut microbial imbalance. Additionally, Neo administration reduced colonic inflammation and tissue damage. Mechanistic studies revealed that Neo suppressed the MPTP-induced inflammatory response by inhibiting excessive activation of NF-κB and MAPK pathways. In summary, the present study demonstrated that Neo administration attenuates neurodegeneration in MPTP-injected mice by inhibiting inflammatory responses and regulating the gut microbial composition. This study may provide the scientific basis for the use of Neo in the treatment of PD and other related diseases.
Asunto(s)
Microbioma Gastrointestinal , Hesperidina/análogos & derivados , Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Enfermedad de Parkinson , Ratones , Animales , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neuroinflamatorias , Enfermedad de Parkinson/metabolismo , Ratones Endogámicos C57BL , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacologíaRESUMEN
Parkinson's disease (PD) is an incurable neurological disorder that causes typical motor deficits. In this study, we investigated the effects of creatine supplementation and exercise in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We found that 2% creatine supplementation and/or exercise intervention for 4 weeks elicited neurobehavioral recovery and neuroprotective effects regarding dopaminergic cell loss in MPTP-treated mice; this effect implies functional preservation of dopaminergic cells in the substantia nigra, as reflected by tyrosine hydroxylase expression recovery. Creatine and exercise reduced necroptotic activity in dopaminergic cells by lowering mixed lineage kinase domain-like protein (MLKL) modification to active phenotypes (phosphorylation at Ser345 and oligomerization) and phosphorylated receptor-interacting protein kinase 1 (RIPK1) (Ser166-p) and RIPK3 (Ser232-p) levels. In addition, creatine and exercise reduced the MPTP-induced increase in pathogenic α-synuclein forms, such as Ser129 phosphorylation and oligomerization. Furthermore, creatine and exercise had anti-inflammatory and antioxidative effects in MPTP mice, as evidenced by a decrease in microglia activation, NF-κB-dependent pro-inflammatory molecule expression, and increase in antioxidant enzyme expression. These phenotypic changes were associated with the exercise/creatine-induced AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2) and sirtuin 3 (SIRT3)/forkhead box O3 (FoxO3a) signaling pathways. In all experiments, combining creatine with exercise resulted in considerable improvement over either treatment alone. Consequently, these findings suggest that creatine supplementation with exercise has anti-inflammatory, antioxidative, and anti-α-synucleinopathy effects, thereby reducing necroptotic cell death in a PD mouse model.
Asunto(s)
Fármacos Neuroprotectores , Enfermedad de Parkinson , Ratones , Animales , Enfermedad de Parkinson/tratamiento farmacológico , alfa-Sinucleína/metabolismo , Creatina/farmacología , Creatina/uso terapéutico , Necroptosis , Neuronas Dopaminérgicas/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Antiinflamatorios/farmacología , Suplementos Dietéticos , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/metabolismoRESUMEN
Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms and neuropathological features, such as loss of dopaminergic neurons in the substantia nigra pars compacta and accumulation of alpha-synuclein (α-Syn). Progranulin (PGRN) is a secreted growth factor that exhibits anti-inflammatory properties and regulates lysosomal function. Although autophagy-lysosome pathway is the main degradative pathway for α-Syn, the molecular mechanistic relationship between PD and PGRN remains unclear. In this study, we investigated the role of PGRN in PD pathology. PGRN protein expression in striatum was increased in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice. Intracerebroventricular (i.c.v.) administration of PGRN ameliorated the decrease in expression of tyrosine hydroxylase, a dopaminergic neuron marker, in MPTP-treated mice. Furthermore, i.c.v. administration of PGRN ameliorated 6-hydroxydopamine-induced motor deficits. In SH-SY5Y human neuroblastoma cells, 1-methyl-4-phenylpyridinium ion (MPP+), an active metabolite of MPTP, increased α-Syn expression. In contrast, PGRN ameliorated MPP+-induced increase in α-Syn expression. Although PGRN decreased the levels of autophagy-related proteins Sequestosome-1 (p62) and MAP1LC3 (LC3)-II, PGRN did not influence the phosphorylation of AMP-activated protein kinase and mechanistic target of rapamycin, which are also proteins that regulate autophagy. Immunostaining analysis showed that PGRN ameliorated MPP+-induced increase of LC3 puncta, indicator of autophagosome, and co-localization of LC3 and α-Syn. The DALGreen assay showed that PGRN ameliorated MPP+-induced decreasing trend of autolysosomes. These results suggest that PGRN participates in α-Syn degradation via acceleration of the autophagy-lysosome pathway and is a potential therapeutic target for PD.
Asunto(s)
Neuroblastoma , Enfermedad de Parkinson , Animales , Humanos , Ratones , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , alfa-Sinucleína/metabolismo , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Lisosomas/metabolismo , Ratones Endogámicos C57BL , Neuroblastoma/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Progranulinas/metabolismoRESUMEN
Trolox is a potent antioxidant and a water-soluble analog of vitamin E. It has been used in scientific studies to examine oxidative stress and its impact on biological systems. Trolox has been shown to have a neuroprotective effect against ischemia and IL-1ß-mediated neurodegeneration. In this study, we investigated the potential protective mechanisms of Trolox against a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mouse model. Western blotting, immunofluorescence staining, and ROS/LPO assays were performed to investigate the role of trolox against neuroinflammation, the oxidative stress mediated by MPTP in the Parkinson's disease (PD) mouse model (wild-type mice (C57BL/6N), eight weeks old, average body weight 25-30 g). Our study showed that MPTP increased the expression of α-synuclein, decreased tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels in the striatum and substantia nigra pars compacta (SNpc), and impaired motor function. However, Trolox treatment significantly reversed these PD-like pathologies. Furthermore, Trolox treatment reduced oxidative stress by increasing the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Lastly, Trolox treatment inhibited the activated astrocytes (GFAP) and microglia (Iba-1), also reducing phosphorylated nuclear factor-κB, (p-NF-κB) and tumor necrosis factor-alpha (TNF-α) in the PD mouse brain. Overall, our study demonstrated that Trolox may exert neuroprotection on dopaminergic neurons against MPTP-induced oxidative stress, neuroinflammation, motor dysfunction, and neurodegeneration.
Asunto(s)
Trastornos Motores , Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Ratones , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Enfermedades Neuroinflamatorias , Vitamina E/farmacología , Trastornos Motores/metabolismo , Sustancia Negra/metabolismo , Ratones Endogámicos C57BL , Tirosina 3-Monooxigenasa/metabolismo , Neuronas Dopaminérgicas/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/metabolismo , Estrés Oxidativo , Modelos Animales de EnfermedadRESUMEN
Previous studies have shown that peptides isolated from C-phycocyanin (C-PC) possess various functions including antioxidant and anticancer activities. However, there is little research on C-PC peptides applied for the neuroprotective effect against a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) model. In this study, twelve novel peptides from C-PC were isolated, purified and identified, and the anti-PD effect of the synthesized peptides was evaluated in a zebrafish PD model. As a result, three of these peptides (MAAAHR, MPQPPAK, and MTAAAR) significantly reversed the loss of dopamine neurons and cerebral vessels, and reduced the locomotor impairment in PD zebrafish. In addition, three novel peptides could inhibit the MPTP-induced decrease of antioxidant enzymes (SOD, CAT, and GSH-Px) and increase the ROS and protein carbonylation content. In addition, they can also alleviate apoptosis of brain regions and acetylcholinesterase (AChE) activity in zebrafish. Further studies elucidated the potential molecular mechanism of peptides' anti-PD effects in the larvae. The results showed that C-PC peptides could modulate multiple genes associated with oxidative stress, autophagy and apoptosis signaling pathways, and thereby alleviate the occurrence of PD symptoms. Overall, our results highlight the neuroprotective effects of three novel peptides and provide valuable mechanistic insights and a promising drug target for the treatment of PD.
Asunto(s)
Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Ratones , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Pez Cebra/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Ficocianina/farmacología , Ficocianina/uso terapéutico , Antioxidantes/metabolismo , Acetilcolinesterasa , Péptidos/farmacología , Péptidos/uso terapéutico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
Parkinson's disease (PD) is closely linked to lifestyle factors, particularly dietary patterns, which have attracted interest as potential disease-modifying factors. Eating a low-protein, high-carbohydrate (LPHC) diet is a promising dietary intervention against brain aging; however, its protective effect on PD remains elusive. Here, we found that an LPHC diet ameliorated 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced motor deficits, decreased dopaminergic neuronal death, and increased the levels of striatal dopamine, serotonin, and their metabolites in PD mice. Levels of fibroblast growth factor 21 (FGF-21), a member of the fibroblast growth factor family, were elevated in PD mice following LPHC treatment. Furthermore, the administration of FGF-21 exerted a protective effect on MPTP-induced PC12 cells, similar to the effect of an LPHC diet in MPTP-induced mice. Sequencing of the 16S rDNA from fecal microbiota revealed that an LPHC diet normalized the gut bacterial composition imbalance in PD mice, as evidenced by the increased abundance of the genera Bifidobacterium, Ileibacterium, Turicibacter, and Blautia and decreased abundance of Bilophila, Alistipes, and Bacteroides. PICRUSt-predicted fecal microbiome function revealed that an LPHC diet suppressed lipopolysaccharide biosynthesis and the citrate cycle (TCA cycle), biosynthesis of ubiquinone and other terpenoid-quinones, and oxidative phosphorylation pathways caused by MPTP, and enhanced the biosynthesis of amino acids, carbohydrate metabolism, and biosynthesis of other secondary metabolites. A nonmetabolomic analysis of the serum and feces showed that an LPHC diet significantly increased the levels of aromatic amino acids (AAAs), including tryptophan, tyrosine, and phenylalanine. In addition, an LPHC diet elevated the serum concentrations of bile acids (BAs), particularly tauroursodeoxycholic acid (TUDCA) and taurine. Collectively, our current findings point to the potential mechanism of administering an LPHC diet in attenuating movement impairments in MPTP-induced PD mice, with AAAs, microbial metabolites (TUDCA and taurine), and FGF-21 as key mediators along the gut-microbiota-brain axis.
Asunto(s)
Microbiota , Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Ratones , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Fármacos Neuroprotectores/farmacología , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Ácido Tauroquenodesoxicólico/farmacología , Encéfalo/metabolismo , Dopamina/metabolismo , Dieta , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra that results in a decrease in dopamine levels, resulting in motor-type disturbances. Different vertebrate models, such as rodents and fish, have been used to study PD. In recent decades, Danio rerio (zebrafish) has emerged as a potential model for the investigation of neurodegenerative diseases due to its homology to the nervous system of humans. In this context, this systematic review aimed to identify publications that reported the utilization of neurotoxins as an experimental model of parkinsonism in zebrafish embryos and larvae. Ultimately, 56 articles were identified by searching three databases (PubMed, Web of Science, and Google Scholar). Seventeen studies using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 4 1-methyl-4-phenylpyridinium (MPP+), 24 6-hydroxydopamine (6-OHDA), 6 paraquat/diquat, 2 rotenone, and 6 articles using other types of unusual neurotoxins to induce PD were selected. Neurobehavioral function, such as motor activity, dopaminergic neuron markers, oxidative stress biomarkers, and other relevant parameters in the zebrafish embryo-larval model were examined. In summary, this review provides information to help researchers determine which chemical model is suitable to study experimental parkinsonism, according to the effects induced by neurotoxins in zebrafish embryos and larvae.
Asunto(s)
Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Trastornos Parkinsonianos , Humanos , Animales , Neurotoxinas/efectos adversos , Pez Cebra , Enfermedad de Parkinson/etiología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Larva , Trastornos Parkinsonianos/inducido químicamente , Modelos Teóricos , Modelos Animales de EnfermedadRESUMEN
Neuroinflammation and oxidative stress have been emerging as important pathways contributing to Parkinson's disease (PD) pathogenesis. In PD brains, the activated microglia release inflammatory factors such as interleukin (IL)-ß, IL-6, tumor necrosis factor (TNF)-α, and nitric oxide (NO), which increase oxidative stress and mediate neurodegeneration. Using 1-methyl-4-phenylpyridinium (MPP+)-activated human microglial HMC3 cells and the sub-chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, we found the potential of indole derivative NC009-1 against neuroinflammation, oxidative stress, and neurodegeneration for PD. In vitro, NC009-1 alleviated MPP+-induced cytotoxicity, reduced NO, IL-1ß, IL-6, and TNF-α production, and suppressed NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in MPP+-activated HMC3 cells. In vivo, NC009-1 ameliorated motor deficits and non-motor depression, increased dopamine and dopamine transporter levels in the striatum, and reduced oxidative stress as well as microglia and astrocyte reactivity in the ventral midbrain of MPTP-treated mice. These protective effects were achieved by down-regulating NLRP3, CASP1, iNOS, IL-1ß, IL-6, and TNF-α, and up-regulating SOD2, NRF2, and NQO1. These results strengthen the involvement of neuroinflammation and oxidative stress in PD pathogenic mechanism, and indicate NC009-1 as a potential drug candidate for PD treatment.
Asunto(s)
Enfermedad de Parkinson , Ratones , Humanos , Animales , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Neurotoxinas/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Enfermedades Neuroinflamatorias , Interleucina-6/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Microglía/metabolismo , 1-Metil-4-fenilpiridinio/toxicidad , Estrés Oxidativo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversosRESUMEN
For centuries, Sophora alopecuroides L. has been used both as a food and an herbal medicine in northern China. A new cytisine-type alkaloid, N-methylene-(5,7,4[Formula: see text]-trihydroxy)-isoflavone (LY01), was found in the fruits of Sophora alopecuroides L. and shows neuroprotective effects against Parkinson's disease (PD). PD is a frequently occurring, irreversible neurodegenerative disease that seriously threatens the health of the elderly population. There is no cure for PD. The available treatments help manage the symptoms, but their use is limited by multiple side effects. Therefore, more pharmacological treatments addressing this pathology are urgently required. This study aimed to evaluate the neuroprotective effects of LY01 against PD, as well as their underlying mechanisms, using both in vitro and in vivo experimental models. A 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride (MPTP)-induced mouse model of PD was used to assess the effects of LY01 on the motor coordination deficit, progression of the pathology, and molecular characteristics. 1-Methyl-4-phenylpyridinium (MPP[Formula: see text])-activated SH-SY5Y cells and lipopolysaccharide (LPS)-activated BV-2 cells were used to evaluate LY01 effects on oxidative damage and neuroinflammation. In the rotarod test, LY01 alleviated the impaired motor coordination in PD mice. Furthermore, LY01 treatment prevented the loss of dopaminergic neurons in the substantia nigra and striatum of the PD mice, reduced neuroinflammation in the mice with MPTP-induced PD and the LPS-activated BV-2 cells, and diminished oxidative stress in the PD mice and the MPP[Formula: see text]-induced SH-SY5Y cells. In conclusion, these results suggest the potential of LY01 as a therapeutic agent for treating PD.
Asunto(s)
Neuroblastoma , Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Enfermedad de Parkinson , Anciano , Humanos , Ratones , Animales , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Fármacos Neuroprotectores/farmacología , Enfermedades Neurodegenerativas/tratamiento farmacológico , Lipopolisacáridos/efectos adversos , Enfermedades Neuroinflamatorias , Neuroblastoma/patología , Estrés Oxidativo , Neuronas Dopaminérgicas/patología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversosRESUMEN
Nervonic acid is one of the most promising bioactive fatty acids, which is believed to be beneficial for the recovery of human cognitive disorders. However, the detailed neuroprotective effects and mode of action of nervonic acid have not yet been fully elucidated. In this study, we used an MPTP-stimulated mouse Parkinson's disease (PD) model as a target to investigate the neuroprotective effects by behavioral tests and integrative analysis of trancriptomes and metabolomes of PD mouse brain with nervonic acid injections. The KEGG pathway enrichment analysis of transcriptomes showed that the genes involved in neuroinflammation were significantly increased after MPTP induction and have been greatly inhibited by nervonic acid injection, while nervonic acid also greatly improved nerve growth and synaptic plasticity pathways which were significantly downregulated by MPTP. At the same time, the upregulation of oleic acid and arachidonic acid metabolism pathways and the downregulation of amino acid metabolism pathways in metabolomes were particularly highlighted in the nervonic acid protection groups compared with the PD model. Meanwhile, it was found that arachidonic acid, oleic acid and taurine play an important regulatory role in the neuroprotective mechanism of nervonic acid through fatty acid metabolism by integrative analysis. Therefore, our study laid a solid foundation for further studies on the specific role of nervonic acid in the inhibition of PD at the level of metabolic regulation.
Asunto(s)
Fármacos Neuroprotectores , Enfermedad de Parkinson , Humanos , Animales , Ratones , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Transcriptoma , Enfermedades Neuroinflamatorias , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Ácidos Araquidónicos , Ácidos Oléicos , Ratones Endogámicos C57BL , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Modelos Animales de EnfermedadRESUMEN
Parkinson's disease (PD) is a neurodegenerative disease (NDD) with high and ongoing morbidity, bringing heavy burdens to PD patients seriously. Finding neurotrophic drugs still remains vital due to the limited drug spectrum available currently. Substantial evidence suggests that glucagon-like peptide 1 (GLP-1) exerts neuroprotection on PD, yet the short-lived biological activity markedly hindered its application. Herein, we investigated the neurotrophic role of the next-generation probiotic strain L. lactis MG1363-pMG36e-GLP-1 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice and elucidated the mechanisms. Our data suggested that L. lactis MG1363-pMG36e-GLP-1 markedly enhanced motor deficits induced by MPTP via rescuing dopaminergic (DAergic) neurodegeneration in substantia nigra (SN). We found that L. lactis MG1363-pMG36e-GLP-1 exerts neurotrophic effects via activating the Keap1/Nrf2/GPX4 signalling pathway to down-regulate ACSL4 and up-regulate FSP1 to suppress ferroptosis. Additionally, the decreased oxidative stress levels via suppressing generations of ROS and MDA supported our findings. Lastly, we identified that the L. lactis MG1363-pMG36e-GLP-1 administration reversed dysbiosis in PD mice by increasing Akkermansia, Oscillospira, and Sutterella at the genus level. These results indicated that the neurotrophic effects of the next-generation probiotics L. lactis MG1363-pMG36e-GLP-1 against MPTP-induced Parkinsonism are mediated by modulating oxidative stress, inhibiting ferroptosis, and redressing dysbiosis.
Asunto(s)
Ferroptosis , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Probióticos , Ratones , Animales , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Disbiosis , Factor 2 Relacionado con NF-E2/metabolismoRESUMEN
N-methyl-D-aspartate (NMDA) receptors have been implicated in L-Dopa-induced dyskinesias (LID) in Parkinson's disease patients, but the use of antagonists that directly inhibit this receptor is associated with severe side effects. L-4-chlorokynurenine (4-Cl-KYN or AV-101) is a pro-drug of 7-chlorokynurenic acid (7-Cl-KYNA), a potent and specific antagonist of the glycine (GlyB) co-agonist site of NMDA receptors. The 7-Cl-KYNA has limited ability to cross the blood-brain barrier, whereas AV-101 readily accesses the brain. We investigated if AV-101 reduces LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys while maintaining the antiparkinsonian activity of L-Dopa. A first pilot study using three dyskinetic MPTP monkeys showed that acute AV-101 treatment (250 and 450 mg/kg) reduced LID and maintained the antiparkinsonian activity of L-Dopa. The main study using six additional dyskinetic MPTP monkeys showed that repeated AV-101 treatment (250 mg/kg, b.i.d. for 4 consecutive days) maintained their L-Dopa antiparkinsonian response. We measured significantly less LID when AV-101 was combined with L-Dopa treatment. AV-101 alone or with L-Dopa had no non-motor adverse effects in MPTP monkeys. Our study showed antidyskinetic activity of AV-101 in MPTP monkeys was comparable to amantadine tested previously in our laboratory in this model. We observed no adverse effects with AV-101, which is an improvement over amantadine, with its known side effects.
Asunto(s)
Discinesia Inducida por Medicamentos , Fármacos Neuroprotectores , Trastornos Parkinsonianos , Profármacos , Animales , Levodopa/efectos adversos , Receptores de N-Metil-D-Aspartato , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Discinesia Inducida por Medicamentos/etiología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Glicina/farmacología , Glicina/uso terapéutico , Proyectos Piloto , Trastornos Parkinsonianos/inducido químicamente , Macaca fascicularis , Antiparkinsonianos/efectos adversos , Fármacos Neuroprotectores/uso terapéutico , Amantadina/farmacología , Amantadina/uso terapéuticoRESUMEN
Accumulating evidence has shown that Parkinson's disease (PD) is a systemic disease other than a mere central nervous system (CNS) disorder. One of the most important peripheral symptoms is gastrointestinal dysfunction. The enteric nervous system (ENS) is regarded as an essential gateway to the environment. The discovery of the prion-like behavior of α-synuclein makes it possible for the neurodegenerative process to start in the ENS and spread via the gut-brain axis to the CNS. We first confirmed that synucleinopathies existed in the stomachs of chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid (MPTP/p)-induced PD mice, as indicated by the significant increase in abnormal aggregated and nitrated α-synuclein in the TH-positive neurons and enteric glial cells (EGCs) of the gastric myenteric plexus. Next, we attempted to clarify the mechanisms in single MPTP-injected mice. The stomach naturally possesses high monoamine oxidase-B (MAO-B) activity and low superoxide dismutase (SOD) activity, making the stomach susceptible to MPTP-induced oxidative stress, as indicated by the significant increase in reactive oxygen species (ROS) in the stomach and elevated 4-hydroxynonenal (4-HNE) in the EGCs after MPTP exposure for 3 h. Additionally, stomach synucleinopathies appear before those of the nigrostriatal system, as determined by Western blotting 12 h after MPTP injection. Notably, nitrated α-synuclein was considerably increased in the EGCs after 3 h and 12 h of MPTP exposure. Taken together, our work demonstrated that the EGCs could be new contributors to synucleinopathies in the stomach. The early-initiated synucleinopathies might further influence neighboring neurons in the myenteric plexus and the CNS. Our results offer a new experimental clue for interpreting the etiology of PD.
Asunto(s)
Intoxicación por MPTP , Enfermedad de Parkinson , Trastornos Parkinsonianos , Sinucleinopatías , Ratones , Animales , alfa-Sinucleína , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Neuroglía , EstómagoRESUMEN
There is mounting evidence that the microbiota-gut-brain axis (MGBA) is critical in the pathogenesis and progression of Parkinson's disease (PD), suggesting that probiotic therapy restoring gut microecology may slow down disease progression. In this study, we examined the disease-alleviating effects of Bifidobacterium breve CCFM1067, orally administered for 5 weeks in a PD mouse model. Our study shows that supplementation with the probiotic B. breve CCFM1067 protected dopaminergic neurons and suppressed glial cell hyperactivation and neuroinflammation in PD mice. In addition, the antioxidant capacity of the central nervous system was enhanced and oxidative stress was alleviated. Moreover, B. breve CCFM1067 protected the blood-brain and intestinal barriers from damage in the MPTP-induced mouse model. The results of fecal microbiota analysis showed that B. breve CCFM1067 intervention could act on the MPTP-induced microecological imbalance in the intestinal microbiota, suppressing the number of pathogenic bacteria (Escherichia-Shigella) while increasing the number of beneficial bacteria (Bifidobacterium and Akkermansia) in PD mice. In addition, the increase in short chain fatty acids (acetic and butyric acids) may explain the anti-inflammatory action of B. breve CCFM1067 in the gut or brain of the MPTP-induced PD mouse model. In conclusion, we demonstrated that the probiotic B. breve CCFM1067, which can prevent or treat PD by modulating the gut-brain axis, can be utilized as a possible new oral supplement for PD therapy.
Asunto(s)
Bifidobacterium breve , Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Ratones , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/prevención & control , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Bifidobacterium , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
Parkinson's disease (PD) is a neurodegenerative disease in which neuronal apoptosis and associated inflammation are involved in its pathogenesis. However, there is still no specific treatment that can stop PD progression. Isoalantolactone (IAL) plays a role in many inflammation-related diseases. However, its effect and mechanism in PD remain unclear. In this study, results showed that IAL administration ameliorated 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD-related pathological impairment and decreased motor activity in mice. Results from in vitro mechanistic studies showed that IAL regulated apoptosis-related proteins by activating the AKT/Nrf2 pathway, thereby suppressing the apoptosis of SN4741 cells induced by N-methyl-4-phenylpyridinium Iodide (MPP+). On the other hand, IAL inhibited LPS-induced release of pro-inflammatory mediators in BV2 cells by activating the AKT/Nrf2/HO-1 pathway and inhibiting the NF-κB pathway. In addition, IAL protected SN4741 from microglial activation-mediated neurotoxicity. Taken together, these results highlight the beneficial role of IAL as a novel therapy and potential PD drug due to its pharmacological profile.
Asunto(s)
Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Animales , Ratones , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , 1-Metil-4-fenilpiridinio , Apoptosis , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Yoduros/efectos adversos , Lipopolisacáridos/efectos adversos , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2 , FN-kappa B/metabolismo , Enfermedad de Parkinson/metabolismo , Proteínas Proto-Oncogénicas c-akt , Pirrolidinas , SesquiterpenosRESUMEN
Neurodegenerative diseases such as Parkinson's disease (PD) are known to be related to oxidative stress and neuroinflammation, and thus, modulating neuroinflammation offers a possible means of treating PD-associated pathologies. Morin (2',3,4',5,7-pentahydroxy flavone) is a flavonol with anti-oxidative and anti-inflammatory effects found in wines, herbs, and fruits. The present study was undertaken to determine whether a morin-containing diet has protective effects in an MPTP-induced mouse model of PD. Mice were fed a control or morin diet for 34 days, and then MPTP (30 mg/kg, i.p.) was administered daily for 5 days to induce a PD-like pathology. We found that dietary morin prevented MPTP-induced motor dysfunction and ameliorated dopaminergic neuronal damage in striatum (STR) and substantia nigra (SN) in our mouse model. Furthermore, MPTP-induced neuroinflammation was significantly reduced in mice fed morin. In vitro studies showed that morin effectively suppressed glial activations in primary microglia and astrocytes, and biochemical analysis and a docking simulation indicated that the anti-inflammatory effects of morin were mediated by blocking the extracellular signal-regulated kinase (ERK)-p65 pathway. These findings suggest that morin effectively inhibits glial activations and has potential use as a functional food ingredient with therapeutic potential for the treatment of PD and other neurodegenerative diseases associated with neuroinflammation.
Asunto(s)
Flavonas , Ingredientes Alimentarios , Intoxicación por MPTP , Fármacos Neuroprotectores , Enfermedad de Parkinson , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Flavonas/farmacología , Flavonoles/metabolismo , Flavonoles/farmacología , Flavonoles/uso terapéutico , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/patología , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/etiologíaRESUMEN
Parkinson's disease (PD) is a neurodegenerative disease with an impairment of movement execution that is related to age and genetic and environmental factors. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin widely used to induce PD models, but the effect of MPTP on the cells and genes of PD has not been fully elucidated. By single-nucleus RNA sequencing, we uncovered the PD-specific cells and revealed the changes in their cellular states, including astrocytosis and endothelial cells' absence, as well as a cluster of medium spiny neuron cells unique to PD. Furthermore, trajectory analysis of astrocyte and endothelial cell populations predicted candidate target gene sets that might be associated with PD. Notably, the detailed regulatory roles of astrocyte-specific transcription factors Dbx2 and Sox13 in PD were revealed in our work. Finally, we characterized the cell-cell communications of PD-specific cells and found that the overall communication strength was enhanced in PD compared with a matched control, especially the signaling pathways of NRXN and NEGR. Our work provides an overview of the changes in cellular states of the MPTP-induced mouse brain.