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Microbiota in the gut affect brain physiology via various pathways, and dysbiosis seems to play a role in the pathogenesis of Parkinson's disease (PD). Probiotics showed pleiotropic effects on functions of the central nervous system via microbiota-gut-brain axis. However, no studies displayed the neuroprotective effects of probiotics in the Parkinson's disease. This study aimed to test the neuroprotective effects of probiotics in two different models of PD. We evaluated neuroprotective effects of a probiotic cocktail containing Lactobacillus rhamnosus GG, Bifidobacterium animalis lactis, and Lactobacillus acidophilus in PD models induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone utilizing behavioral tests, immunohistochemistry and neurochemical analysis. To assure the neuroprotection came from increased production of butyrate, we further determined beneficial effects of butyrate in the MPTP-mediated PD model. The probiotic mixture overtly protected the dopaminergic neurons against MPTP neurotoxicity. However, the probiotics downregulated expression of monoamine oxidase (MAO) B in the striatum, which was accompanied by a lower level of 1-methyl-4-phenylpyridinium (MPP+), the main neurotoxic metabolite of MPTP. Thus, we extended the investigation into the rotenone-induced PD model. Rescuing effects of the probiotics were observed in the setup, which came with increased levels of neurotrophic factors and butyrate in the brain. Lactobacillus rhamnosus GG was identified to be a major contributor to the induction of neurotrophic factors and downregulation of MAO B. Finally, we demonstrated that sodium butyrate attenuated MPTP-induced neuronal loss in the nigrostriatal pathway. Probiotics could ameliorate neurodegeneration at least partially by increasing butyrate level. These data highlight the role of probiotics for brain health, and their potential as a preventive measure for neurodegenerative diseases such as PD. [ABSTRACT FROM AUTHOR]

Highlights • Effects of IL-32β on neuroinflammation were evaluated. • Enhanced neuroinflammation was observed in IL-32β transgenic mice. • Prolonged activation of NF-κB might be related to extended neuroinflammation. Abstract IL-32 is a proinflammatory cytokine, and involved in various diseases including infection, inflammation, and cancer. However, effects of IL-32 on neuroinflammation remain obscure. Herein, we examined the effects of IL-32β on systemic LPS-induced neuroinflammation using IL-32β transgenic (Tg) mice. IL-32β wild type (WT) and Tg mice received LPS injection (5 mg/kg, i.p.), and then neuroinflammatory responses were evaluated. Systemic LPS caused remarkable gliosis in the brain at 12 h regardless of genotypes. The gliosis in WT mice was sustained by 24 h, whereas it became more severe in Tg mice by 24 h. Proinflammatory cytokines and proteins were increased at 12 h both in WT and Tg brains. The elevated levels of TNFα and VCAM-1were not altered over time, while levels of IL-6, IL-1β and iNOS were dropped in WT mice. In contrast, elevated levels IL-6, IL-1β, iNOS and VCAM-1 were sustained, and level of TNFα was augmented in Tg brains by 24 h. Interestingly, level of IL-10 mRNA in Tg mice was remarkably higher than in WT mice at 0 h, which was decreased at 12 h and maintained by 24 h. In WT brain, mRNA level of IL-10 was raised at 12 h after LPS injection, and further increased at 24 h. Activation of NF-κB signaling pathway was detected in glia cells after LPS injection which was exaggerated at 24 h in Tg mice in comparison to WT mice. These results indicate that IL-32β enhances neuroinflammatory responses caused by systemic LPS, and this might be attributable to prolonged activation of NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disorder characterized by prominent loss of the nigral dopaminergic neurons and motor symptoms, such as resting tremor and bradykinesia. Evidence suggests that neuroinflammation may play a critical role in PD pathogenesis. Interleukin (IL)-32 is a newly-identified proinflammatory cytokine, which regulates innate and adaptive immune responses by activating p38 MAPK and NF-κB signaling pathways. The cytokine has been implicated in cancers and autoimmune, inflammatory, and infectious diseases. In this study, we attempted to identify the effects of IL-32β on dopaminergic neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), using IL-32β transgenic mice. Male wild type and IL-32β transgenic mice received intraperitoneal injections of vehicle or MPTP (15 mg/kg × 4). Immunohistochemistry showed that overexpression of IL-32β significantly increased MPTP-mediated loss of dopaminergic neurons in the substantia nigra and deletion of tyrosine hydroxylase-positive fibers in the striatum. Dopamine depletion in the striatum and deficit in locomotor activity were enhanced in IL-32β transgenic mice. These results were accompanied by higher neuroinflammatory responses in the brains of transgenic mice. Finally, we found that IL-32β exaggerated MPTP-mediated activation of p38 MAPK and JNK pathways, which have been shown to be involved in MPTP neurotoxicity. These results suggest that IL-32β exacerbates MPTP neurotoxicity through enhanced neuroinflammatory responses. [ABSTRACT FROM AUTHOR]

In spite of the massive research for the identification of neurorestorative or neuroprotective intervention for curing Parkinson's disease (PD), there is still lack of clinically proven neuroprotective agents. Metformin, a common anti-hyperglycemic drug has been known to possess neuroprotective properties. However, specific mechanisms by which metformin protects neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity remain to be elucidated. In this study, we assessed the neuroprotective effects of metformin in the subchronic MPTP model of PD, and explored its feasible mechanisms for neuroprotection. Animals received saline or MPTP injection (30 mg/kg/day) for the first 7 days, and then saline or metformin (200 mg/kg/day) for the next 7 days. Immunohistochemical stainings showed that metformin rescued the tyrosine hydroxylase-positive neurons and attenuated astroglial activation in the nigrostriatal pathway. In parallel, metformin restored dopamine depletion and behavioral impairments exerted by MPTP. Western blot analysis revealed that metformin ameliorated MPTP-induced α-synuclein phosphorylation which was accompanied by increased methylation of protein phosphatase 2A (PP2A), a phosphatase related to α-synuclein dephosphorylation. Moreover, the metformin regimen significantly increased the level of brain derived neurotrophic factor in the substantia nigra, and activated signaling pathways related to cell survival. Proof of concept study revealed that inhibition of PP2A or tropomyosin receptor kinase B reversed neuroprotective property of metformin in SH-SY5Y cells. Our results indicate that metformin provides neuroprotection against MPTP neurotoxicity, which might be mediated by inhibition of α-synuclein phosphorylation and induction of neurotrophic factors. [ABSTRACT FROM AUTHOR]