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Parkinson's disease (PD) is the second major neurodegenerative disease.The pathogenesis of PI) is still unclear.It is generally believed that neural damage, mitochondrial dysfunction, inflammation, oxidative stress and autophagy dysfunction caused by the transmission and aggregation of a- synuclein play an important role in the occurrence and development of PD.More and more research show- that metabolic disorder is one of the pathogenesis of PD.We examined whether overexpression of a- synuclein could induce metabolic disorder in mice and the possible mechanisms.Mice were divided into two groups: Thyl-aSYN transgenic mice (TG) and the control wild-type (WT) group.The rotarod test was used to analyze motor function in mice.We detected the body weight, plasma insulin content, glucose tolerance and insulin tolerance in the two group mice.The morphology of islets in the two groups were observed by hematoxylin eosin (HE) staining, and the islets were isolated to detect the glucose- stimulated insulin secretion (GSIS).The results showed that compared with the WT group, exercise tolerance of 12-month-old TG group decreased by 23.1% (P < 0.05) , body weight increased by 7% (P < 0.01), glucose tolerance decreased (P < 0.05), insulin tolerance decreased (P < 0.05), and insulin contents in the peripheral blood decreased by 20% (P < 0.05).Compared with the WT group, the levels of ce -syn proteins in the pancreas of the TG group increased by 1.32 times (P < 0.05) , the area of islets in the TG group decreased (P < 0.05 ) , the number of islets decreased (P < 0.01) , and the insulin secretion function decreased (P< 0.01).This study showed that the role of a-synuclein in PD is not limited to the damage of dopaminergic neurons, it also can affect metabolism and the morphology and function of peripheral organs, which provides a new theoretical basis for the pathogenesis of PD.
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Aim To investigate the potential protective function of nervonic acid (NA) on the motor disorder in mice subjected to MPTP and the underlying mechanism. Methods The PD mice model was constructed and divided into control group, model group, nervonic acid (20 mg • k g
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OBJECTIVE To evaluate these activities of Rg1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahy?dropyridine (MPTP)/probenecid (MPTP/p)-induced PD mouse model for the first time and to elucidate the underlying mechanisms. METHODS Male C57BL/6 mice were randomly assigned to six groups. One hour prior to MPTP/p injection, Group Ⅲ-Ⅵ mice received 10 mg·kg-1, 20 mg·kg-1, or 40 mg·kg-1 Rg1 or 3 mg·kg-1 selegiline, respectively, orally from D (-3) to D49. Group Ⅰ-Ⅱ mice received solvent water. Subsequently, GroupⅡ-Ⅵ mice received by injection MPTP-HCl (25 mg·kg- 1 bw dissolved in 0.9% saline, sc) on a 40-d schedule at intervals of 4 d between consecutive doses in combination with an adjuvant drug, probenecid (250 mg·kg- 1 bw in 0.03 mL of DMSO, ip); GroupⅠ mice were injected with saline and probenecid. Behavioral performance was assessed in the open field test, pole test and rotarod test. Neurotransmitters in the striatum were detected using HPLC. Protein levels were measured by Western blot. Pathological characteristics were examined by immunohistochemistry. Ultrastructure changes were observed by electron microscopy. RESULTS Oral treatment with Rg1 significantly attenuated the high MPTP-induced mortality, behavior defects, loss of dopamine neurons and abnormal ultrastructure changes in the SNpc. Other assays indicated that the protective effect of Rg1 may be mediated by its anti-neuroinflammatory properties. Rg1 regulated MPTP-induced reactive astrocytes and microglia and decreased the release of cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1b (IL-1b) in the SNpc. Rg1 also alleviated the unusual MPTP induced increase in oligomeric, phosphorylated and disease-related a-synuclein in the SNpc. CONCLUSION Rg1 protects dopaminergic neurons, most likely by reducing aberrant a-synuclein-mediated neuroinflammation, and holds promise for Parkinson disease therapeutics.
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Parkinson's disease (PD) is a common neurodegenerative disorder associated with aging.Recent studies in animal models of PD and analyses of brain specimen from PD patients revealed an increase in the level and activity of the non-receptor tyrosine kinase Abelson (c-Abl) in dopaminergic neurons with phosphorylation of protein substrates,such as a-synuclein and the E3 ubiquitin ligase, Parkin.Most significantly inhibition of c-Abl kinase activity by small molecular compounds used in the clinic to treat human leukemia has shown promising neuroprotective effects in cell and animal models of PD.This has raised hope that similar beneficial outcome may also be observed in the treatment of PD patients by using c-Abl inhibitors.Here we highlight the background for the current optimism, reviewing c-Abl and its relationship to pathophysiological pathways prevailing in PD, as well as discussing issues related to the pharmacology and safety of current c-Abl inhibitors.Clearly more rigorously controlled and well-designed trials are needed before the c-Abl inhibitors can be used in the neuroclinic to possibly benefit an increasing number of PD patients.