ABSTRACT
OBJECTIVE In this study,the effects of live Lactobacillus murinus(L.m)and heat-killed L.muri-nus(H-k L.m)on DA neuronal damage in rats and the underlying mechanisms were investigated.METHODS Male SD rats were randomly divided into five groups:vehicle group,L.m/H-k L.m(1×109 cfu)group,6-OHDH group,6-OHDH + L.m/H-k L.m(1×107 cfu)group,and 6-OHDH + L.m/H-k L.m(1×109 cfu)group.Wild-type and NLRP3 knockout mice were divided into three groups:sham(vehicle),6-OHDH,and 6-OHDH + H-k L.m(1×109 cfu).The model was established after five weeks of pre-administration.Motor ability of experimental mice was assessed by rotarod,mine,and stepping experiments;the expression of dopaminergic neuron markers—tyro-sine hydroxylase(TH),microglial cell markers—ionized calnexin 1(IBA-1),and NOD-like receptor family protein 3(NLRP3)in the substantia nigra was detected by immunohistochemistry and immunofluorescence experi-ments.The expression changes of TH,IBA-1,NLRP3,apoptosis-associated microparticle protein(ASC),cas-pase 1,and inflammatory factors such as interleukin-1β(IL-1β),IL-18,and tumor necrosis factor-α(TNF-α)were detected by immunoblotting experiments.RESULTS H-k L.m ameliorated 6-OHDH-induced motor dysfunctions and loss of substantia nigra DA neurons,while no protec-tion was shown in live L.m treatment.At the same time,H-k L.m reduced the activation of NLRP3 inflammasome in microglia and the secretion of pro-inflammatory factors,thus inhibiting the development of neuroinflammation.Fur-thermore,H-k L.m failed to display its original neuropro-tective properties in NLRP3 inflammasome knockout mice.CONCLUSION H-k L.m conferred neuroprotec-tion against DA neuronal loss via the inhibition of microglial NLRP3 inflammasome activation,these findings provide a promising potential for future applications of L.m,and also beneficial strategy for PD treatment.
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@#Parkinson's disease(PD)is the second common neurodegenerative disease that mostly occurs in middle-aged and elderly people. Currently,Levodopa is the main first-line treatment drug,but the long-term efficacy of patients is not good,and even side effects such as“on-off”phenomenon and orthostatic hypotension occur. Glucagon-like peptide-1receptor agonists(GLP-1RA)and analogues are endogenous peptide hormones that can be released into the blood and enter the central nervous system to exert neuroprotection by crossing the blood-brain barrier. Numerous studies have shown that GLP-1RA can improve movement disorders and restore dopaminergic neuron activity in PD. However,the mechanism of GLP-1RA is not yet fully clear. This paper summarized the mechanism of GLP-1RA and its analogues in improving PD movement disorders and restoring dopaminergic neuron activity,and reviewed the aspects of reducing neuroinflammation,inhibiting oxidative stress,inhibiting apoptosis,regulating mitochondrial morphology,increasing neuronal protrusions,enhancing autophagy,and regulating intestinal flora homeostasis,so as to provide new ideas for research of the mechanisms of PD and development of GLP-1RA-related new drugs.
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AIM:To investigate the regulatory effect of JAK 2-STAT3 signaling pathway on the neuroprotection of ischemic postconditioning (IPoC) in tree shrews, and to explore the mechanisms of cerebral injury deterioration after in-hibiting the JAK2-STAT3 pathway .METHODS:The model of thrombotic cerebral ischemia was induced by photochemical reaction in tree shrews and the IPoC was established at 4 h after ischemia followed by clipping ipsilateral common carotid ar-tery on the ischemia side for 5 min ( 3 times ) .After IPoC and intracerebroventricular injection of AG 490 ( JAK2 inhibi-tor), the changes of cerebral infarction area were detected by TTC staining , and the histological and ultrastructural changes of cortical neurons were observed under light and electron microscopes , respectively .The protein levels of t-STAT3 and p-STAT3 in the cortical tissue were determined by Western blot .RESULTS:The neuronal pycnosis , mitochondrial swelling and vanish of the mitochondrial cristae were found in cortical cortex , and the infarction area was (24.78 ±3.30)%at 24 h after cerebral ischemia .Meanwhile, the phosphorylation level of STAT 3 protein in the cortical tissue was significantly in-creased (P<0.01).The cortical neuronal damage and mitochondrial swelling were decreased after IPoC , the area of cere-bral infarction was significantly reduced to (17.67 ±1.83)%(P<0.01), and the phosphorylation level of STAT3 protein was further increased ( P<0.01 ) .However , the neuronal damage was aggravated , the infarction area was expanded to (23.85 ±2.77)%(P<0.05) after treatment with AG490, and the phosphorylation level of STAT3 protein was also signif-icantly reduced ( P <0.05 ) .CONCLUSION: IPoC may reduce cerebral injury by regulating the phosphorylation of STAT3 protein, and inhibition of JAK2-STAT3 signaling pathway may counteract the cerebral protective effect of IPoC and aggravate brain injury .
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Aim To the investigate the protective effect of ginsenoside Rg1 in Alzheimer's disease ( AD)-like neurotoxicity model induced by okadaic acid ( OKA) in the cellular level , and explore the mecha-nism preliminarily. Methods The PC12 cells model, simulate neurons, induced by OKA was given Rg1 (1, 5,10 μmol·L-1), and melatonin (Melat) 10 μmol· L-1 was given as a positive control. MTT and LDH were carried out to assess the cell viability and mortality. To detect the accumulation of ROS, the DCFH-DA fluores-cent probe was conducted. And to assess the change of the activity of a variety of antioxidant enzymes, various kits were used, including ABTS、CAT、SOD、GSH-Px and GSSG/GSH. Results Compared with the control group, the survival rate of PC12 cell in OKA group re-duces significantly, the mortality rate was increased sig-nificantly , the number of early apoptotic cells was in-creased significantly (P<0. 01). Oxidative stress-relat-ed indicators show that ROS accumulation within the cells of OKA group increases significantly ( P<0. 01 ) , and the total antioxidant capacity ( ABTS ) decreases significantly ( P < 0. 01 ) , the activity of peroxidase (Catalase, CAT) (P <0. 01), glutathione peroxidase (glutathione peroxidase, GSH-Px) and superoxide dis-mutase ( superoxide dismutase, SOD) decreased signifi-cantly ( P <0. 05 ) , the rate of GSSG/GSH increased significantly ( P <0. 01 ) . Compared with the model group, the different doses of Rg1 could improve the sur-vival rate and decrease the mortality rate of PC12 cell significantly in the group of OKA, and could decrease the level of the accumulation of ROS, improve the activ-ity of antioxidant enzymes. Conclusion Ginsenoside Rg1 can decrease PC12 cell apoptosis by exerting an-tioxidant effects, and protect the nerve cells in AD-like pathology model induced by OKA.