Patients with Parkinson's disease(PD) have impaired insulin signaling in the brain. Incretin hormones, including glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide(GIP), can re-sensiti...Patients with Parkinson's disease(PD) have impaired insulin signaling in the brain. Incretin hormones, including glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide(GIP), can re-sensitize insulin signaling. In a recent phase II clinical trial, the first GLP-1 mimic, exendin-4, has shown reliable curative effect in patients with PD. DA-CH5 is a novel GLP-1/GIP receptor unimolecular coagonist with a novel peptide sequence added to cross the blood-brain barrier. Here we showed that both exendin-4 and DA-CH5 protected against 6-hydroxydopamine(6-OHDA) cytotoxicity, inhibited apoptosis, improved mitogenesis and induced autophagy flux in SH-SY5Y cells via activation of the insulin receptor substrate-1(IRS-1)/alpha serine/threonine-protein kinase(Akt)/c AMP response element-binding protein(CREB) pathway. We also found that DA-CH5(10 nmol/kg) daily intraperitoneal administration for 30 days post-lesion alleviated motor dysfunction in rats and prevented stereotactic unilateral administration of 6-OHDA induced dopaminergic neurons loss in the substantia nigra pars compacta. However, DA-CH5 showed curative effects in reducing the levels of α-synuclein and the levels of pro-inflammatory cytokines(tumor necrosis factor-α, interleukin-1β). It was also more effective than exendin-4 in inhibiting apoptotic process and protecting mitochondrial functions. In addition, insulin resistance was largely alleviated and the expression of autophagy-related proteins was upregulated in PD model rats after DA-CH5 treatment. These results in this study indicate DA-CH5 plays a therapeutic role in the 6-OHDAunilaterally lesioned PD rat model and is superior to GLP-1 analogue exendin-4. The study was approved by the Animal Ethics Committee of Shanxi Medical University of China.展开更多
In our previous studies,we have shown that(D-Ser2)oxyntomodulin(Oxm),a glucagon-like peptide 1(GLP-1)receptor(GLP1R)/glucagon receptor(GCGR)dual agonist peptide,protects hippocampal neurons against Aβ1-42-induced cyt...In our previous studies,we have shown that(D-Ser2)oxyntomodulin(Oxm),a glucagon-like peptide 1(GLP-1)receptor(GLP1R)/glucagon receptor(GCGR)dual agonist peptide,protects hippocampal neurons against Aβ1-42-induced cytotoxicity,and stabilizes the calcium homeostasis and mitochondrial membrane potential of hippocampal neurons.Additionally,we have demonstrated that(D-Ser2)Oxm improves cognitive decline and reduces the deposition of amyloid-beta in Alzheimer’s disease model mice.However,the protective mechanism remains unclear.In this study,we showed that 2 weeks of intraperitoneal administration of(D-Ser2)Oxm ameliorated the working memory and fear memory impairments of 9-month-old 3×Tg Alzheimer’s disease model mice.In addition,electrophysiological data recorded by a wireless multichannel neural recording system implanted in the hippocampal CA1 region showed that(D-Ser2)Oxm increased the power of the theta rhythm.In addition,(D-Ser2)Oxm treatment greatly increased the expression level of synaptic-associated proteins SYP and PSD-95 and increased the number of dendritic spines in 3×Tg Alzheimer’s disease model mice.These findings suggest that(D-Ser2)Oxm improves the cognitive function of Alzheimer’s disease transgenic mice by recovering hippocampal synaptic function and theta rhythm.展开更多
Epilepsy is a common disease in the central nervous system.There is growing evidence that epilepsy is associated with glial cells,including astrocytes.Tumor necrosis factorα(TNFα)is a“master regulator”of proinflam...Epilepsy is a common disease in the central nervous system.There is growing evidence that epilepsy is associated with glial cells,including astrocytes.Tumor necrosis factorα(TNFα)is a“master regulator”of proinflammatory cytokine production and is secreted by microglia and astrocytes.TNFαsecreted by microglia can activate astrocytes.Additionally,TNFαcan regulate neuron activity and induce epilepsy by increasing the glutamate release,reducing the expression ofγ-aminobutyric acid,inducing neuroinflammation and affecting the synaptic function in astrocytes.This review summarizes the signaling pathways and receptors of TNFαacting on astrocytes that are related to epilepsy and provides insights into the potential therapeutic strategies of epilepsy for clinical practice.展开更多
基金supported by the Doctoral Start-Up Foundation of Shanxi Province of China,No. SD1817 (to QQJ)。
文摘Patients with Parkinson's disease(PD) have impaired insulin signaling in the brain. Incretin hormones, including glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide(GIP), can re-sensitize insulin signaling. In a recent phase II clinical trial, the first GLP-1 mimic, exendin-4, has shown reliable curative effect in patients with PD. DA-CH5 is a novel GLP-1/GIP receptor unimolecular coagonist with a novel peptide sequence added to cross the blood-brain barrier. Here we showed that both exendin-4 and DA-CH5 protected against 6-hydroxydopamine(6-OHDA) cytotoxicity, inhibited apoptosis, improved mitogenesis and induced autophagy flux in SH-SY5Y cells via activation of the insulin receptor substrate-1(IRS-1)/alpha serine/threonine-protein kinase(Akt)/c AMP response element-binding protein(CREB) pathway. We also found that DA-CH5(10 nmol/kg) daily intraperitoneal administration for 30 days post-lesion alleviated motor dysfunction in rats and prevented stereotactic unilateral administration of 6-OHDA induced dopaminergic neurons loss in the substantia nigra pars compacta. However, DA-CH5 showed curative effects in reducing the levels of α-synuclein and the levels of pro-inflammatory cytokines(tumor necrosis factor-α, interleukin-1β). It was also more effective than exendin-4 in inhibiting apoptotic process and protecting mitochondrial functions. In addition, insulin resistance was largely alleviated and the expression of autophagy-related proteins was upregulated in PD model rats after DA-CH5 treatment. These results in this study indicate DA-CH5 plays a therapeutic role in the 6-OHDAunilaterally lesioned PD rat model and is superior to GLP-1 analogue exendin-4. The study was approved by the Animal Ethics Committee of Shanxi Medical University of China.
基金supported by the National Natural Science Foundation of China,No.31600865(to ZJW)“Sanjin Scholars”of Shanxi Province of China,No.[2016]7(to MNW)+5 种基金Shanxi Province Science Foundation for Excellent Young Scholars of China,No.201801D211005(to MNW)the Applied Basic Research Program of Shanxi Province of China,No.201901D111358(to GZY)the Doctoral Startup Research Fund of Shanxi Medical University of China,No.03201536(to GZY)the Doctoral Startup Research Fund of the First Hospital of Shanxi Medical University of China,No.YJ1507(to GZY)the National Undergraduate Innovation Program of China,No.201910114019(to JXW)the Undergraduate Innovation Program of Shanxi Province of China,No.2020189(to XRZ).
文摘In our previous studies,we have shown that(D-Ser2)oxyntomodulin(Oxm),a glucagon-like peptide 1(GLP-1)receptor(GLP1R)/glucagon receptor(GCGR)dual agonist peptide,protects hippocampal neurons against Aβ1-42-induced cytotoxicity,and stabilizes the calcium homeostasis and mitochondrial membrane potential of hippocampal neurons.Additionally,we have demonstrated that(D-Ser2)Oxm improves cognitive decline and reduces the deposition of amyloid-beta in Alzheimer’s disease model mice.However,the protective mechanism remains unclear.In this study,we showed that 2 weeks of intraperitoneal administration of(D-Ser2)Oxm ameliorated the working memory and fear memory impairments of 9-month-old 3×Tg Alzheimer’s disease model mice.In addition,electrophysiological data recorded by a wireless multichannel neural recording system implanted in the hippocampal CA1 region showed that(D-Ser2)Oxm increased the power of the theta rhythm.In addition,(D-Ser2)Oxm treatment greatly increased the expression level of synaptic-associated proteins SYP and PSD-95 and increased the number of dendritic spines in 3×Tg Alzheimer’s disease model mice.These findings suggest that(D-Ser2)Oxm improves the cognitive function of Alzheimer’s disease transgenic mice by recovering hippocampal synaptic function and theta rhythm.
基金supported by the UCB Foundation of China Association Against Epilepsy(2017007)the National Natural Science Foundation of China(81601038)the Department of Resource and Social Security of Shanxi Province(Jin fiscal and Social Council[2019]91st).
文摘Epilepsy is a common disease in the central nervous system.There is growing evidence that epilepsy is associated with glial cells,including astrocytes.Tumor necrosis factorα(TNFα)is a“master regulator”of proinflammatory cytokine production and is secreted by microglia and astrocytes.TNFαsecreted by microglia can activate astrocytes.Additionally,TNFαcan regulate neuron activity and induce epilepsy by increasing the glutamate release,reducing the expression ofγ-aminobutyric acid,inducing neuroinflammation and affecting the synaptic function in astrocytes.This review summarizes the signaling pathways and receptors of TNFαacting on astrocytes that are related to epilepsy and provides insights into the potential therapeutic strategies of epilepsy for clinical practice.