Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease affecting both upper and lower motor neurons(MNs)with large unmet medical needs.Multiple pathological mechanisms are considered to contribut...Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease affecting both upper and lower motor neurons(MNs)with large unmet medical needs.Multiple pathological mechanisms are considered to contribute to the progression of ALS,including neuronal oxidative stress and mitochondrial dysfunction.Honokiol(HNK)has been reported to exert therapeutic effects in several neurologic disease models including ischemia stroke,Alzheimer’s disease and Parkinson’s disease.Here we found that honokiol also exhibited protective effects in ALS disease models both in vitro and in vivo.Honokiol improved the viability of NSC-34 motor neuron-like cells that expressed the mutant G93A SOD1 proteins(SOD1-G93A cells for short).Mechanistical studies revealed that honokiol alleviated cellular oxidative stress by enhancing glutathione(GSH)synthesis and activating the nuclear factor erythroid 2-related factor 2(NRF2)-antioxidant response element(ARE)pathway.Also,honokiol improved both mitochondrial function and morphology via fine-tuning mitochondrial dynamics in SOD1-G93A cells.Importantly,honokiol extended the lifespan of the SOD1-G93A transgenic mice and improved the motor function.The improvement of antioxidant capacity and mitochondrial function was further confirmed in the spinal cord and gastrocnemius muscle in mice.Overall,honokiol showed promising preclinical potential as a multiple target drug for ALS treatment.展开更多
Previous studies have indicated that the pathogenesis of amyotrophic lateral sclerosis(ALS) is closely linked to 5-hydroxytryptamine(5-HT).To investigate this further,we administered 5-HT receptor antagonists to SOD1*...Previous studies have indicated that the pathogenesis of amyotrophic lateral sclerosis(ALS) is closely linked to 5-hydroxytryptamine(5-HT).To investigate this further,we administered 5-HT receptor antagonists to SOD1*G93A transgenic(ALS mouse model) and wide-type mice.This involved intraperitoneal injections of either granisetron,piboserod,or ritanserin,which inhibit the 5-HT3,5-HT4,and 5-HT2 receptors,respectively.The transgenic mice were found to have fewer5-HT-positive cells in the spinal cord compared with wide-type mice.We found that the administration of granisetron reduced the body weight of the transgenic mice,while piboserod and ritanserin worsened the motor functioning,as assessed using a hanging wire test.However,none of the 5-HT receptor antagonists affected the disease progression.We analyzed the distribution and/or expression of TAR DNA binding protein 43(TDP-43) and superoxide dismutase 1 G93A(SOD1-G93A),which fo rm abnormal aggregates in ALS.We found that the expression of these proteins increased following the administration of all three 5-HT receptor antagonists.In addition,the disease-related mislocalization of TD P-43 to the cytoplasm increased markedly for all three drugs.In ce rtain anatomical regions,the 5-HT receptor antagonists also led to a marked increase in the number of astrocytes and microglia and a decrease in the number of neurons.These results indicate that 5-HT deficiency may play a role in the pathogenesis of amyotrophic lateral sclerosis by inducing the abnormal expression and/or distribution of TDP-43 and SOD1-G93A and by activating glial cells.5-HT co uld therefore be a potential therapeutic target for amyotrophic lateral sclerosis.展开更多
The amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder primarily involving motoneurons in the cerebral cortex, brainstem, and spinal cord. SOD1-G93A mice, which express multiple ...The amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder primarily involving motoneurons in the cerebral cortex, brainstem, and spinal cord. SOD1-G93A mice, which express multiple copies of the mutant form of the human Cu/Zn SOD, are one of the most widely used animal models for ALS pathology. However, the onset of the disease can vary between animals of 1-2 weeks while the progression is quite fast. In order to evaluate the efficacy of any treatment, it is very important to treat all animals at the early onset of the disease, instead of at a fixed age-point. To this aim, we performed behavioral analysis and measured hSOD1 mRNA expression to identify the appearance of the first motor deficits. Rotarod and PaGE tests revealed to be the most sensitive approaches to detect the beginning of the symptomatic phase of the disease, while neurological score and weight monitoring showed significant differences only at later stages in ALS pathology. Furthermore, we found a better correlation between hSOD1 mRNA expression with disease onset than with a transgene copy number. Therefore, the association of behavioral tests and molecular analysis represents a sensible and accurate tool to early detect the murine symptoms.展开更多
基金supported by the grants from National Natural Science Foundation of China(Nos.82073835 and 81872855)National Key R&D Program of China(No.2019YFC1708901)+2 种基金CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1028)Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study(BZ0150,China)Disciplines construction project(201920200802,China)。
文摘Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease affecting both upper and lower motor neurons(MNs)with large unmet medical needs.Multiple pathological mechanisms are considered to contribute to the progression of ALS,including neuronal oxidative stress and mitochondrial dysfunction.Honokiol(HNK)has been reported to exert therapeutic effects in several neurologic disease models including ischemia stroke,Alzheimer’s disease and Parkinson’s disease.Here we found that honokiol also exhibited protective effects in ALS disease models both in vitro and in vivo.Honokiol improved the viability of NSC-34 motor neuron-like cells that expressed the mutant G93A SOD1 proteins(SOD1-G93A cells for short).Mechanistical studies revealed that honokiol alleviated cellular oxidative stress by enhancing glutathione(GSH)synthesis and activating the nuclear factor erythroid 2-related factor 2(NRF2)-antioxidant response element(ARE)pathway.Also,honokiol improved both mitochondrial function and morphology via fine-tuning mitochondrial dynamics in SOD1-G93A cells.Importantly,honokiol extended the lifespan of the SOD1-G93A transgenic mice and improved the motor function.The improvement of antioxidant capacity and mitochondrial function was further confirmed in the spinal cord and gastrocnemius muscle in mice.Overall,honokiol showed promising preclinical potential as a multiple target drug for ALS treatment.
基金supported by the National Natural Science Foundation of China,Nos.30560042,81160161,8136019882160255+2 种基金Education Department of Jiangxi Province,Nos.GJJ13198 and GJJ170021Jiangxi Provincial Department of Science and Technology,Nos.20142BBG70062,20171 BAB215022,20192BAB205043Health and Family Planning Commission of Jiangxi Province,No.20181019 (all to RSX)。
文摘Previous studies have indicated that the pathogenesis of amyotrophic lateral sclerosis(ALS) is closely linked to 5-hydroxytryptamine(5-HT).To investigate this further,we administered 5-HT receptor antagonists to SOD1*G93A transgenic(ALS mouse model) and wide-type mice.This involved intraperitoneal injections of either granisetron,piboserod,or ritanserin,which inhibit the 5-HT3,5-HT4,and 5-HT2 receptors,respectively.The transgenic mice were found to have fewer5-HT-positive cells in the spinal cord compared with wide-type mice.We found that the administration of granisetron reduced the body weight of the transgenic mice,while piboserod and ritanserin worsened the motor functioning,as assessed using a hanging wire test.However,none of the 5-HT receptor antagonists affected the disease progression.We analyzed the distribution and/or expression of TAR DNA binding protein 43(TDP-43) and superoxide dismutase 1 G93A(SOD1-G93A),which fo rm abnormal aggregates in ALS.We found that the expression of these proteins increased following the administration of all three 5-HT receptor antagonists.In addition,the disease-related mislocalization of TD P-43 to the cytoplasm increased markedly for all three drugs.In ce rtain anatomical regions,the 5-HT receptor antagonists also led to a marked increase in the number of astrocytes and microglia and a decrease in the number of neurons.These results indicate that 5-HT deficiency may play a role in the pathogenesis of amyotrophic lateral sclerosis by inducing the abnormal expression and/or distribution of TDP-43 and SOD1-G93A and by activating glial cells.5-HT co uld therefore be a potential therapeutic target for amyotrophic lateral sclerosis.
文摘The amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder primarily involving motoneurons in the cerebral cortex, brainstem, and spinal cord. SOD1-G93A mice, which express multiple copies of the mutant form of the human Cu/Zn SOD, are one of the most widely used animal models for ALS pathology. However, the onset of the disease can vary between animals of 1-2 weeks while the progression is quite fast. In order to evaluate the efficacy of any treatment, it is very important to treat all animals at the early onset of the disease, instead of at a fixed age-point. To this aim, we performed behavioral analysis and measured hSOD1 mRNA expression to identify the appearance of the first motor deficits. Rotarod and PaGE tests revealed to be the most sensitive approaches to detect the beginning of the symptomatic phase of the disease, while neurological score and weight monitoring showed significant differences only at later stages in ALS pathology. Furthermore, we found a better correlation between hSOD1 mRNA expression with disease onset than with a transgene copy number. Therefore, the association of behavioral tests and molecular analysis represents a sensible and accurate tool to early detect the murine symptoms.
