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
Objective:To study the influence of methanolic and aqueous extract of Withania somnifera (W.somnifera) root on the marble-burying behavior of mice a well-accepted model of obsessive compulsive behavior.Methods:Mice we...Objective:To study the influence of methanolic and aqueous extract of Withania somnifera (W.somnifera) root on the marble-burying behavior of mice a well-accepted model of obsessive compulsive behavior.Methods:Mice were divided in different groups(n=6).Fluoxetine(5,10,15 mg/kg), (10,25,50,100 mg/kg) and melhanolic extract W.somnifera(MEWS)(10,25,50,100 mg/kg) were administered i.p.30 min.prior to the assessment of marble burying behavior and locomotor activity.The control group received vehicle of the extract.Results:Administration of aqueous extracts W.somnifera(AEWS) and MEWS(50 mg/kg) successively decreaesed the marble burying behavior activity without affecting motor activity.This effect of AEWS and MEWS was comparable to standard fluoxetine,ritanserin and parachlorophenylalanine.Conclusions:W.somnifera extract is effective in treating obsessive compulsive disorder.展开更多
One specific example reflecting the completity ofcardiovascular responses induced by serotonin(5-hydroxytryptamine;5-HT)and the progress achieved inthe pharmacological characterization of the receptorsinvolved can be ...One specific example reflecting the completity ofcardiovascular responses induced by serotonin(5-hydroxytryptamine;5-HT)and the progress achieved inthe pharmacological characterization of the receptorsinvolved can be illustrated by the effects of 5-HT on thecanine external carotid artery bed.Within thisframework,it has been shown that the external carotidvasoconstrictor response to 5-HT in the dog is mediatedby'5-HT_(1)-like'receptors,which being blocked by the5-HT_(1B/1D)receptor antagonist GR127935,resemble 5-HT_(1B/1D)(previously called 5-HT_(1B/1D))receptors.It was proposed that these receptors coilld belong to the 5-HT_(lB),rather than the 5-HT_(lD),subtype on the basis of their resistance to blockade by a high dose of ritanserin(a potential 5-HT_(lD)receptor antagomst and the presence of mRNA for 5-HT_(lB)(5-HT_(lDB))receptors,but not for 5-HT_(lD)(5-HT_(lD))receptors,in vascalar smooth muscle.With the advent of subtype-selective antagonists it was subsequently shown that the external carotid vasocenstriction to 5-HT and surmantriptan is dose-dependently antagonized by the selective 5-HT_(lB)receptor antagonist SB224289[2,3,6.7-telrahydro-I'-methyl-5-[2'-methyl-4(5-methyl-1,2,4-oxadiazol-3-y1)biphenyl-4-carbonyl]]furo[2,3-f]indole-3-spiro-4'-piperidine hydrochloride],whereas the selective 5-HT_(lD)receptor antagonist BRL15572[l(3-chloropheny1)-4-[3,3-diphenyl(2-(S,R)hydroxypropany1)piperazine]hydrochloride was inefective.These findings represent the first in vivo evidence showing that vascular constriction induced by 5-HT and sumatriptan is mediated primarily via 5-HT_(lB),but not 5-HT_(lD)receptors.The pharmacological profile of these receptors could be similar(isolated human temporal artery and porcine carotid arteriovenous anastomoses)to other putative 5-HT_(lB)receptors mediating vasoconstrictor responses.In view of the putative pathophysiologic role of external carotid(and extracerebral)vasodilation in migraine,the constriction of these blood vessels by sumatriptan via 5-HT_(lB)receptors may be,at least partly,responsible for its therapeutic efficacy in migraine.展开更多
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Objective:To study the influence of methanolic and aqueous extract of Withania somnifera (W.somnifera) root on the marble-burying behavior of mice a well-accepted model of obsessive compulsive behavior.Methods:Mice were divided in different groups(n=6).Fluoxetine(5,10,15 mg/kg), (10,25,50,100 mg/kg) and melhanolic extract W.somnifera(MEWS)(10,25,50,100 mg/kg) were administered i.p.30 min.prior to the assessment of marble burying behavior and locomotor activity.The control group received vehicle of the extract.Results:Administration of aqueous extracts W.somnifera(AEWS) and MEWS(50 mg/kg) successively decreaesed the marble burying behavior activity without affecting motor activity.This effect of AEWS and MEWS was comparable to standard fluoxetine,ritanserin and parachlorophenylalanine.Conclusions:W.somnifera extract is effective in treating obsessive compulsive disorder.
基金Project supported by Consejo Nacional de Ciencia y Tecnologia(Mexico City)
文摘One specific example reflecting the completity ofcardiovascular responses induced by serotonin(5-hydroxytryptamine;5-HT)and the progress achieved inthe pharmacological characterization of the receptorsinvolved can be illustrated by the effects of 5-HT on thecanine external carotid artery bed.Within thisframework,it has been shown that the external carotidvasoconstrictor response to 5-HT in the dog is mediatedby'5-HT_(1)-like'receptors,which being blocked by the5-HT_(1B/1D)receptor antagonist GR127935,resemble 5-HT_(1B/1D)(previously called 5-HT_(1B/1D))receptors.It was proposed that these receptors coilld belong to the 5-HT_(lB),rather than the 5-HT_(lD),subtype on the basis of their resistance to blockade by a high dose of ritanserin(a potential 5-HT_(lD)receptor antagomst and the presence of mRNA for 5-HT_(lB)(5-HT_(lDB))receptors,but not for 5-HT_(lD)(5-HT_(lD))receptors,in vascalar smooth muscle.With the advent of subtype-selective antagonists it was subsequently shown that the external carotid vasocenstriction to 5-HT and surmantriptan is dose-dependently antagonized by the selective 5-HT_(lB)receptor antagonist SB224289[2,3,6.7-telrahydro-I'-methyl-5-[2'-methyl-4(5-methyl-1,2,4-oxadiazol-3-y1)biphenyl-4-carbonyl]]furo[2,3-f]indole-3-spiro-4'-piperidine hydrochloride],whereas the selective 5-HT_(lD)receptor antagonist BRL15572[l(3-chloropheny1)-4-[3,3-diphenyl(2-(S,R)hydroxypropany1)piperazine]hydrochloride was inefective.These findings represent the first in vivo evidence showing that vascular constriction induced by 5-HT and sumatriptan is mediated primarily via 5-HT_(lB),but not 5-HT_(lD)receptors.The pharmacological profile of these receptors could be similar(isolated human temporal artery and porcine carotid arteriovenous anastomoses)to other putative 5-HT_(lB)receptors mediating vasoconstrictor responses.In view of the putative pathophysiologic role of external carotid(and extracerebral)vasodilation in migraine,the constriction of these blood vessels by sumatriptan via 5-HT_(lB)receptors may be,at least partly,responsible for its therapeutic efficacy in migraine.
