L-DOPA is the primary drug used to treat Parkinson’s disease (PD) symptoms, but motor side effects limit its long term use. Previous experimental studies show that L-DOPA acts on supersensitive D1 receptors in the ba...L-DOPA is the primary drug used to treat Parkinson’s disease (PD) symptoms, but motor side effects limit its long term use. Previous experimental studies show that L-DOPA acts on supersensitive D1 receptors in the basal ganglia to induce extracellular signal-regulated kinases 1 and 2 (ERK1/2), a pair of MAP-kinase proteins that may be involved in induction of motor side effects. Since GABA is known to be intimately involved in basal ganglia function, we investigated whether elevating GABA levels via a GABA-transaminase (GABA-T) inhibitor affects the L-DOPA-induced ERK1/2 phosphorylation in the striatum and substantia nigra (SN) using a rat model of PD. Unilateral dopaminergic lesions of median forebrain bundle neurons were done using the neurotoxin 6-hydroxydopamine. Rats were prescreened for the extent of the lesion by apomorphine-induced rotation test. Lesioned rats were treated with aminooxyacetic acid (AOAA, a GABA-T inhibitor), L-DOPA, or in combination. Immunohistochemistry of tyrosine hydroxylase (TH, a direct indicator of dopaminergic lesion), substance P (SP, an indirect marker that decreases after lesion), and phospho-ERK1/2 was done using slices at the level of striatum and SN. Unilateral dopaminergic lesioned rats, as expected, exhibited >90% TH loss and a modest SP loss in the striatum and SN. L-DOPA alone induced a 343% and 330% increase in phospho-ERK1/2 in the striatum and SN, respectively. We report here a novel finding that pretreatment with AOAA attenuated the L-DOPA induced increase in phospho-ERK1/2 by 62% and 68% in the striatum and SN, respectively, suggesting a DA-GABA-ERK1/2 link in the therapeutic and/or side effects of L-DOPA.展开更多
Parkinson’s disease (PD) is characterized by degeneration of nigrostriatal dopamine (DA) neurons. The primary drug used to treat PD symptoms is L-DOPA, but side effects such as dyskinesias limit its use. Previous fin...Parkinson’s disease (PD) is characterized by degeneration of nigrostriatal dopamine (DA) neurons. The primary drug used to treat PD symptoms is L-DOPA, but side effects such as dyskinesias limit its use. Previous findings show that L-DOPA treatment induces extracellular signal-regulated kinase (ERK1/2), a MAP-kinase protein. γ-aminobutyric acid (GABA) is intimately involved in basal ganglia function. Our previous study using a unilaterally lesioned rat model of PD indicated that elevating GABA levels by GABA transaminase inhibitor, aminooxyacetic acid significantly attenuated L-DOPA-induced ERK phosphorylation in the striatum and substantia nigra (SN). The aim of the present study was to assess the role of GABA-A and GABA-B receptor by using a selective agonists, muscimol and baclofen respectively, on L-DOPA-induced ERK phosphorylation in the striatum and SN. Unilaterally 6-OHDA-lesioned rats were prescreened by apomorphine induced rotation test for the extent of DA loss. Lesioned rats were treated with L-DOPA alone or after muscimol or baclofen pretreatment. Appropriate control groups were used. Phospho-ERK levels, tyrosine hydroxylase (to ascertain DA loss) and substance P (an indirect marker for DA loss) levels were assessed by immunohistochemistry using coronal slices at the level of striatum and SN. L-DOPA administration induced a robust increase (>300%) in phospho-ERK1/2 levels in the striatum and SN. Muscimol as well as baclofen pretreatment attenuated the L-DOPA-induced increase in phospho-ERK1/2 levels by >60% in the striatum and SN. Muscimol and baclofen pretreatment also greatly reduced the number of L-DOPA induced phospho-ERK1/2 stained cells in the striatum as well as the contralateral rotational behavior. The present data taken together with our previous study indicate that the L-DOPA induced increase in ERK1/2 is attenuated by GABA via a GABA-A and GABA-B receptor linked mechanism. The study provides further insight into a dopamine-GABA-ERK interaction in the therapeutic and/or side effects of L展开更多
Infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the right common carotid artery produced hemiparkinsonian syndrome on contralateral limbs in 5 rhesus monkeys. The hemiparkinsonian syndrome produce...Infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the right common carotid artery produced hemiparkinsonian syndrome on contralateral limbs in 5 rhesus monkeys. The hemiparkinsonian syndrome produced responded to madopar medication and the circling motion changed from toward the MPTP-treated side to away from the MPTP-treated side. Long term use of madopar developed a peak-dose dyskinesia of the face and limbs at the contralateral side. The toxic effect of MPTP was confirmed biochemically by reduction of nigrostriatal DA and histologically by degeneration of nigral neurons on the MPTP-treated side. It is concluded that this hemiparkinsonian monkey model will be of value in the elucidation of the neural mechanism underlying L-DOPA or DA agonists induced dyskinesia in Parkinson’s disease and in the search for newer methods of treatment which would produce less dyskinesia.展开更多
目的探讨双能X线骨密度扫描(dual energy X-ray absorptiometry,DXA)技术诊断早期偏侧性帕金森病(Parkinson’s disease,PD)的临床价值。方法选取2019年9月至2022年3月就诊于上海健康医学院附属周浦医院诊断为早期偏侧性PD的患者80例为P...目的探讨双能X线骨密度扫描(dual energy X-ray absorptiometry,DXA)技术诊断早期偏侧性帕金森病(Parkinson’s disease,PD)的临床价值。方法选取2019年9月至2022年3月就诊于上海健康医学院附属周浦医院诊断为早期偏侧性PD的患者80例为PD组,另选同期年龄、性别及体重指数(body mass index,BMI)相匹配的健康体检者60例为对照组。采用双能X线骨密度扫描仪测定所有纳入对象的股骨颈骨密度、髋部总骨密度、腰椎总骨密度,并检测血清25-羟维生素D[25-hydroxyvitamin D,25(OH)D]水平,比较两组骨密度、25(OH)D水平,分析PD组骨质疏松发生的危险因素。结果PD组腰椎总骨密度、股骨颈骨密度、髋部总骨密度、25(OH)D水平均低于对照组,差异有显著性(P<0.05)。PD组中27.5%(22例)患者出现骨质疏松,骨质疏松发生率高于对照组,差异有显著性(P<0.05)。多因素logistic回归分析显示年龄、女性、低BMI、低25(OH)D水平是早期偏侧性PD患者发生骨质疏松的危险因素。结论DXA能检测出偏侧性PD患者在病程早期阶段的骨密度,结合血清25(OH)D水平的降低等因素,对存在危险因素的患者应进行必要的早期预防和及时干预措施,以减少骨质疏松的发生,降低骨折风险。展开更多
文摘L-DOPA is the primary drug used to treat Parkinson’s disease (PD) symptoms, but motor side effects limit its long term use. Previous experimental studies show that L-DOPA acts on supersensitive D1 receptors in the basal ganglia to induce extracellular signal-regulated kinases 1 and 2 (ERK1/2), a pair of MAP-kinase proteins that may be involved in induction of motor side effects. Since GABA is known to be intimately involved in basal ganglia function, we investigated whether elevating GABA levels via a GABA-transaminase (GABA-T) inhibitor affects the L-DOPA-induced ERK1/2 phosphorylation in the striatum and substantia nigra (SN) using a rat model of PD. Unilateral dopaminergic lesions of median forebrain bundle neurons were done using the neurotoxin 6-hydroxydopamine. Rats were prescreened for the extent of the lesion by apomorphine-induced rotation test. Lesioned rats were treated with aminooxyacetic acid (AOAA, a GABA-T inhibitor), L-DOPA, or in combination. Immunohistochemistry of tyrosine hydroxylase (TH, a direct indicator of dopaminergic lesion), substance P (SP, an indirect marker that decreases after lesion), and phospho-ERK1/2 was done using slices at the level of striatum and SN. Unilateral dopaminergic lesioned rats, as expected, exhibited >90% TH loss and a modest SP loss in the striatum and SN. L-DOPA alone induced a 343% and 330% increase in phospho-ERK1/2 in the striatum and SN, respectively. We report here a novel finding that pretreatment with AOAA attenuated the L-DOPA induced increase in phospho-ERK1/2 by 62% and 68% in the striatum and SN, respectively, suggesting a DA-GABA-ERK1/2 link in the therapeutic and/or side effects of L-DOPA.
文摘Parkinson’s disease (PD) is characterized by degeneration of nigrostriatal dopamine (DA) neurons. The primary drug used to treat PD symptoms is L-DOPA, but side effects such as dyskinesias limit its use. Previous findings show that L-DOPA treatment induces extracellular signal-regulated kinase (ERK1/2), a MAP-kinase protein. γ-aminobutyric acid (GABA) is intimately involved in basal ganglia function. Our previous study using a unilaterally lesioned rat model of PD indicated that elevating GABA levels by GABA transaminase inhibitor, aminooxyacetic acid significantly attenuated L-DOPA-induced ERK phosphorylation in the striatum and substantia nigra (SN). The aim of the present study was to assess the role of GABA-A and GABA-B receptor by using a selective agonists, muscimol and baclofen respectively, on L-DOPA-induced ERK phosphorylation in the striatum and SN. Unilaterally 6-OHDA-lesioned rats were prescreened by apomorphine induced rotation test for the extent of DA loss. Lesioned rats were treated with L-DOPA alone or after muscimol or baclofen pretreatment. Appropriate control groups were used. Phospho-ERK levels, tyrosine hydroxylase (to ascertain DA loss) and substance P (an indirect marker for DA loss) levels were assessed by immunohistochemistry using coronal slices at the level of striatum and SN. L-DOPA administration induced a robust increase (>300%) in phospho-ERK1/2 levels in the striatum and SN. Muscimol as well as baclofen pretreatment attenuated the L-DOPA-induced increase in phospho-ERK1/2 levels by >60% in the striatum and SN. Muscimol and baclofen pretreatment also greatly reduced the number of L-DOPA induced phospho-ERK1/2 stained cells in the striatum as well as the contralateral rotational behavior. The present data taken together with our previous study indicate that the L-DOPA induced increase in ERK1/2 is attenuated by GABA via a GABA-A and GABA-B receptor linked mechanism. The study provides further insight into a dopamine-GABA-ERK interaction in the therapeutic and/or side effects of L
文摘Infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the right common carotid artery produced hemiparkinsonian syndrome on contralateral limbs in 5 rhesus monkeys. The hemiparkinsonian syndrome produced responded to madopar medication and the circling motion changed from toward the MPTP-treated side to away from the MPTP-treated side. Long term use of madopar developed a peak-dose dyskinesia of the face and limbs at the contralateral side. The toxic effect of MPTP was confirmed biochemically by reduction of nigrostriatal DA and histologically by degeneration of nigral neurons on the MPTP-treated side. It is concluded that this hemiparkinsonian monkey model will be of value in the elucidation of the neural mechanism underlying L-DOPA or DA agonists induced dyskinesia in Parkinson’s disease and in the search for newer methods of treatment which would produce less dyskinesia.
文摘目的探讨双能X线骨密度扫描(dual energy X-ray absorptiometry,DXA)技术诊断早期偏侧性帕金森病(Parkinson’s disease,PD)的临床价值。方法选取2019年9月至2022年3月就诊于上海健康医学院附属周浦医院诊断为早期偏侧性PD的患者80例为PD组,另选同期年龄、性别及体重指数(body mass index,BMI)相匹配的健康体检者60例为对照组。采用双能X线骨密度扫描仪测定所有纳入对象的股骨颈骨密度、髋部总骨密度、腰椎总骨密度,并检测血清25-羟维生素D[25-hydroxyvitamin D,25(OH)D]水平,比较两组骨密度、25(OH)D水平,分析PD组骨质疏松发生的危险因素。结果PD组腰椎总骨密度、股骨颈骨密度、髋部总骨密度、25(OH)D水平均低于对照组,差异有显著性(P<0.05)。PD组中27.5%(22例)患者出现骨质疏松,骨质疏松发生率高于对照组,差异有显著性(P<0.05)。多因素logistic回归分析显示年龄、女性、低BMI、低25(OH)D水平是早期偏侧性PD患者发生骨质疏松的危险因素。结论DXA能检测出偏侧性PD患者在病程早期阶段的骨密度,结合血清25(OH)D水平的降低等因素,对存在危险因素的患者应进行必要的早期预防和及时干预措施,以减少骨质疏松的发生,降低骨折风险。
