Preferential hemeoxygenase 1 activation in striatal astrocytes antagonized dopaminergic neurons degeneration in MPTP-intoxicated mice

【作者】 宋宁； Xiaofeng Xu； Xiaojun Yu； Hong Jiang； Junxia Xie；

【Author】 Ning Song;Xiaofeng Xu;Xiaojun Yu;Hong Jiang;Junxia Xie;Department of Physiology,Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines:Physiology,Qingdao University;

【机构】 青岛大学； Department of Physiology,Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines:Physiology,Qingdao University；

【摘要】 Parkinson’s disease(PD)is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta(SNpc)with accompanying evidence of increased oxidative damage.Heme oxygenase-1(HO-1)is crucial to the response to oxidative stress via the catabolism of heme into carbon monoxide,biliverdin and iron.The present study aims to investigate neuroprotective effects of HO-1 activation induced by cobalt protoporphyrin IX(Co PPIX)in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)intoxicated mice.The results showed that MPTP triggered a robust HO-1 activation in the astrocytes of striatum after 1d treatment,and then dropped dramatically.Intraventricular administration of Copp IX for 8days could preferentially activate HO-1 in astrocytes in striatum rather than SNpc.The loss of dopaminergic neurons was blocked and striatal dopamine content were restored in the subacute MPTP models with Co PPIX administration.We then analyzed HO-1 response in primary cultured ventral mesencephalic astrocytes and neurons treated by 1-methyl-4-phenyl-pyridinium(MPP+).The results showed HO-1 up-regulation in astrocytes appeared much earlier than that in neurons.Although HO-1activation induced by Copp IX might be double-edged in neurons,it always showed cytoprotective effects in astrocytes.These results indicated that preferential HO-1 activation in striatal astrocytes might convey neuroprotective effects on dopaminergic neurons in PD.This also provided evidence for targeting HO-1 in striatal astrocytes for PD therapeutics.更多还原

【Abstract】 Parkinson’s disease(PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta(SNpc) with accompanying evidence of increased oxidative damage.Heme oxygenase-1(HO-1) is crucial to the response to oxidative stress via the catabolism of heme into carbon monoxide,biliverdin and iron.The present study aims to investigate neuroprotective effects of HO-1 activation induced by cobalt protoporphyrin IX(Co PPIX) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) intoxicated mice.The results showed that MPTP triggered a robust HO-1 activation in the astrocytes of striatum after 1d treatment,and then dropped dramatically.Intraventricular administration of Copp IX for 8 days could preferentially activate HO-1 in astrocytes in striatum rather than SNpc.The loss of dopaminergic neurons was blocked and striatal dopamine content were restored in the subacute MPTP models with Co PPIX administration.We then analyzed HO-1 response in primary cultured ventral mesencephalic astrocytes and neurons treated by 1-methyl-4-phenyl-pyridinium(MPP+).The results showed HO-1 up-regulation in astrocytes appeared much earlier than that in neurons.Although HO-1activation induced by Copp IX might be double-edged in neurons,it always showed cytoprotective effects in astrocytes.These results indicated that preferential HO-1 activation in striatal astrocytes might convey neuroprotective effects on dopaminergic neurons in PD.This also provided evidence for targeting HO-1 in striatal astrocytes for PD therapeutics.更多还原