Astrocyte-derived nitric oxide in manganese neurotoxicity: from cellular and molecular mechanisms underlying selective neuronal vulnerability in the basal ganglia to potential therapeutic modalities

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Title: Astrocyte-derived nitric oxide in manganese neurotoxicity: from cellular and molecular mechanisms underlying selective neuronal vulnerability in the basal ganglia to potential therapeutic modalities
Author: Liu, Xuhong
Abstract: Chronic exposure to manganese (Mn ) causes the neurodegenerative movement disorder , manganism . A mouse model was developed to elucidate mechanisms involved in the etiology and progression of injury . Twelve -week old female C57Bl /6J mice were exposed to MnCl2 (100 mg /kg /day ) by oral gavage daily for 8 weeks . After the experiment striatal dopamine (DA ) content was decreased with the manifestation of hypoactivity . A distinct population of neurons was vulnerable to the effects of Mn , including enkephalin (ENK ) -positive projection neurons , interneurons expressing neuronal nitric oxide synthetase (nNOS /NOS1 ) , and choline acetyltransferase (ChAT ) -expressing interneurons . Activation of surrounding astrocytes occurred with expression of inducible nitric oxide synthase (iNOS /NOS2 ) and production of nitric oxide (NO ) /peroxynitrite (ONOO - ) . Activated astrocytes were detected primarily near the microvasculature in both the striatum and globus pallidus (GP ) . It is suggested that Mn exposure may damage the blood -brain barrier (BBB ) and induce astrocytosis and NOS2 expression , subsequent NO production may cause the death of adjacent neurons . This hypothesis was also tested in an in vitro co -culture model . Differentiated pheochromocytoma cells (PC12 cells ) were co -cultured with primary astrocytes and exposed to Mn and inflammatory cytokines . Mn and cytokines induced NOS2 expression and NO production in astrocytes , which correlated with apoptosis of PC12 cells . Apoptosis of PC12 cells was prevented by overexpression of a phosphorylation -deficient mutant of I ? ? ? ?B ? ? ? ? that inhibited NOS2 expression in astrocytes . It is concluded that Mn -and cytokine -dependent apoptosis in PC12 cells requires astrocyte -derived NO and nuclear factor ? ? ? ?B (NF - ? ? ? ?B ) -dependent expression of NOS2 . To explore possible means of interdicting this inflammatory process in astrocytes , a noval pharmacologic ligands of the peroxisome proliferator -activated receptor gamma (PPAR ? ? ? ? ) agonist , 1 ,1 -Bis (3' -indolyl ) -1 - (p -trifluoromethylphenyl ) methane (DIM -C -pPhCF3 ) were used in the same co -culture system . DIM -C -pPhCF3 protected PC12 cells from apoptosis through inhibition of NOS2 expression in astrocytes after Mn and cytokines exposure . By contrast , the PPAR ? ? ? ? antagonist , 2 -chloro -5 -nitrobenzanilide (GW9622 ) , had the opposite effect , increasing both NO production in astrocytes and neuronal injury . It is concluded that PPAR ? ? ? ? is involved in the regulation of NOS2 expression in astrocytes and that agonists of PPAR ? ? ? ? may represent a potential treatment method for Mn neurotoxicity .
URI: http : / /hdl .handle .net /1969 .1 /4958
Date: 2007-04-25

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Astrocyte-derived nitric oxide in manganese neurotoxicity: from cellular and molecular mechanisms underlying selective neuronal vulnerability in the basal ganglia to potential therapeutic modalities. Available electronically from http : / /hdl .handle .net /1969 .1 /4958 .

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