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Calcineurin/NFAT-induced up-regulation of the Fas ligand/Fas death pathway is involved in methamphetamine-induced neuronal apoptosis.
Jayanthi, Subramaniam; Deng, Xiaolin; Ladenheim, Bruce; McCoy, Michael T; Cluster, Andrew; Cai, Ning-Sheng; Cadet, Jean Lud.
Afiliação
  • Jayanthi S; Molecular Neuropsychiatry Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
Proc Natl Acad Sci U S A ; 102(3): 868-73, 2005 Jan 18.
Article em En | MEDLINE | ID: mdl-15644446
Methamphetamine [METH ("speed")] is an abused psychostimulant that can cause psychotic, cognitive, and psychomotor impairment in humans. These signs and symptoms are thought to be related to dysfunctions in basal ganglionic structures of the brain. To identify possible molecular bases for these clinical manifestations, we first used cDNA microarray technology to measure METH-induced transcriptional responses in the striatum of rats treated with an apoptosis-inducing dose of the drug. METH injection resulted in increased expression of members of the Jun, Egr, and Nur77 subfamilies of transcription factors (TFs), changes that were confirmed by quantitative PCR. Because pathways linked to these factors are involved in the up-regulation of Fas ligand (FasL), FasL mRNA was quantified and found to be increased. Immunohistochemical studies also revealed METH-induced increased FasL protein expression in striatal GABAergic neurons that express enkephalin. Moreover, there were METH-mediated increases in calcineurin, as well as shuttling of nuclear factor of activated T cells (NFAT)c3 and NFATc4 from the cytosol to the nucleus of METH-treated rats, mechanisms also known to be involved in FasL regulation. Furthermore, METH induced cleavage of caspase-3 in FasL- and Fas-containing neurons. Finally, the METH-induced changes in the FasL-Fas death pathway were attenuated by pretreatment with the dopamine D1 receptor antagonist, SCH23390, which also caused attenuation of METH-induced apoptosis. These observations indicate that METH causes some of its neurodegenerative effects, in part, via stimulation of the Fas-mediated cell death pathway consequent to FasL up-regulation mediated by activation of multiple TFs.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Glicoproteínas de Membrana / Proteínas Nucleares / Apoptose / Proteínas de Ligação a DNA / Metanfetamina / Neurônios Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2005 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Glicoproteínas de Membrana / Proteínas Nucleares / Apoptose / Proteínas de Ligação a DNA / Metanfetamina / Neurônios Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2005 Tipo de documento: Article