Intrastriatal Dopamine Injection Induces Apoptosis Through Oxidation-Involved Activation of Transcription Factors AP-1 and NF-κB in Rats

Abstract

ABSTRACT

More and more evidence suggests that increases in dopamine (DA) in striata may participate in neurodegenerative processes during acute ischemia, hypoxia, and excitotoxicity. With a rat model of intrastriatal DA injection, we studied the molecular events involved in DA toxicity. Intrastriatal injections of DA in amounts from 1 to 2 μmol result in apoptotic cell death, as indicated by terminal deoxynucleotidyl transferase labeling of DNA strand breaks and Klenow polymerase-catalyzed [³²P]deoxycytidine triphosphate-labeled DNA laddering. Injections of DA produce a strong and prolonged activated protein 1 (AP-1) activity that contains c-fos, c-jun, and phosphorylated c-jun protein. DA injections also stimulate the activity of nuclear factor-κB (NF-κB), an oxidative stress-responsive transcription factor. Injection of curcumin at a dose that selectively inhibits AP-1 activation without affecting NF-κB activity attenuates DNA laddering induced by DA. Preinjection with SN50, a specific permeable recombinant NF-κB translocation inhibitor peptide, reduces DA-induced NF-κB activation and apoptosis. Moreover, preinjection of the antioxidant GSH significantly inhibits both DA-induced activation of transcription factors AP-1 and NF-κB and subsequent apoptosis. Thus, our data suggest that DA-oxidative stress-induced apoptosis in vivo is mediated by activation of transcription factors AP-1 and NF-κB.