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Vol. 56, Issue 2, 254-264, August 1999

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

Yongquan Luo, Akinori Hattori, James Munoz, Zheng-Hong Qin, and George S. Roth

Molecular Physiology and Genetics Section, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland (Y.L., A.H., J.M., G.S.R.); and Experimental Therapeutic Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland (Z.-H.Q.)

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-kappa B (NF-kappa B), an oxidative stress-responsive transcription factor. Injection of curcumin at a dose that selectively inhibits AP-1 activation without affecting NF-kappa B activity attenuates DNA laddering induced by DA. Preinjection with SN50, a specific permeable recombinant NF-kappa B translocation inhibitor peptide, reduces DA-induced NF-kappa B activation and apoptosis. Moreover, preinjection of the antioxidant GSH significantly inhibits both DA-induced activation of transcription factors AP-1 and NF-kappa B 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-kappa B.

Copyright © 1999 by U.S. Government


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