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NEUROPHARMACOLOGY

Neuroprotective Effect of Protein Kinase C Inhibitor Rottlerin in Cell Culture and Animal Models of Parkinson's Disease

Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa

Recent studies from our laboratory demonstrated that the protein kinase C (PKC) isoform is an oxidative stress-sensitive kinase and a key mediator of apoptotic cell death in Parkinson's Disease (PD) models (Eur J Neurosci 18:1387–1401, 2003; Mol Cell Neurosci 25:406–421, 2004). We showed that native PKC is proteolytically activated by caspase-3 and that suppression of PKC by dominant-negative mutant or small interfering RNA against the kinase can effectively block apoptotic cell death in cellular models of PD. In an attempt to translate the mechanistic studies to a neuroprotective strategy targeting PKC, we systematically characterized the neuroprotective effect of a PKC inhibitor, rottlerin, in 1-methyl-4-phenylpyridinium (MPP⁺)-treated primary mesencephalic neuronal cultures as well as in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of PD. Rottlerin treatment in primary mesencephalic cultures significantly attenuated MPP⁺-induced tyrosine hydroxylase (TH)-positive neuronal cell and neurite loss. Administration of rottlerin, either intraperitoneally or orally, to C57 black mice showed significant protection against MPTP-induced locomotor deficits and striatal depletion of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid. Notably, rottlerin post-treatment was effective even when MPTP-induced depletion of dopamine and its metabolites was greater than 60%, demonstrating its neurorescue potential. Furthermore, the dose of rottlerin used in neuroprotective studies effectively attenuated the MPTP-induced PKC kinase activity. Importantly, stereological analysis of nigral neurons revealed rottlerin treatment significantly protected against MPTP-induced TH-positive neuronal loss in the substantia nigra compacta. Collectively, our findings demonstrate the neuroprotective effect of rottlerin in both cell culture and preclinical animal models of PD, and they suggest that pharmacological modulation of PKC may offer a novel therapeutic strategy for treatment of PD.

Address correspondence to: Dr. Anumantha G. Kanthasamy, Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, 2062 Veterinary Medicine Bldg., Iowa State University, Ames, IA 50011-1250. E-mail: akanthas{at}iastate.edu

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