Neuroprotective Effect of Protein Kinase Cδ Inhibitor Rottlerin in Cell Culture and Animal Models of Parkinson's Disease (original) (raw)
Research ArticleNEUROPHARMACOLOGY
Journal of Pharmacology and Experimental Therapeutics September 2007, 322 (3) 913-922; DOI: https://doi.org/10.1124/jpet.107.124669
Abstract
Recent studies from our laboratory demonstrated that the protein kinase C (PKC) δ 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 PKCδ is proteolytically activated by caspase-3 and that suppression of PKCδ 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 PKCδ, we systematically characterized the neuroprotective effect of a PKCδ 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 PKCδ 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 PKCδ may offer a novel therapeutic strategy for treatment of PD.
Footnotes
This work was supported by National Institutes of Health Grants NS 38644 and ES10586.
A.G.K. was awarded the W. Eugene and Linda Lloyd Endowed Professorship.
United States patent is pending for the development of rottlerin and its analogs as potential neurotherapeutic agents.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.107.124669.
ABBREVIATIONS: PD, Parkinson's disease; SNc, substantia nigra compacta; PKC, protein kinase C; siRNA, small interfering RNA; MPP+, 1-methyl-4-phenylpyridinium; TH, tyrosine hydroxylase; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; E, embryonic day; DA, dopamine; PBS, phosphate-buffered saline; DMSO, dimethyl sulfoxide; HPLC, high-performance liquid chromatography; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; CNS, central nervous system.
Received April 20, 2007.
Accepted June 11, 2007.
The American Society for Pharmacology and Experimental Therapeutics
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