Recent studies from our laboratory demonstrated that the
protein kinase C (PKC) delta
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 delta is proteolytically activated by
caspase-3 and that suppression of PKC delta 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 delta, we systematically characterized the
neuroprotective effect of a PKC delta 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 delta
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 delta may offer a novel therapeutic strategy for treatment of PD.