A Wayne State University professor recently received a nearly $1.7 million grant from the National Institutes of Drug Abuse of the National Institutes of Health to explore whether proteasome and parkin — two components of the ubiquitin-proteasome system — are potential pharmaceutical drug targets that can be manipulated to promote survival and recovery of dopaminergic terminals after binge and chronic administration of toxic doses of methamphetamine.
Methamphetamine, a potent and highly addictive psychostimulant, is significantly abused around the world and known to cause neurotoxicity at high doses. Cocaine, another highly abused psychostimulant, is not neurotoxic. Cocaine prolongs dopamine actions in the brain by blocking the re-absorption (re-uptake) of the neurotransmitter dopamine by signaling nerve cells. Methamphetamine also blocks the re-uptake of dopamine, but it also increases the release of dopamine from the storage vesicles into the cytosol and subsequently into the synapse (the gap between neurons). Released dopamine readily autoxidizes, triggering oxidative stress and toxicity to dopaminergic nerve terminals.
The grant, "Proteasome and Parkin as Drug Targets Against Methamphetamine Toxicity," aims to better understand the molecular mechanisms regulating the ubiquitin-proteasome system in animal brains exposed to high doses of methamphetamine and to determine whether two components of this system — the proteasome and E3 ligase parkin — are potential pharmaceutical drug targets that can be used to promote neuronal survival and recovery after administration of high doses of methamphetamine.
According to Anna Moszczynska, Ph.D., assistant professor of pharmaceutical sciences in the Eugene Applebaum College of Pharmacy and Health Sciences and principal investigator on the grant, functions of both proteasome and parkin are decreased in the rat striatum, a brain region rich in dopamine, shortly after administration of high doses of the drug. Augmentation of their functions may lead to novel neuroprotective strategies to combat methamphetamine neurotoxicity and other brain disorders involving damage to the striatum such as Parkinson's disease.
The research proposed in the R01 grant will test the hypothesis that augmentation of parkin and proteasome function after chronic or binge methamphetamine will promote survival and/or recovery from neurotoxicity of the drug. Findings from the proposed research may lead to novel neuroprotective therapeutic strategies to combat methamphetamine neurotoxicity and other brain disorders involving damage to the brain's dopaminergic system such as Parkinson's disease.
"Despite years of active research on methamphetamine neurotoxicity, no specific medications have been developed to counteract the damaging effects that it has on the brain," said Moszczynska. "Due to its widespread abuse, there is a compelling need for effective pharmaceuticals that can protect and/or restore the brain from the toxic effects of acute methamphetamine overdose and chronic methamphetamine abuse. Thus, it is necessary to identify molecular drug targets in order to develop novel pharmaceuticals."
The findings from Moszczynska's research may lead to novel treatments for chronic human methamphetamine users.
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