Methamphetamine, Inflammation and the Ubiquitin/Proteasome Pathway: Impact on Neurodegeneration
Methamphetamine (METH) is an addictive psychostimulant and the second most abused drug worldwide. Long term and short term METH use contribute to brain inflammation by causing upregulation of the enzyme cyclooxygenase-2 (COX-2). COX-2 is a key enzyme in the biosynthesis of prostaglandins (PGs) which are lipids synthesized at the site of injury to help regulate inflammation. Although inflammation is a protective response it also induces damaging effects, such as impairing the ubiquitin/proteasome pathway (UPP). The UPP is the primary pathway for the removal and degradation of ubiquitin tagged proteins. Ubiquitin is a regulatory protein that is attached to damaged or misfolded proteins by a highly complex enzymatic cascade. Upon inflammation, the UPP is impaired causing the aggregation of ubiquitinated proteins. Failure to remove these aggregates contributes to cell damage that can lead to cell death via an apoptotic pathway. We investigated the link between inflammation and neurodegeneration induced by METH, by assessing the accumulation of ubiquitinated proteins in rat embryonic cerebral cortical neurons in vitro. To compare the levels of ubiquitinated proteins, neurons were treated with METH or prostaglandin J2 (PGJ2)—used to mimic the pathology of inflammation. Furthermore, we characterized the neuronal death pathway induced by METH. Our findings suggest a correlation between METH-induced COX-2 upregulation and impairment of the UPP leading to neurodegeneration. While there are many well known deleterious effects of METH use, this data uncovers a novel mechanism by which METH can lead to the demise of CNS neurons.