Neuroprotection against Methamphetamine Induced Neurotoxicity: Applications for Parkinson’s Disease

Abstract

Parkinson’s disease is a progressive neurodegenerative disorder associated with selective degeneration of nigrostriatal dopaminergic neurons. It is the most common of the neurodegenerative movement disorders, affecting approximately 1% of the population over age 65. In Parkinson’s disease, the shortage of dopamine in the striatum causes various motor abnormalities and complete immobility usually occurs, despite treatment. Studies have implicated exposure to toxins like methamphetamine as contributors to the development of Parkinson’s disease. There is a significant degree of striatal dopamine depletion produced by methamphetamine, making the toxin useful in the creation of an animal model to study the disease. In this study a mouse model of Parkinson’s disease was created by administering two intraperitoneal injections of methamphetamine (10mg/kg) two hours apart. The neurotoxic effects of methamphetamine and neuroprotective effect of ramelteon, amantadine and salicylic acid were evaluated both in vitro and in vivo. Effects of reduced energy metabolism and oxidative stress were evaluated using biochemical assays. Changes in neurotransmitter levels (norepinepherine, serotonin and its metabolite, 5-HIAA, dopamine and its metabolites, DOPAC and HVA) were measured using high pressure liquid chromatography (HPLC)-electrochemical detection. In addition, behavioral analysis was performed on the treated mice to evaluate the effect of methamphetamine on movement (catalepsy, akinesia, swim score, straub tail and tremor). Results of these studies revealed that methamphetamine caused significant generation of reactive oxygen species, significantly increased superoxide dismutase activity and significantly decreased Complex I activity both in vitro and in vivo. Methamphetamine caused significant dopamine depletion in the striatum of treated mice and caused significant alterations in movement behaviors as compared to controls. Ramelteon did not block the neurotoxic effects of methamphetamine. Amantadine (1mg/kg) blocked the neurotoxic effects of methamphetamine and salicylic acid (50 & 100mg/kg) also blocked the neurotoxic effects of methamphetamine, causing a reduced amount of dopamine depletion in the striatum.