Amphetamine-induced dopaminergic toxicity:: a single dose animal model of Parkinson's disease

Parkinson's disease affects millions of people worldwide and is characterized by loss of dopaminergic neurons of the nigro-striatal pathway. Although many mechanisms have been postulated to account for the destruction of these cells, no clear cause has been elucidated. The hypothesis that oxidative stress plays an important role in dopamine depletion in Parkinson's disease was examined through use of amphetamine, a dopaminergic toxicant known to act through oxidative stress. First, a thorough characterization of a single high dose of amphetamine was completed as a new model of Parkinson's disease. Then, antioxidant and anti-inflammatory treatments were used to protect against amphetamine's neurotoxic effects. The antioxidant ascorbic acid was successful in attenuating amphetamine-induced dopamine depletion, while others tested, including Trolox and EGCG, did not attenuate dopaminergic toxicity. In addition, an end product of lipid peroxidation, malondialdehyde, was measured in response to amphetamine treatment and evaluated with the time course of amphetamine-induced dopamine depletion. Studies have shown increased levels of malondialdehyde in the blood and brains of Parkinson's patients. Finally, the behavior and sensitivity of mice with selective deletions of genes coding for GSTM1, PAK5, PAK6, or both PAK5 and PAK6 to amphetamine was examined. Multiple genes have been implicated in the etiology of Parkinson's disease, some of which may be associated with oxidative stress response, mitochondrial function, protein kinase function and/or neuronal survival mechanisms. A null mutation in GSTM1 has been associated with Parkinson's disease and plays a role as an antioxidant in the brain. Mice lacking the GSTM1 gene did not show an abnormal behavioral phenotype compared to controls and were not sensitive to amphetamine toxicity. The p21-activated kinases (PAKs) are highly expressed in the brain as well and have been implicated in several neurological disorders, including Parkinson's disease. Mice lacking one or more of the PAK genes showed motoric similarities to Parkinson's disease, although they were relatively resistant to amphetamine toxicity. Collectively, these experiments explored the role of oxidative stress, antioxidant function and related genetic components in a single dose, amphetamine animal model of Parkinson's disease.Ph.D.Includes bibliographical references (p. 253-266)