Free radicals and other reactive oxygen species (ROS) constitute a normal part of the intracellular environment. Endogenous enzymes such as catalase, superoxide dismutase and the thiol redox systems, glutathione and oxidized glutathione, serve as reducing agents to minimize the harm ROS might cause in the cell. An excess of ROS, however, can tilt the delicate balance leading to oxidative stress. It is now well known that oxidative stress (OS) plays an important role in many neurodegenerative disorders such as Parkinson disease, Alzheimer’s disease, amyotrophic lateral sclerosis and other disorders with neurodegenerative effects, including adrenoleukodystrophy (ALD). Many antioxidants have been studied in an effort to ameliorate the oxidative stress, slow the progression or treat the symptoms of these and other neurodegenerative disorders, mostly with limited success. The potential reasons for the limited success of these compounds are discussed in this thesis, and the dissertation research on the potential use of N-acetylcysteine, (NAC) a well-known antioxidant and glutathione precursor, is described in detail. The first portion of the dissertation research described herein focused on characterizing the pharmacokinetics of intravenously administered NAC as adjunctive therapy with hematopoietic cell transplant (HCT) in ALD. The objectives of this research were to characterize the pharmacokinetics of i.v. NAC and to explore one of the mechanisms by which NAC is thought to exert its antioxidant effects: through the provision of cysteine for the synthesis of glutathione, the most powerful endogenous antioxidant in the body. The second clinical study described in this thesis focused on the effect of i.v. administered NAC on glutathione concentrations measured directly in the brain of people with Parkinson’s disease, Gaucher disease and healthy control subjects, through the use of magnetic resonance spectroscopy. The research described in this dissertation represents the first report of the pharmacokinetics and direct pharmacodynamic effects of i.v. NAC administration in those affected by disorders of neurodegeneration. This research now serves as the basis for other pharmacokinetic and pharmacodynamic studies of NAC in other populations as well as with other dosage forms and formulations, with the hope of developing effective antioxidant treatments for those suffering from neurodegenerative disorders.
University of Minnesota Ph.D. dissertation. August 2015. Major: Experimental & Clinical Pharmacology. Advisor: James Cloyd. 1 computer file (PDF); ix, 123 pages.
Pharmacology and Clinical Effects of N-acetylcysteine in Neurodegenerative Disorders.
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