STUDIES OF OXIDATIVE DAMAGE, BRAIN PROTEOME, AND NEUROCHEMICAL METABOLITES IN COGNITIVE AND NEURODEGENERATIVE DISORDERS: (1) CHEMOTHERAPY-INDUCED COGNITIVE IMPAIRMENT; (2) PARKINSON DISEASE RAT MODEL

OF DISSERTATION STUDIES OF OXIDATIVE DAMAGE, BRAIN PROTEOME, AND NEUROCHEMICAL METABOLITES IN COGNITIVE AND NEURODEGENERATIVE DISORDERS: (1) CHEMOTHERAPY-INDUCED COGNITIVE IMPAIRMENT; (2) PARKINSON DISEASE RAT MODEL The rate of cancer patients is increasing as the development of science and technology. Twenty million cancer survivors are estimated living in the United States by 2025. However, many cancer survivors show cognitive dysfunction, negatively affecting the quality of life. These cognitive impairments are recognized as chemotherapy-induced cognitive impairment (CICI), also called "chemo brain" by cancer survivors, including the diminished ability of memory and learning, hard to concentrate and focus, as well as diminution of executive function and processing speed. The etiologies and pathologies of CICI are complicated, especially in most cases the anti-cancer drug cannot cross the bloodbrain barrier (BBB). One of the significant candidate mechanisms underlying CICI is chemotherapyinduced, oxidative damage-mediated tumor necrosis factor-alpha (TNF-a) elevation. One of the prototypes of reactive oxygen species (ROS)-generating chemotherapeutic agents is Doxorubicin, normally used as part of multi-drug chemotherapeutic regimens to treat solid tumors and lymphomas. In this dissertation, TNF-a null (TNFKO) mice were used to investigate the role of TNF-a in Dox-induced, oxidative damage-mediated alterations in brain. Dox-induced oxidative damage in brain is ameliorated and brain mitochondrial function is preserved in brains of TNFKO mice. Both Dox-decreased levels of hippocampal choline-containing compounds and activities of brain phospholipases are partially protected in the TNFKO group. It is shown in this dissertation that Dox-targeted mitochondrial damage and the levels of brain choline-containing metabolites, as well as the activities of phosphatidylcholine-specific phospholipase C (PC-PLC) and phospholipase D (PLD), are decreased in the CNS and associated with oxidative damage mediated by TNF-a. The results are discussed with respect to identifying a potential therapeutic target to protect against cognitive problems after chemotherapy and thereby improve the quality of life of cancer survivors. We also tested the effect of a chemotherapy drug adjuvant, 2-mercaptoethane sulfonate sodium (MESNA), on CICI in this dissertation research. In this dissertation research, MESNA ameliorates Dox-induced oxidative protein damage in plasma and decreases subsequent oxidative damage in brain of Dox-treated mice. MESNA also is demonstrated to rescue the memory deficits caused by Dox in the novel object recognition test. The activity of PC-PLC is preserved when MESNA was co-administered with Dox. This study demonstrates the protective effects of MESNA on Dox-related protein oxidation, cognitive decline, phosphocholine levels, and PC-PLC activity in brain and suggests novel potential therapeutic targets and strategies to mitigate CICI. Parkinson Disease (PD) is considered as the second most neurodegenerative disease, associated with aging and gender. Although the detailed mechanisms remain unknown, inflammation and oxidative damage are two main etiological factors of PD. Certain genetic factors have been discovered related to this disease. Thus, using rodent models with relative gene mutations are the main strategies to investigate PD. However, an ideal rodent model of PD, showing same clinical and biochemical features of PD, has not been found. PTENinduced putative kinase -1 (PINK1) knockout (KO) rat is the rodent model investigated in this dissertation research. The oxidative damage in the brain of PINK1 KO rats, the ventricle sizes, and neurochemical metabolite profiles in these rats as a function of age and gender were measured. Distinct genderand age-related alterations were found, many consistent with those in PD. The proteome of brain of PINK1 KO rat as a function of age also was studied. Based on the collected data, the suitability of this unique rat as a faithful model of known characteristics of PD is discussed.