Strategies & mechanisms to reduce locomotor impairment in aging & Parkinson's disease




Kasanga, Ella A.


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The maintenance of physical function throughout the lifespan is a hallmark of successful aging. However, vulnerability to motor impairment during aging is evident in a substantial fraction of those reaching their seventh to ninth decade of life. Aging-related Parkinsonism is a major source of aging-related motor impairment and manifests similarly to Parkinson's disease (PD). Such disability is associated with a loss of independent living, frailty and mortality. Aging is a major risk factor for these two conditions and with the expected exponential increase in the aging population, their prevalence will also increase. Thus, there is the need to identify interventions which can attenuate this motor impairment, and elucidate the mechanisms mediating their protective benefits. Both pharmacological and non-pharmacological interventions, including exercise, have been proposed to ameliorate motor impairment in this target population. However, most of these interventions are instituted in preclinical models before motor function decline is evident. Also, in the quest to elucidate the underlying neurobiological mechanisms, most studies investigate the role of striatal dopamine (DA) regulation which is presumed to be paramount for the initiation or maintenance of locomotor activities. However, many studies do not report a corresponding increase in striatal DA regulation despite improved motor function. This dissertation research, therefore, evaluates interventions designed to prevent further motor decline in both aging and PD rat models after the onset of motor decline. It is hypothesized that improvement in motor function from the implemented interventions: caloric restriction, treadmill exercise and a pharmacological therapy-ceftriaxone, may not be dependent on only increased striatal, but also nigral, dopaminergic transmission. From several angles of intervention to mitigate motor decline in the models used, it is clear that motor function preservation or recovery can occur if interventions are initiated at a time-point when motor decline is already evident. The body of results show that preservation of motor function is not associated with preservation or restoration of striatal tyrosine hydroxylase expression, the rate-limiting enzyme in the synthesis of DA. Taken together, this dissertation delineates the efficacy of select interventions to attenuate motor decline and identifies key mechanistic targets for possible translation in this vulnerable population.