Can exercise ameliorate the symptoms of Parkinson’s disease? modes and mechanisms

This report is submitted in fulfilment of the requirements for the degree of PhD in Exercise Physiology, University of BedfordshireMovement disorders are the hallmark of Parkinson’s disease (PD) and can severely compromise an individual’s ability to perform well-learned motor skills such as walking, writing, turning around and transferring in and out of bed. The first symptoms of PD typically do not appear until a critical threshold of 70-80% loss of the striatal neurotransmitter called Dopamine (DA) is exceeded. The loss of DA compromises the connection between the striatum and the Substania Nigra (SN); this connection is essential for the control of body movement. The lifelong management of individuals with PD needs a multidisciplinary approach, which includes coordination of pharmacological and non-pharmacological interventions. The use of prescribed exercise as a non-invasive PD symptom management tool is well recognized. What needs further research and development is an evidence-base for the type, frequency, intensity, duration etc. of exercise bouts. It is however ethically, socially and morally challenging to put unknown physical demands on PD sufferers, therefore in vivo and in vitro studies will be essential in delineating and targeting appropriate interventions. Additionally, in order to establish whether the various interventions are effective will also require a simple measure, preferably one that can be detected following exercise. Ca2+ plays an important role in the synthesis of DA via the Ca2+ calmodulin system and its increase in exercise coincidences with the reported positive effects of exercise on dopamenirgic neuron activity. The aim of this thesis was therefore to use in vivo, in vitro and human methodologies to establish a role for physical exercise in the amelioration of the symptoms of PD. The in vivo study comprised of four groups of experimental animals (rats): a control group (C), a training exercise group (E), a group in which Parkinson’s was induced via systemic injections of PD toxin MPTP (PD) and a group where PD-induced animals were trained/exercised (PDE). (E) and (PDE) groups were trained with 8 weeks of endurance exercise at 90% of the lactate threshold (LT), 5 times a week with each bout lasting for 45 min using a custom-built rodent treadmill. After 8 weeks, all animals were sacrificed and brain samples were collected for immunohistochemistry and western blot analysis. Ca2+ calmodulin kinases I (CaMK-1) and IV (CaMK-4) were investigated as indicators of the activity of the Ca2+ calmodulin pathway. Immunohistochemical analysis of SN region indicated that in the PD group, CaMK-1 and CaMK-4 expression was suppressed when compared with control (C) animals. This phenotype was apparently rescued by endurance exercise as those animals. The western blot results also showed quantitative differences in CaMK-1 and CaMK-4 proteins in the studied brain regions in the (PDE) and (E) groups compared with the PD group. It was concluded from this data that endurance exercise could up regulate the expression of both CaMK-1 and CaMK-4 in the brain of PD sufferers. It was postulated that changes in Ca2+ levels might therefore drive the neuroprotective effect of exercise. The in vitro study was designed to test the hypothesis generated from the in vivo work that Ca2+ is a main effector of the neuroprotective effect of exercise. The SH-SY5Y human neuroblastoma cell line is used as a model of DA neurons as it has DA activity and can synthesize DA. PD was simulated in these cells by exposure to the toxin 6-OHDA whilst addition of Ca2+ was used as an “exercise mimic”. Results showed differences in the survival of SH-SY5Y cells after exposure to specific concentration of Ca2+ following treatment with 6-OHDA. Finally, in order to assess the importance of this data to the clinical population and to further develop the concept that Ca2+ is a major effector of the positive effect of exercise, the effect of moderate-level exercise on the levels of blood Ca2+ in subjects with PD was investigated. Measures of cardiovascular physiology and blood biochemistry (total blood Ca2+) were obtained during cycling exercise at an intensity of 90% of the lactate threshold. Results indicated exercise to be beneficial in alleviating motor symptoms of PD