EFFECT OF REPEATED MPTP ADMINISTRATION ON STRIATAL ENERGY METABOLISM IN FREELY MOVING RATS

Neurochemical pathways implicated in brain physiological functions or neurodegenerative diseases are mostly unknown. Because of its high energetic metabolism, related to anatomical characteristics and physiology, the central nervous system (CNS) is assumed to be particularly sensitive to reactive oxygen species (ROS). Two different pathways are involved in the metabolism of glucose: one aerobic (Kreb’s cycle) and one anaerobic (glycolytic pathway). The Kreb’s cycle occurs in the mitochondria, requires pyruvate and oxygen and results in a higher energy production compared to glycolysis which doesn’t need oxygen and converts pyruvate to lactate. Lactate/pyruvate ratio (L/P ratio) is one of the best indicators of the predominant energy pathway. MPP+, produced during MPTP metabolism, acts as a potent inhibitor of the mitochondrial electron transport chain resulting in mitochondrial impairment and ROS production. Adult male Wistar rats (280-330 g) were uses in this study. Animals were housed under controlled conditions of temperature and light until stereotaxic surgery which was performed under chloral hydrate anesthesia. Microdialysis probe was inserted in the right striatum and experiments, started 24 h after surgery, were repeated for three consecutive days. Systemic MPTP was administered as follows: 25 mg/Kg (day 1), 15 mg/Kg (day 2), 10 mg/Kg (day 3). Control animals received only the vehicle (2.5 ml). Striatal levels of glucose, lactate, pyruvate and L/P ratio were evaluated using a spectrophotometric method (CMA Iscus Analyzer). Baseline values were: 0.9±0.32 mM for glucose, 0.47±0.12 mM for lactate and 0.075±0.009 mM for pyruvate with L/P ratio of 8±0.7. The first MPTP dose (day 1) induced an increase in all studied neurochemicals. On day 2 baseline levels of glucose and pyruvate were decreased compared to day 1, while and increase in lactate levels were observed. After the second and the third MPTP injections a progressive reduction in glucose and pyruvate levels were measured with a concomitant further increase of lactate. L/P ratio increased in a linear fashion starting from the first MPTP dose reaching the highest increase after the third administration (80±11). These in-vivo results are suggestive of an energetic impairment consequent to mitochondrial damage due to MPP+.