Role of Inflammation in MPTP-Induced Dopaminergic Degeneration
Annual rept. 1 Dec 2004-30 Nov 2005
COLUMBIA UNIV NEW YORK
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We are investigating the role of inflammation in the death of the dopamine DA neuron in the substantia nigra of MPTP- treated mice. Studies in our model over the course of this program project show that microglia are the source of superoxide and nitric oxide through up-regulation of the microglial enzymes NADPH oxidase and inducible nitric oxide synthase INOS. We show that activation of microglia in vivo occurs as early as 24 hours after MPTP administration at which time the presence of superoxide in the SNpc after MPTP is noted using hydroethidium histochemistry. M4O4Ol, a nonpeptidyl SOD mimetic with catalytic activity equal to or greater than native MnSOD decreased the presence of superoxide and attenuated microglial activation in the SNpc of our mice. Minocycline a second generation antibiotic, inhibited INOS up-regulation and also reduced microglial activation. Further, we demonstrate that cyclooxygenase-2 is a part of the inflammatory response in MPTP-treated mice. Our neuronalmicroglial cultures now that they are up and running, should give a more exact timeframe of microglial activation in relation to DA neuron death in the MPTP mouse model of PD. Furthermore, we identify components of microglia that may be therapeutic targets.
- Anatomy and Physiology
- Medicine and Medical Research