Progesterone and Neurodegenerative Diseases: Reduction of Neuropathology and Hyperexpression of NADPH-Diaphorase in a Murine Model of Motoneurone Disease

GONZÁLEZ DENISELLE, M.C.; GARAY, L. I.; LÓPEZ COSTA J.J; SCHUMACHER M; DE NICOLA A.F

Río de Janeiro, Brasil

Congreso; II Internacional Congreso on Neuroregeneration; 2004

Motor neuron degeneration characterizes the spinal cord of patients with amyotrophic lateral sclerosis (ALS) and the Wobbler mouse mutant. Considering that progesterone (PROG) provides neuroprotection in experimental ischemia and injury, its potential role in neurodegeneration was studied in the murine model. Three month-old symptomatic Wobbler mice were left untreated or received s.c. a 20 mg PROG implant for 15 days. Both light and electron microscopy of Wobbler mice spinal cord showed severely affected motor neurons with profuse cytoplasmic vacuolation of the endoplasmic reticulum and/or Golgi apparatus and ruptured mitochondria with damaged cristae, a profile indicative of a type II cytoplasmic form of cell death. In contrast to untreated mice, neuropathology was less severe in Wobbler mice receiving PROG; including a reduction of vacuolation, of the number of vacuolated cells and better conservation of mitochondrial ultrastructure. In biochemical studies, we determined the mRNA for the a3 subunit of Na, K-ATPase, a neuronal enzyme controlling ion fluxes, neurotransmission, membrane potential and nutrient uptake. In untreated Wobbler mice, mRNA levels in motor neurons were reduced by half compared to controls, whereas PROG treatment of Wobbler mice restored the expression of a3 subunit Na, K-ATPase mRNA. Extensive cytoplasmic vacuolation may be related to excess formation of free-radicals. NO is a highly reactive species and high levels of nitric oxide synthase (NADPH-diaphorase) are measured in motoneurons of the mutant mice. It is likely that excess NO, by virtue of its capacity to block electron transport chain, is responsible for the release of free radicals from the mitochondria, damaging the membranes of several intracellular organelles. We demonstrated that PROG significantly attenuated the activity of NADPH-diaphorase in motoneurons and astrocytes. Then, it is possible that PROG prevented NO from reaching neurotoxic levels and protected endomembranes and mitochondria from oxidative damage occurring at the progressive or type 2 stages of the Wobbler disease.