Progesterone Neuroprotection in the Wobbler mouse, a genetic model of spinal cord Motor Neuron Disease

GONZÁLEZ DENISELLE, M. C.; LOPEZ COSTA, J.J; PECCI SAAVEDRA J; PIETRANERA L; GONZALEZ S.L; GARAY L; GUENNOUN R; SCHUMACHER M; DE NICOLA AF

NEUROBIOLOGY OF DISEASE

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2002 vol. 11 p. 457 - 468

0969-9961

 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. Two 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. Therefore, PROG was able to rescue motor neurons from degeneration, based on recovery of histopathological abnormalities and of mRNA levels of the sodium pump. These data suggests a new role for PROG in the prevention of neuronal death in spinal cord neurodegenerative diseases.