Molecular and behavioral evidence for progesterone protection in motoneuron degeneration

DE NICOLA A.F.; GONZALEZ DENISELLE M.C.; MEYER M. ; GARGIULO G. ; GUENNOUN R.; SCHUMACHER M

Cerdeña

Congreso; Annual Meeting of the International Behavioral Neuroscience Society; 2010

International Behavioral Neuroscience Society

MOLECULAR AND BEHAVIORAL EVIDENCES FOR PROGESTERONE AND NEUROSTEROID PROTECTION IN MOTONEURON DEGENERATION De Nicola, A.F., Gonzalez Deniselle, M.C., Meyer, M., Gargiulo, G., Guennoun R., Schumacher,M. Instituto de Biologia y Medicina Experimental-CONICET, Buenos Aires, and UMR 788 INSERM Paris. The effects of progesterone in nervous system diseases are of increasing interest due to their potential clinical applications. We have studied progesterone neuroprotection in Wobbler mouse spinal cord degeneration. Wobblers present motoneuron vacuolation, astrogliosis, atrophic limbs, tremor and ambulatory difficulty that worsens with disease progression. Wobbler motoneurons show impaired expression of brain-derived neurotrophic factor (BDNF), choline acetyltransferase (ChAT) and Na,K-ATPase and increased expression of nitric oxide synthase (NOS). Mitochondria show vacuolation, edema and crystolysis, decreased activity of respiratory chain complex I activity and increased expression of mitochondrial NOS (mtNOS). In 5-8 month-old Wobblers, at the established stage of the disease, progesterone reverses these abnormalities. Progesterone effectiveness has also been studied at early (12 months) and late (12 months) stages of neurodegeneration. In untreated Wobblers, vacuolated motoneurons are initially abundant, experience a slight reduction at the established stage and dramatically diminish during the late period. ChAT and BDNF are reduced at all stages of the Wobbler disease. Progesterone significantly reduces motoneuron vacuolation, enhances ChAT immunoreactivity during the early progressive and established stages, whereas up regulation of BDNF occurs at the established and late periods. Untreated Wobblers show high density of glial fibrillary acidic protein (GFAP) astrocytes, which are down-regulated by progesterone at all stage periods. Long-term progesterone treatment enhances survival and muscle strength, according to the time spent on a vertical grid and on a horizontal rope test. Therefore, progesterone may constitute a novel therapeutic tool to attenuate the course of neurodegeneration. Studies are in progress to study progesterone effects in patients with amyotrophic lateral sclerosis.