Progestins and the nervous system: A hope for neurodegenerative diseases and injuries?

GUENNOUN R; LABOMBARDA F; MEFFRE D; GHOUMARI AM; GAGO N; COIRINI H; GONZALEZ DENISELLE MC; GONZALEZ SL; STEIN D; DE NICOLA AF; SCHUMACHER, M

Innsbruck, Austria

Simposio; 2nd Annual Meeting of the Global College of Neuroprotection and Neuroregeneration; 2005

Global College of Neuroprotection and Neuroregeneration

Some steroids, called « neurosteroids » can be synthesised within the nervous system. Progesterone, originally considered as a hormone involved only in reproductive functions, has promyelinating and neuroprotective effects. Moreover, it can be synthesised locally in the nervous system by neurones and glial cells and can thus be considered to be a "neurosteroid?. Pregnenolone is converted to progesterone by 3b-hydroxysteroid dehydrogenase enzyme (3b-HSD). We have shown that sensory neurones of spinal ganglia synthesise progesterone and that the expression and activity of 3b-HSD enzyme are induced in Schwann cells by a diffusible neuronal factor. The enzyme´s activity was measured and characterised in sciatic nerve homogenates. In the brain and spinal cord 3b-HSD messenger RNA is widely distributed. The persistence of significant levels of pregnenolone and progesterone after castration and adrenalectomy is an argument in favour of local synthesis of these steroids. A study of the synthesis of progesterone by cells of the oligodendrocyte lineage allowed us to show that neural progenitors which express the polysialysed form of the neuronal adhesion molecule (PSA-NCAM+ pre-progenitors and progenitors) express 3b-HSD and synthesise progesterone but mature oligodendrocytes do not. Further, pre-progenitors actively metabolise it to 3a,5a-tetrahydroprogesterone (3a,5a-THP = allopregnanolone), a positive modulator of GABAA receptors. This is the first demonstration of a modification of neurosteroid metabolism during cell differentiation Progesterone?s important role in the formation of myelin sheaths was first shown in the regenerating mouse sciatic nerve and in co-cultures of neurons and glial cells. We have shown that progesterone can stimulate MBP expression in central nervous system by using orgnotypic cultures of cerebellum slices from rats. Two recent papers have shown that chronic treatment with progestagens allows the anomalies of peripheral nerve myelin due to age to be improved and that the intracellular progesterone receptor is a pharmacological target for treating demyelinating forms of Charcot-Marie-Tooth disease. Furthermore, several observations indicated that progesterone may play a role in the pathogenesis of multiple sclerosis and may have a partially protective effects in this disease. Attention has been drawn to the neuroprotective effects of progesterone by the observation that female rats recover better from traumatic brain injury than do males. The neuroprotective effects of progesterone have been shown in different models: contusion of the prefrontal cortex, transection of spinal cord, and a model of spontaneous motoneurone neurodegeneration (Wobbler mouse). Progesterone´s neuroprotective effects involve a normalisation of, or an increase in, gene expression in astrocytes or neurones. Despite the therapeutic stakes, there exists surprisingly little information on the mechanisms involved in the neuroprotective effects of progesterone. Progesterone can exert its effects by binding to specific nuclear or membrane receptors. Our recent results, suggest that the protein 25-Dx, a membrane binding site of progesterone, may have a potentially important role after traumatic brain injury and spinal cord transection.