Cellular Basis for Progesterone Neuroprotection in the Injured Spinal Cord

Abstract

Progesterone (PROG) exerts beneficial and neuroprotective effects in the injured central and peripheral nervous system. In the present work, we examine PROG effects on three measures of neuronal function under negative regulation (choline acetyltransferase [ChAT] and Na,K-ATPase) or stimulated (growth-associated protein [GAP-43]) after acute spinal cord transection injury in rats. As expected, spinal cord injury reduced ChAT immunostaining intensity of ventral horn neurons. A 3-day course of intensive PROG treatment of transected rats restored ChAT immunoreactivity, as assessed by frequency histograms that recorded shifts from predominantly light neuronal staining to medium, dark or intense staining typical of control rats. Transection also reduced the expression of the mRNA for the alpha3 catalytic and beta1 regulatory subunits of neuronal Na,K-ATPase, whereas PROG treatment restored both subunit mRNA to normal levels. Additionally, the upregulation observed for GAP-43 mRNA in ventral horn neurons in spinal cord-transected rats, was further enhanced by PROG administration. In no case did PROG modify ChAT immunoreactivity, Na,K-ATPase subunit mRNA or GAP-43 mRNA in control, sham-operated rats. Further, the PROG-mediated effects on these three markers were observed in large, presumably Lamina IX motoneurons, as well as in smaller neurons measuring approximately <500 micro2. Overall, the stimulatory effects of PROG on ChAT appears to replenish acetylcholine, with its stimulatory effects on Na,K-ATPase seems capable of restoring membrane potential, ion transport and nutrient uptake. PROG effects on GAP-43 also appear to accelerate reparative responses to injury. As the cellular basis for PROG neuroprotection becomes better understood it may prove of therapeutic benefit to spinal cord injury patients.