Progesterone up-regulates neuronal brain-derived neurotrophic factor expression in the injured spinal cord

Abstract

Progesterone (PROG) provides neuroprotection to the injured central and peripheral nervous system. These effects may be due to regulation of myelin synthesis in glial cells and also to direct actions on neuronal function. Recent studies point to neurotrophins as possible mediators of hormone action. Here, we show that the expression of brain-derived neurotrophic factor (BDNF) at both the mRNA and protein levels was increased by PROG treatment in ventral horn motoneurons from rats with spinal cord injury (SCI). Semiquantitative in situ hybridization revealed that SCI reduced BDNF mRNA levels by 50% in spinal motoneurons (control: 53.5±7.5 grains/mm 2 vs. SCI: 27.5±1.2, P<0.05), while PROG administration to injured rats (4 mg/kg/day during 3 days, s.c.) elicited a three-fold increase in grain density (SCI+PROG: 77.8±8.3 grains/mm 2, P<0.001 vs. SCI). In addition, PROG enhanced BDNF immunoreactivity in motoneurons of the lesioned spinal cord. Analysis of the frequency distribution of immunoreactive densities (χ 2: 812.73, P<0.0001) showed that 70% of SCI+PROG motoneurons scored as dark stained whereas only 6% of neurons in the SCI group belonged to this density score category ( P<0.001). PROG also prevented the lesion-induced chromatolytic degeneration of spinal cord motoneurons as determined by Nissl staining. In the normal intact spinal cord, PROG significantly increased BDNF inmunoreactivity in ventral horn neurons, without changes in mRNA levels. Our findings suggest that PROG enhancement of endogenous neuronal BDNF could provide a trophic environment within the lesioned spinal cord and might be part of the PROG activated-pathways to provide neuroprotection.