Expression of the activin axis and neuronal rescue effects of recombinant activin A following hypoxic-ischemic brain injury in the infant rat

Neurotrophic factors are induced in the brain in response to injury and may restrict the extent of neuronal loss and facilitate recovery. We have prev iously reported a strong neuronal induction of activin PA subunit mRNA expr ession after a hypoxic-ischemic (HI) injury in the rat brain, Here, we furt her extended our studies to examine a role for the activin inhibitory bindi ng protein, follistatin after injury and also to determine the potential of activin as a neuronal rescue agent. Ribonuclease protection assay (RPA) wa s used to quantify the time course of the mRNA expression of activin PA sub unit and follistatin, following a 60-min HI brain injury. Activin PA subuni t mRNA level increased in the contralateral hemisphere 5 h after injury and returned to normal at 10 h post injury. In contrast, follistatin mRNA leve ls decreased in the same hemisphere at 5 and 10 h after injury. The effect of intracerebroventrically (i.c.v.) administered recombinant human activin A or its antagonist, inhibin A, on neuronal death after a 15-min HI brain i njury was determined for a number of brain regions. One microgram activin A (n = 23) reduced the neuronal loss in the hippocampal CA1/2 region, dorsol ateral striatum but not in the parietal cortex. In contrast, 1 mu g of inhi bin A (n = 18) did not have a significant effect on the extent of neuronal loss in any of the affected regions. This pattern of neuroprotection was co nsistent with the distribution of immunoreactivity for the activin receptor type n subunit. These results demonstrate that activin A, but not its func tional antagonist inhibin A, can enhance the survival of injured hippocampa l and striatal neurons. Since follistatin is thought to exert a neutralisin g effect on activin A activity, the down-regulation of follistatin expressi on post injury may be allowing activin A to become more accessible to neuro ns after injury. Overall, these results suggest a role of the activin axis in modulating the survival of specific populations of injured neurons. (C) 1999 Elsevier Science B.V. All rights reserved.