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 previously reported a strong neuronal induction of activin betaA subunit mRNA expression after a hypoxic-ischemic (HI) injury in the rat brain. Here, we further extended our studies to examine a role for the activin inhibitory binding protein, follistatin after injury and also to determine the potential of activin as a neuronal rescue agent. Ribonuclease protection assay (RPA) was used to quantify the time course of the mRNA expression of activin betaA subunit and follistatin, following a 60-min HI brain injury. Activin betaA subunit mRNA level increased in the contralateral hemisphere 5 h after injury and returned to normal at 10 h post injury. In contrast, follistatin mRNA levels 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 injury was determined for a number of brain regions. One microgram activin A (n=23) reduced the neuronal loss in the hippocampal CA1/2 region, dorsolateral striatum but not in the parietal cortex. In contrast, 1 microg of inhibin 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 consistent with the distribution of immunoreactivity for the activin receptor type II subunit. These results demonstrate that activin A, but not its functional antagonist inhibin A, can enhance the survival of injured hippocampal and striatal neurons. Since follistatin is thought to exert a neutralising effect on activin A activity, the down-regulation of follistatin expression post injury may be allowing activin A to become more accessible to neurons after injury. Overall, these results suggest a role of the activin axis in modulating the survival of specific populations of injured neurons.
Research Centre for Developmental Medicine and Biology, School of Medicine, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
D D
DD
Wu
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M
Lai
P E
PE
Hughes
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E
Sirimanne
P D
PD
Gluckman
C E
CE
Williams
D028341:Activins; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology*; D015536:Down-Regulation; D005260:Female; D038681:Follistatin; D007839:Functional Laterality / Q000502:physiology; D006023:Glycoproteins / Q000235:genetics; D002534:Hypoxia, Brain / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D007265:Inhibins / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D009414:Nerve Growth Factors / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D038681:Follistatin; D006023:Glycoproteins; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D028341:Activins; D007265:Inhibins