Abdipranoto-Cowley Andrea, Park Jin Sung, Croucher David, Daniel James, Henshall Susan, Galbraith Sally, Mervin Kyle, Vissel Bryce
Neuroscience Program, The Garvan Institute of Medical Research, Sydney, Australia.
Stem Cells. 2009 Jun;27(6):1330-46. doi: 10.1002/stem.80.
It has long been proposed that excitotoxicity contributes to nerve cell death in neurodegenerative diseases. Activin A, a member of the transforming growth factor-beta superfamily, is expressed by neurons following excitotoxicity. We show for the first time that this activin A expression is essential for neurogenesis to proceed following neurodegeneration. We found that intraventricular infusion of activin A increased the number of newborn neurons in the dentate gyrus, CA3, and CA1 layers of the normal adult hippocampus and also, following lipopolysaccharide administration, had a potent inhibitory effect on gliosis in vivo and on microglial proliferation in vivo and in vitro. Consistent with the role of activin A in regulating central nervous system inflammation and neurogenesis, intraventricular infusion of follistatin, an activin A antagonist, profoundly impaired neurogenesis and increased the number of microglia and reactive astrocytes following onset of kainic acid-induced neurodegeneration. These results show that inhibiting endogenous activin A is permissive for a potent underlying inflammatory response to neurodegeneration. We demonstrate that the anti-inflammatory actions of activin A account for its neurogenic effects following neurodegeneration because co-administration of nonsteroidal anti-inflammatory drugs reversed follistatin's inhibitory effects on neurogenesis in vivo. Our work indicates that activin A, perhaps working in conjunction with other transforming growth factor-beta superfamily molecules, is essential for neurogenesis in the adult central nervous system following excitotoxic neurodegeneration and suggests that neurons can regulate regeneration by suppressing the inflammatory response, a finding with implications for understanding and treating acute and chronic neurodegenerative diseases.
长期以来，人们一直认为兴奋性毒性在神经退行性疾病中导致神经细胞死亡。激活素A是转化生长因子-β超家族的成员，在兴奋性毒性后由神经元表达。我们首次表明，这种激活素A的表达对于神经退行性变后神经发生的进行至关重要。我们发现，脑室内注入激活素A可增加正常成年海马齿状回、CA3和CA1层新生神经元的数量，并且在给予脂多糖后，对体内胶质细胞增生以及体内外小胶质细胞增殖具有强大的抑制作用。与激活素A在调节中枢神经系统炎症和神经发生中的作用一致，脑室内注入激活素A拮抗剂卵泡抑素，在 kainic 酸诱导的神经退行性变发生后，严重损害神经发生，并增加小胶质细胞和反应性星形胶质细胞的数量。这些结果表明，抑制内源性激活素A会引发对神经退行性变的潜在强烈炎症反应。我们证明，激活素A的抗炎作用解释了其在神经退行性变后的神经发生作用，因为非甾体抗炎药的共同给药逆转了卵泡抑素在体内对神经发生的抑制作用。我们的工作表明，激活素A可能与其他转化生长因子-β超家族分子协同作用，对于兴奋性毒性神经退行性变后成年中枢神经系统的神经发生至关重要，并表明神经元可以通过抑制炎症反应来调节再生，这一发现对理解和治疗急性和慢性神经退行性疾病具有重要意义。
