O'Driscoll C M, Gorman A M
Department of Biochemistry, National University of Ireland, Galway, Ireland.
Neuroscience. 2005;131(2):321-9. doi: 10.1016/j.neuroscience.2004.11.015.
Development of the nervous system is a complex process, involving coordinated regulation of diverse cellular processes including proliferation, differentiation and synaptogenesis. Disturbances to brain development such as pre- and perinatal hypoxia have been linked to behavioural and late onset of neurological disorders. This study examines the effect of hypoxia on neurite outgrowth in PC12 cells. Hypoxia not only caused a rapid induction of neurite outgrowth, but also synergistically enhanced nerve growth factor (NGF)-induced neurite outgrowth up to 24 h. Transactivation of TrkA receptors was ruled out since the TrkA inhibitor K252a did not block hypoxia-induced neurite outgrowth. Adenosine deaminase prevented hypoxia-induced neurite outgrowth indicating that the effect is mediated by adenosine. Use of the specific adenosine A2A receptor agonist CGS21680 and antagonist 8-3(chlorostyryl)caffeine demonstrated that activation of this receptor is critical for hypoxia-induced neurite outgrowth. Hypoxia-induced neurite outgrowth was blocked by the adenylate cyclase inhibitor, MDL-12,330A, indicating a role for activation of this enzyme in the pathway. Hypoxia was further shown to cause a decrease in growth-associated protein (GAP)-43 levels and a lack of induction of betaIII tubulin, in contrast to NGF treatment which resulted in increased cellular levels of both of these proteins. These findings suggest that hypoxia induces neurite outgrowth in PC12 cells via a pathway distinct from that activated by NGF. Thus, exposure to hypoxia at critical stages of development may contribute to aberrant neurite outgrowth and could be a factor in the pathogenesis of certain delayed developmental neurological disorders.
神经系统的发育是一个复杂的过程，涉及对多种细胞过程的协调调节，包括增殖、分化和突触形成。诸如产前和围产期缺氧等对大脑发育的干扰已与行为和神经系统疾病的迟发有关。本研究考察了缺氧对PC12细胞神经突生长的影响。缺氧不仅迅速诱导神经突生长，而且在长达24小时内协同增强神经生长因子（NGF）诱导的神经突生长。由于TrkA抑制剂K252a不阻断缺氧诱导的神经突生长，因此排除了TrkA受体的反式激活。腺苷脱氨酶可阻止缺氧诱导的神经突生长，表明该效应由腺苷介导。使用特异性腺苷A2A受体激动剂CGS21680和拮抗剂8-3（氯苯乙烯基）咖啡因表明，该受体的激活对缺氧诱导的神经突生长至关重要。缺氧诱导的神经突生长被腺苷酸环化酶抑制剂MDL-12,330A阻断，表明该酶的激活在该途径中起作用。与NGF处理导致这两种蛋白质的细胞水平增加相反，进一步表明缺氧导致生长相关蛋白（GAP）-43水平降低且未诱导βIII微管蛋白。这些发现表明，缺氧通过不同于NGF激活的途径诱导PC12细胞的神经突生长。因此，在发育的关键阶段暴露于缺氧可能导致异常的神经突生长，并且可能是某些延迟性发育性神经系统疾病发病机制中的一个因素。
