Caglayan Ahmet Burak, Beker Mustafa Caglar, Sertel Evren Elif, Caglayan Berrak, Kilic Ülkan, Ates Nilay, Caglayan Aysun, Dasdelen Muhammed Furkan, Doeppner Thorsten Roland, Saarma Mart, Hermann Dirk Matthias, Kilic Ertugrul
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
International School of Medicine, Department of Physiology, Istanbul Medipol University, Istanbul, Turkey.
Transl Stroke Res. 2023 Apr;14(2):263-277. doi: 10.1007/s12975-022-01035-2. Epub 2022 May 18.
Considerable efforts are currently made to develop strategies that boost endogenous recovery once a stroke has occurred. Owing to their restorative properties, neurotrophic factors are attractive candidates that capitalize on endogenous response mechanisms. Non-conventional growth factors cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) promote neuronal survival and reduce neurological deficits in the acute phase of ischemic stroke in mice. Their effects on endogenous repair and recovery mechanisms in the stroke recovery phase were so far unknown. By intracerebroventricular delivery of CDNF or MANF starting 3 days post-stroke (1 µg/day for 28 days via miniosmotic pumps), we show that delayed CDNF and MANF administration promoted functional neurological recovery assessed by a battery of behavioral tests, increased long-term neuronal survival, reduced delayed brain atrophy, glial scar formation, and, in case of CDNF but not MANF, increased endogenous neurogenesis in the perilesional brain tissue. Besides, CDNF and MANF administration increased long-distance outgrowth of terminal axons emanating from the contralesional pyramidal tract, which crossed the midline to innervate ipsilesional facial nucleus. This plasticity promoting effect was accompanied by downregulation of the axonal growth inhibitor versican and the guidance molecules ephrin B1 and B2 in the previously ischemic hemisphere at 14 dpi, which represents a sensitive time-point for axonal growth. CDNF and MANF reduced the expression of the proinflammatory cytokines IL1β and TNFα in both hemispheres. The effects of non-conventional growth factors in the ischemic brain should further be examined since they might help to identify targets for restorative stroke therapy.
目前人们付出了巨大努力来制定策略，以便在中风发生后促进内源性恢复。由于其修复特性，神经营养因子是利用内源性反应机制的有吸引力的候选物。非传统生长因子脑源性多巴胺神经营养因子（CDNF）和中脑星形胶质细胞源性神经营养因子（MANF）可促进小鼠缺血性中风急性期的神经元存活并减少神经功能缺损。到目前为止，它们对中风恢复期内源性修复和恢复机制的影响尚不清楚。通过在中风后3天开始脑室内注射CDNF或MANF（通过微型渗透泵每天1μg，持续28天），我们发现延迟给予CDNF和MANF可通过一系列行为测试促进功能性神经恢复，增加长期神经元存活，减少延迟性脑萎缩、胶质瘢痕形成，并且就CDNF而言而非MANF，可增加损伤周围脑组织中的内源性神经发生。此外，给予CDNF和MANF可增加对侧锥体束发出的终末轴突的长距离生长，这些轴突穿过中线以支配同侧面神经核。这种促进可塑性的作用伴随着在缺血后14天轴突生长抑制剂多功能蛋白聚糖以及先前缺血半球中导向分子ephrin B1和B2的下调，这是轴突生长的一个敏感时间点。CDNF和MANF降低了两个半球中促炎细胞因子IL1β和TNFα的表达。非传统生长因子在缺血性脑中的作用应进一步研究，因为它们可能有助于确定恢复性中风治疗的靶点。
