Lentivirally administered glial cell line-derived neurotrophic factor promotes post-ischemic neurological recovery, brain remodeling and contralesional pyramidal tract plasticity by regulating axonal growth inhibitors and guidance proteins

胶质细胞源性神经生长因子 神经科学 神经营养因子 神经发生 神经保护 神经可塑性 胶质瘢痕 神经营养素 皮质脊髓束 医学 生物 中枢神经系统 内科学 受体 星形胶质细胞 磁共振弥散成像 磁共振成像 放射科
作者
Merve Beker,Ahmet Burak Çağlayan,Mustafa Çağlar Beker,Serdar Altunay,Reyda Karaçay,Arman Dalay,Mehmet Özgen Altıntaş,Gamze Torun Köse,Dirk M. Hermann,Ertuğrul Kılıç
出处
期刊:Experimental Neurology [Elsevier]
卷期号:331: 113364-113364 被引量:20
标识
DOI:10.1016/j.expneurol.2020.113364
摘要

Owing to its potent longterm neuroprotective and neurorestorative properties, glial cell line-derived neurotrophic factor (GDNF) is currently studied in neurodegenerative disease clinical trials. However, little is known about the longterm effect of GDNF on neurological recovery, brain remodeling and neuroplasticity in the post-acute phase of ischemic stroke. In a comprehensive set of experiments, we examined the effects of lentiviral GDNF administration after ischemic stroke. GDNF reduced neurological deficits, neuronal injury, blood-brain barrier permeability in the acute phase in mice. As compared with control, enhanced motor-coordination and spontaneous locomotor activity were noted in GDNF-treated mice, which were associated with increased microvascular remodeling, increased neurogenesis and reduced glial scar formation in the peri-infarct tissue. We observed reduced brain atrophy and increased plasticity of contralesional pyramidal tract axons that crossed the midline in order to innervate denervated neurons in the ipsilesional red and facial nuclei. Contralesional axonal plasticity by GDNF was associated with decreased abundance of the axonal growth inhibitors brevican and versican in contralesional and ipsilesional brain tissue, reduced abundance of the growth repulsive guidance molecule ephrin b1 in contralesional brain tissue, increased abundance of the midline growth repulsive protein Slit1 in contralesional brain tissue and reduced abundance of Slit1's receptor Robo2 in ipsilesional brain tissue. These data indicate that GDNF potently induces longterm neurological recovery, peri-infarct brain remodeling and contralesional neuroplasticity, which are associated with the fine-tuned regulation of axonal growth inhibitors and guidance molecules that facilitate the growth of contralesional corticofugal axons in the direction to the ipsilesional hemisphere.
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