Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China.
Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China.
Brain Res Bull. 2024 Oct 15;217:111078. doi: 10.1016/j.brainresbull.2024.111078. Epub 2024 Sep 11.
The aim of this study is to elucidate the underlying mechanism through which glial cell line-derived neurotrophic factor (GDNF) improves cognitive deficits in adults resulting from neonatal surgical interventions.
Newborn Sprague-Dawley rats, regardless of gender, were randomly allocated into seven groups on postnatal day 7 as follows (n=15): (1) Control group (not subjected to anesthesia, surgery, or any pharmaceutical interventions); (2) GDNF group (received intracerebroventricular injection of GDNF); (3) Surgery group (underwent right carotid artery exposure under anesthesia with 3 % sevoflurane); (4) Surgery plus GDNF group; (5) Surgery plus GDNF and type II JAK inhibitor NVP-BBT594 (BBT594) group (administered intraperitoneal injection of BBT594); (6) BBT group; and (7) Surgery plus BBT group. Starting from postnatal day 33, all rats underwent Barnes maze and fear conditioning tests, followed by decapitation under sevoflurane anesthesia for subsequent analyses. The left hemibrains underwent Golgi staining, while the right hemibrains were used for hippocampal protein extraction to assess Protein kinase Mζ (PKMζ) and Kalirin expression through western blotting.
GDNF demonstrated a mitigating effect on spatial learning and memory impairment, as well as context-related fear memory impairment, reductions in dendritic total lengths, and spinal density within the hippocampus induced by surgical intervention. Notably, all of these ameliorative effects of GDNF were reversed upon administration of the RET inhibitor BBT594. Additionally, GDNF alleviated the downregulation of protein expression of PKMζ and Kalirin in the hippocampus of rats subjected to surgery, subsequently reversed by BBT594.
The effective impact of GDNF on learning and memory impairment caused by surgical intervention appears to be mediated through the RET pathway. Moreover, GDNF may exert its influence by upregulating the expression of PKMζ and Kalirin, consequently enhancing the development of dendrites and dendritic spines.
本研究旨在阐明胶质细胞源性神经营养因子（GDNF）改善新生儿手术干预后成年认知功能障碍的潜在机制。
新生 Sprague-Dawley 大鼠，无论性别，于生后 7 天随机分为 7 组（n=15）：（1）对照组（未行麻醉、手术或任何药物干预）；（2）GDNF 组（脑室注射 GDNF）；（3）手术组（在 3%七氟醚麻醉下行右侧颈总动脉暴露）；（4）手术+GDNF 组；（5）手术+GDNF 和 JAK 型 2 型抑制剂 NVP-BBT594（BBT594）组（腹腔注射 BBT594）；（6）BBT 组；（7）手术+BBT 组。从生后第 33 天开始，所有大鼠均进行 Barnes 迷宫和恐惧条件反射测试，然后在七氟醚麻醉下断头，进行后续分析。左半脑行高尔基染色，右半脑用于提取海马蛋白，通过 Western blot 评估蛋白激酶 Mζ（PKMζ）和 Kalirin 的表达。
GDNF 减轻了手术干预引起的空间学习和记忆障碍以及与环境相关的恐惧记忆障碍，减少了海马内树突总长度和棘密度。值得注意的是，所有这些 GDNF 的改善作用在给予 RET 抑制剂 BBT594 后均被逆转。此外，GDNF 减轻了手术大鼠海马蛋白表达的下调，随后被 BBT594 逆转。
GDNF 对手术干预引起的学习和记忆障碍的有效影响似乎是通过 RET 途径介导的。此外，GDNF 可能通过上调 PKMζ和 Kalirin 的表达来发挥作用，从而增强树突和树突棘的发育。
