Department of Neurology, First Hospital of Qinhuangdao, Hebei Medical University, No. 258, Wenhua Road, Qinhuangdao, 066000, Hebei, China.
Hebei Key Laboratory of Vascular Homeostasis and Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, No. 215, Hepingxi Road, Shijiazhuang, 050000, Hebei, China.
J Transl Med. 2023 Feb 23;21(1):139. doi: 10.1186/s12967-022-03824-7.
Exercise-related signaling Fndc5/irisin expresses in brain and acts as a crucial regulator of cognitive function, but its detailed roles in vascular dementia (VaD) are still unclear. Low intensity pulsed ultrasound (LIPUS), a novel brain stimulation approach, has been suggested as a promising treatment for dementia. Here, we investigated the activity and efficacy of Fndc5/irisin in experimental VaD, further explored whether the potential effects of LIPUS on VaD is related to Fndc5/irisin.
Mouse model of VaD was established with chronic cerebral hypoperfusion (CCH) using bilateral common carotid arteries stenosis (BCAS). Transcranial LIPUS was applied 24 h after BCAS and subsequently daily with a stimulation time of 5 min at an ultrasound pressure of 0.51 MPa for a period of 28 days. The levels of Fndc5/irisin in different brain regions, the hippocampal long-term potentiation and anti-inflammatory cytokines were investigated at day 28 after cognitive evaluation. Global Fndc5 knock-out (F5KO), forced expression or knockdown of Fndc5, and recombinant irisin application were respectively employed for mechanism exploration. The neuron dendritic spine density and astrocyte phenotype were detected in vitro.
Fndc5/irisin was reduced in hippocampus of BCAS mice, forced expression hippocampal Fndc5 or bilateral intrahippocampal injection of recombinant irisin respectively improved hippocampal synaptic plasticity or inflammatory microenvironment, and then alleviated the cognitive impairments. LIPUS existed a positive efficacy in enhancing hippocampal Fndc5/irisin in BCAS mice, thus triggering a beneficial neuromodulation for VaD protection. Importantly, the neurorestorative effects of LIPUS on CCH-induced damages were totally reversed by knockdown the expression of hippocampal Fndc5 in WT mice, or in F5KO mice. Moreover, Fndc5 mediated the upregulated effects of LIPUS on spine density as well as irisin secretion of hippocampal neurons. The neuron-secreted irisin further drove reactive astrocytes to a neuroprotective phenotype.
LIPUS induced a neurorestorative stimulation against VaD may be through upregulation of the hippocampal Fndc5/irisin levels. Hippocampal Fndc5/irisin signaling might be a promising strategic target for VaD.
与运动相关的信号分子 Fndc5/irisin 表达于大脑中，作为认知功能的关键调节剂。但其在血管性痴呆（VaD）中的详细作用仍不清楚。低强度脉冲超声（LIPUS）作为一种新的脑刺激方法，已被认为是痴呆症的一种有前途的治疗方法。在这里，我们研究了 Fndc5/irisin 在实验性 VaD 中的活性和功效，进一步探讨了 LIPUS 对 VaD 的潜在影响是否与 Fndc5/irisin 有关。
采用双侧颈总动脉狭窄（BCAS）建立慢性脑低灌注（CCH）小鼠 VaD 模型。在 BCAS 后 24 小时进行颅穿透 LIPUS，随后每天进行 5 分钟的刺激，超声压力为 0.51MPa，持续 28 天。在认知评估后第 28 天，检测不同脑区 Fndc5/irisin 水平、海马长时程增强和抗炎细胞因子。分别采用全局 Fndc5 敲除（F5KO）、强制表达 Fndc5 或 Fndc5 敲低，以及重组 irisin 应用进行机制探讨。在体外检测神经元树突棘密度和星形胶质细胞表型。
BCAS 小鼠海马 Fndc5/irisin 减少，强制表达海马 Fndc5 或双侧海马内注射重组 irisin 分别改善海马突触可塑性或炎症微环境，从而减轻认知障碍。LIPUS 可增强 BCAS 小鼠海马 Fndc5/irisin，从而对 VaD 保护产生有益的神经调节作用。重要的是，在 WT 小鼠或 F5KO 小鼠中敲低海马 Fndc5 的表达，或在 F5KO 小鼠中，LIPUS 对 CCH 诱导损伤的神经修复作用完全逆转。此外，Fndc5 介导了 LIPUS 对海马神经元树突棘密度和 irisin 分泌的上调作用。神经元分泌的 irisin 进一步促使反应性星形胶质细胞向神经保护表型转化。
LIPUS 诱导的对 VaD 的神经修复刺激可能是通过上调海马 Fndc5/irisin 水平实现的。海马 Fndc5/irisin 信号可能是 VaD 的一个有前途的治疗靶点。
