Low-intensity pulsed ultrasound triggers a beneficial neuromodulation in dementia mice with chronic cerebral hypoperfusion via activation of hippocampal Fndc5/irisin signaling

Journal of Translational Medicine

Research

Xinran Bao¹  Xifa Lan¹  Degang Song²  Shuo Geng³  Cong Zhang⁴  Xiangjian Zhang⁴  Na Zhou⁵  Xiaomin Chen⁵  Zhe Zhao⁶  Yi Yuan⁶  Xingran Wang⁶ 

[1] Department of Neurology, First Hospital of Qinhuangdao, Hebei Medical University, No. 258, Wenhua Road, 066000, Qinhuangdao, Hebei, China;Department of Neurology, First Hospital of Qinhuangdao, Hebei Medical University, No. 258, Wenhua Road, 066000, Qinhuangdao, Hebei, China;Hebei Key Laboratory of Vascular Homeostasis and Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, No. 215, Hepingxi Road, 050000, Shijiazhuang, Hebei, China;Hebei Key Laboratory of Vascular Homeostasis and Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, No. 215, Hepingxi Road, 050000, Shijiazhuang, Hebei, China;Department of Biological Sciences, Virginia Tech, 24061, Blacksburg, VG, USA;Hebei Key Laboratory of Vascular Homeostasis and Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, No. 215, Hepingxi Road, 050000, Shijiazhuang, Hebei, China;Department of Neurology, Second Hospital of Hebei Medical University, No. 215, Hepingxi Road, 050000, Shijiazhuang, Hebei, China;Hebei Key Laboratory of Vascular Homeostasis and Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, No. 215, Hepingxi Road, 050000, Shijiazhuang, Hebei, China;Department of Nursing, First Hospital of Qinhuangdao, Hebei Medical University, No. 258, Wenhua Road, 066000, Qinhuangdao, Hebei, China;Hebei Key Laboratory of Vascular Homeostasis and Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, No. 215, Hepingxi Road, 050000, Shijiazhuang, Hebei, China;Institute of Electrical Engineering, Yanshan University, No. 438, Hebei Street, 066000, Qinhuangdao, Hebei, China;

关键词: Fndc5/irisin;    LIPUS;    Dementia;    Hippocampus;    Chronic cerebral hypoperfusion;    Neurons;    Astrocytes;   

DOI  :  10.1186/s12967-022-03824-7

 received in 2022-08-07, accepted in 2022-12-11,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundExercise-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.MethodsMouse 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.ResultsFndc5/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.ConclusionLIPUS 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.

【 授权许可】

CC BY   
© The Author(s) 2023

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