Electroacupuncture Enhances Neuroplasticity by Regulating the Orexin A-Mediated cAMP/PKA/CREB Signaling Pathway in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice

Abstract

Learning and memory disorders and decreased neuroplasticity are the main clinical manifestations of age-induced cognitive dysfunction. Orexin A (OxA) has been reported to show abnormally elevated expression in the cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD) and to be associated with cognitive impairment. Here, we further assessed whether the excitatory neurotransmitter OxA is involved in neuroplasticity and cognitive function in senescence-accelerated mouse prone 8 (SAMP8) mice. In this study, we investigated the mechanism of OxA by using behavioral tests, CSF microdialysis, immunofluorescence, toluidine blue staining, gene silencing, transmission electron microscopy, and Western blotting. The results showed that 10 Hz electroacupuncture (EA) effectively alleviated learning and memory impairment in 7-month-old SAMP8 mice, reduced OxA levels in the CSF, increased the level of the neurotransmitter glutamate, alleviated pathological damage to hippocampal tissue, improved the synaptic structure, enhanced synaptic transmission, and regulated the expression of cAMP/PKA/CREB signaling pathway-related proteins. These results suggest that EA enhances neuroplasticity in SAMP8 mice by regulating the OxA-mediated cAMP/PKA/CREB signaling pathway, thus improving cognitive function. These findings suggest that EA may be beneficial for the prevention and treatment of age-induced cognitive impairment.

Potential Mechanism of Qinggong Shoutao Pill Alleviates Age-associated Memory Decline in D-Galactose-Injured Mice Based on Network Pharmacology, Molecular Docking, and Experimental Verification Integration Strategy

“…Activation of the cAMP pathways can ultimately lead to activation of cAMP response element binding protein (CREB) to facilitate transcription of CRE-dependent genes. Traditional Chinese medicine therapy enhances neuroplasticity in SAMP8 mice by regulating the cAMP/PKA/CREB signaling pathway, thus improving cognitive function [33]. Whereas calcium signaling is involved in neurotransmitter release, synaptic plasticity, gene expression and other important neuronal functions [34][35][36].…”

The neuroprotective and neural circuit mechanisms of acupoint stimulation for cognitive impairment

“…Orexin A-RNAi adenovirus was utilized to silence the orexin gene, simulating the abovementioned consequences of EA. It is hypothesized that 10 Hz EA therapy alters glutamatergic synaptic plasticity mediated by cAMP/PKA/CREB by decreasing cerebrospinal fluid Orexin A levels [ 127 ]. Dopamine (DA) and norepinephrine (NE) and their receptors may also play important roles in synaptic plasticity.…”

Acupuncture Interventions for Alzheimer’s Disease and Vascular Cognitive Disorders: A Review of Mechanisms

“…2-VO rats MA "Baihui" (GV20), "Zusanli" (ST36) [94] Row twist compensation method (<90 °, >120 times/min, 30 s), once a day, 6 days of treatment, 1 day of rest, a total treatment of 12 times SAMP8 mice MA "Danzhong" (CV17), "Zhongwan" (CV12), "Qihai" (CV6) [36] Twisting reinforcing manipulation method, 1 time/d, 15 d, and suspended only on day 7 APP/PS1 mice EA "Baihui" (GV20), "Yongquan" (KI1) [41] 2 ~3 mm, "Baihui": Flat stab, "Yongquan": Straight stab, density wave, 1 Hz/50 Hz, 0.5 mA, 15 min/d, 3 times/week, 6 weeks SAMP8 mice EA "Baihui" (GV20), "Zusanli" (ST36) [64] 3 mm, 1 mA, 10 Hz, 30 min/d, 14 days D-galactose-treated rats EA "Baihui" (GV20), "Shenshu" (BL23) [65] "Baihui": Inserted 15 °obliquely, 2 mm. "Shenshu": Inserted perpendicularly, 4-6 mm.…”

“…Wang et al [ 63 ] found that “olfactory three needle” at “Yintang” (GV29), bilateral “Yingxiang” (LI20) can activate the PI3K-AKT signaling pathway, upregulate the expression of PSD-95, SYN, and GAP43 proteins, improve synaptic plasticity in A β 1-42-treated rats, reduce apoptosis, and alleviate memory impairment. In addition, the study by Hou et al [ 64 ] showed that EA at “Baihui” (GV20), bilateral “Zusanli” (ST36) could improve the memory impairment in SAMP8 mice, and that its mechanism was related to activation of cAMP/PKA/CREB signaling pathway and enhancing synaptic plasticity of hippocampal neurons. Similarly, acupuncture at the corresponding acupoints can inhibit GSK3 β /mTOR in d -galactose-treated rats [ 65 ] and the AMPK/eEF2K/eEF2 [ 66 ] and RhoA/ROCK signaling pathways in SAMP8 mice to promote synaptic plasticity, thereby improving memory impairment [ 67 ].…”

“…Liu et al [ 101 ] used EA at “Baihui” (GV20), “Fengfu” (GV16), “Dazhui” (GV14), and “Shenting” (GV24), and the results showed that EA had a protective effect on neuronal damage in rats with chronic cerebral ischemia and promoted OX1R expression in the hippocampus. Hou et al [ 64 ] reported that EA stimulation could improve memory impairment and inhibited OXA in cerebrospinal fluid by regulating the related proteins and neurotransmitters in a cAMP/PKA/CREB pathway-dependent manner.…”