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. 2024 May 15:17:1388759.
doi: 10.3389/fnmol.2024.1388759. eCollection 2024.

Acupuncture modulates the AMPK/PGC-1 signaling pathway to facilitate mitochondrial biogenesis and neural recovery in ischemic stroke rats

Kaixin Guo  1 , Yan Lu  1
Affiliations

Acupuncture modulates the AMPK/PGC-1 signaling pathway to facilitate mitochondrial biogenesis and neural recovery in ischemic stroke rats

Kaixin Guo et al. Front Mol Neurosci. .

Abstract

Aims: The main objective of this study was to investigate the role and mechanism of acupuncture on anti-nerve injury in the acute phase by regulating mitochondrial energy metabolism via monophosphate-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) axis in rat ischemic stroke.

Main methods: Middle cerebral artery occlusion (MCAO) was established by middle cerebral artery occlusion/reperfusion. One-week of acupuncture was performed during the acute phase of ischemic stroke. The neurological function and brain tissue integrity were evaluated. Mitochondrial function (intracellular ATP level and the activity of mitochondrial respiratory chain complex I) and the level of NADH oxidase (NOX) were detected by enzymatic chemistry. Next, the potential molecular mechanisms were explored by western blotting, fluorescence quantitative PCR and immunohistochemistry method.

Key findings: (1) Acupuncture treatment for MCAO/R rats showed a significant improvement in the infarcted tissue accompanied by functional recovery in Zea-Longa score and balance beam score outcomes, motor function performances. (2) Acupuncture increased the levels of ATP and mitochondrial respiratory chain complex I, decreased the NOX levels in cerebral ischemia established by suture-occluded method. (3) Acupuncture reduced the necrosis dissolution of neuronal cells and meningeal edema, while promoting angiogenesis. (4) Quantitative immunohistochemical staining results showed acupuncture can increase the expression of AMPK, p-AMPK and the mitochondrial transcription factor PGC-1α, NRF2, TFAM and uncoupling protein 2 (UCP2). Meanwhile, acupuncture treatment up-regulated the expression of the corresponding protein. (5) Subsequently, acupuncture enhanced AMPK phosphorylation as well as the expression of PGC-1α, NRF2, TFAM and UCP2, implicated in mitochondrial synthesis and cellular apoptosis. (6) Finally, injections of AMPK antagonists and activators confirmed AMPK as a therapeutic target for the anti-nerve damage effects of acupuncture.

Significance: Acupuncture intervention relieved ischemic stroke progression in MCAO rats by promoting energy metabolism and mitochondrial biogenesis in the brain and alleviating neuronal apoptosis, which was mediated by eliciting AMPK/PGC-1α axis, among them AMPK is a therapeutic target.

Keywords: AMPK/PGC-1α; acupuncture; ischemic stroke; mitochondrial energy metabolism; oxidative stress.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Acupuncture can improve the weight and neurological recovery of rats. (A) Schematic representation of the experimental timeline. (B) Location of acupuncture points in rats. (C) The weight changes of rats in each group at 7 days and the comparison after treatment (n = 10, one-way ANOVA). (D, E) Neurological scores of rats from each group on days 1 and 7, (D) Longa (E) Beam Balance Test (n = 10, one-way ANOVA). (F–H) Effect of acupuncture intervention on energy metabolism in the brain of MCAO rodents (F) ATP, (G) Mitochondrial complex I, (H) NOX (n = 10, one-way ANOVA). All data are presented as the means ± SEM; *P < 0.05, **P < 0.01, ****P < 0.0001 vs. Sham; #P < 0.05, ##P < 0.01, ###P < 0.001, ####P < 0.0001 vs. Mod.
Figure 2
Figure 2
Representative HE staining of brain tissues in the three groups. Black arrow: large area of necrosis of neurons in the model group; Yellow arrow: large number of neovascularization; Red arrow: massive lymphocytes and macrophage infiltration; Blue arrow: cerebral edema and loose connective tissue.
Figure 3
Figure 3
Immunohistochemical staining of various indexes in brain tissue of three groups.
Figure 4
Figure 4
Acupuncture intervention can activate the AMPK/PGC-1α pathway in MCAO rats, (A–F) Average absorbance value of AMPK, p-AMPKβ1, NRF2, NRF, TFAM and UCP2 of brain tissue in the three groups (n = 6, one-way ANOVA). All data are presented as the means ± SEM; *P < 0.05, **P < 0.01 vs. Sham; #P < 0.05, ##P < 0.01 vs. Mod.
Figure 5
Figure 5
Acupuncture intervention can promote the expression of mitochondrial neogenesis related proteins and mRNA. (A) Expression of various proteins including AMPK, p-AMPKβ1, PGC-1α, NRF2, TFAM and UCP2 (n = 4, one-way ANOVA). (B) Expression of mRNA in AMPK, PGC-1α, NRF2, TFAM and UCP (n = 4, one-way ANOVA). All data are presented as the means ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001 vs. Sham; #P < 0.05, ##P < 0.01, ###P < 0.001 vs. Mod.
Figure 6
Figure 6
AMPK mediated the effect of acupuncture to improve neurological function injury in MCAO rodents. (A, B) Experimental representation of the lateral intracerebroventricular (i.c.v) and schematic representation of the experimental timeline. (C, D) Neurological scores of rats from each group after completion of treatment, (C) Longa, (D) Beam Balance Test (n = 6, one-way ANOVA). All data are presented as the means ± SEM; **P < 0.01 vs. Sham; ##P < 0.01 vs. Mod; +P < 0.05, ++P < 0.01 vs. Acu. Compound C, an AMPK antagonist; AICAR, an AMPK agonist; MA, MCAO + Acu.
Figure 7
Figure 7
Acupuncture intervention promotes mitochondrial biogenesis mechanism.
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Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from Natural Science Foundation of Shandong Province (grant number: ZR2020MH364).

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