Ischemic stroke (IS) is one of the leading causes of death and disability. Complicated mechanisms are involved in the pathogenesis of IS. Immunomodulatory mechanisms are crucial to IS. Acupuncture is a traditional non-drug treatment that has been extensively used to treat IS. The exploration of neuroimmune modulation will broaden the understanding of the mechanisms underlying acupuncture treatment. This review summarizes the immune response of immune cells, immune cytokines, and immune organs after an IS. The immunomodulatory mechanisms of acupuncture treatment on the central nervous system and peripheral immunity, as well as the factors that influence the effects of acupuncture treatment, were summarized. We suggest prospects and future directions for research on immunomodulatory mechanisms of acupuncture treatment for IS based on current progress, and we hope that these will provide inspiration for researchers. Additionally, acupuncture has shown favorable outcomes in the treatment of immune-based nervous system diseases, generating new directions for research on possible targets and treatments for immune-based nervous system diseases.

The immunomodulatory mechanism of acupuncture treatment for ischemic stroke: research progress, prospects, and future direction

Abnormalities in hippocampal synaptic plasticity contribute to the pathogenesis of post-traumatic stress disorder (PTSD). The Wnt/β-catenin signaling pathway is critical for the regulation of synaptic plasticity. PTSD symptoms can be alleviated by correcting impaired neural plasticity in the hippocampus (Hipp). Electroacupuncture (EA) has a therapeutic effect by relieving PTSD-like behaviors. However, little is known about whether the Wnt/β-catenin pathway is involved in EA-mediated improvements of PTSD symptoms. In this study, we found that enhanced single prolonged stress (ESPS)-induced PTSD led to abnormal neural plasticity, characterized by the decline of dendritic spines, the expression of postsynaptic density 95 (PSD95), and synaptophysin (Syn) in the stressed Hipp along with the reduction of Wnt3a and β-catenin, and increased GSK-3β. EA significantly alleviated PTSD-like behaviors, as assessed by the open field test, elevated platform maze test and conditioning fear test. This was paralleled by correcting abnormal neural plasticity by promoting the expression of PSD95 and Syn, as well as the number of dendritic spines in the Hipp. Importantly, EA exerted anti-PTSD effects by augmenting the expression levels of Wnt3a and β-catenin, and decreasing that of GSK-3β. The effects mediated by EA were abolished by XAV939, an inhibitor of the Wnt/β-catenin pathway. This suggests that EA relieved ESPS-induced PTSD-like behaviors, which can largely be ascribed to impaired neural plasticity in the Hipp. These findings provide new insights into possible mechanisms linking neural plasticity in the Hipp as potential novel targets for PTSD treatment in EA therapy. 

Electroacupuncture alleviates PTSD-like behaviors by modulating hippocampal synaptic plasticity via Wnt/β-catenin signaling pathway

Ischemic stroke occurs when the arteries supplying blood to the brain are narrowed or blocked, inducing damage to brain tissue due to a lack of blood supply. One effective way to reduce brain damage and alleviate symptoms is to reopen blocked blood vessels in a timely manner and reduce neuronal damage. To achieve this, researchers have focused on identifying key cellular signaling pathways that can be targeted with drugs. These pathways include oxidative/nitrosative stress, excitatory amino acids and their receptors, inflammatory signaling molecules, metabolic pathways, ion channels, and other molecular events involved in stroke pathology. However, evidence suggests that solely focusing on protecting neurons may not yield satisfactory clinical results. Instead, researchers should consider the multifactorial and complex mechanisms underlying stroke pathology, including the interactions between different components of the neurovascular unit. Such an approach is more representative of the actual pathological process observed in clinical settings. This review summarizes recent research on the multiple molecular mechanisms and drug targets in ischemic stroke, as well as recent advances in novel therapeutic strategies. Finally, we discuss the challenges and future prospects of new strategies based on the biological characteristics of stroke. 

Signaling pathways in brain ischemia: Mechanisms and therapeutic implications.

BackgroundImbalances between Bcl-2 and caspase-3 are significant evidence of apoptosis, which is considered an influential factor in rapidly occurring neuronal cell death and the decline of neurological function after stroke. Studies have shown that acupuncture can reduce poststroke brain cell damage via either an increase in Bcl-2 or a reduction in caspase-3 exposure. The current study aimed to investigate whether acupuncture could modulate Bcl-2 and caspase-3 expression through histone acetylation modifications, which could potentially serve as a neuroprotective mechanism.MethodsThis study used TTC staining, Nissl staining, Clark neurological system score, and Evans Blue (EB) extravasation to evaluate neurological damage following stroke. The expression of Bcl-2/caspase-3 mRNA was detected by real-time fluorescence quantification of PCR (real-time PCR), whereas the protein expression levels of Bcl-2, Bax, caspase-3, and cleaved caspase-3 were assessed using western blotting. TUNEL staining of the ischemic cortical neurons determined apoptosis in the ischemic cortex. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities, along with the protein performance of AceH3, H3K9ace, and H3K27ace, were detected to evaluate the degree of histone acetylation. The acetylation enrichment levels of H3K9 and K3K27 in the Bcl-2/caspase-3 gene were assessed using Chromatin Immunoprecipitation (ChIP) assay.ResultsOur data demonstrated that electroacupuncture (EA) exerts a significant neuroprotective effect in middle cerebral artery occlusion (MCAO) rats, as evidenced by a reduction in infarct volume, neuronal damage, Blood-Brain Barrier (BBB) disruption, and decreased apoptosis of ischemic cortical neurons. EA treatment can promote the mRNA and protein expression of the Bcl-2 gene in the ischemic brain while reducing the mRNA and protein expression levels of caspase-3 and effectively decreasing the protein expression levels of Bax and cleaved caspase-3. More importantly, EA treatment enhanced the level of histone acetylation, including Ace-H3, H3K9ace, and H3K27ace, significantly enhanced the occupancy of H3K9ace/H3K27ace at the Bcl-2 promoter, and reduced the enrichment of H3K9ace and H3K27ace at the caspase-3 promoter. However, the Histone Acetyltransferase inhibitor (HATi) treatment reversed these effects.ConclusionsOur data demonstrated that EA mediated the expression levels of Bcl-2 and caspase-3 in MCAO rats by regulating the occupancy of acetylated H3K9/H3K27 at the promoters of these two genes, thus exerting a cerebral protective effect in ischemic reperfusion (I/R) injury. 

Electroacupuncture regulates histone acetylation of Bcl-2 and Caspase-3 genes to improve ischemic stroke injury

Stroke, a cerebrovascular disease with a high mortality rate, is categorized as either ischemic or hemorrhagic. Current existing therapies have limitations, including a narrow time window for treatment. As stroke induces a rapid and large immune response, immune cells and inflammatory mediators have become promising therapeutic targets for both ischemic and hemorrhagic strokes. In recent years, T cells have been investigated for their role in the pathogenesis of secondary injury and their therapeutic potential after stroke. And regulatory T cells, as one of the subpopulations of T cells, have been proved neuroprotective at both acute and recovery stages. In this review, we summarize the existing roles of Tregs in stroke and the various methods available for Treg intervention, and then provide a perspective for the future of immunotherapy in stroke. 

Immunotherapy as a Treatment for Stroke: Utilizing Regulatory T Cells

Electro-acupuncture treatment inhibits the inflammatory response by regulating γδ T and Treg cells in ischemic stroke

Electro-acupuncture treatment ameliorates intestinal inflammatory injury in cerebral ischemia–reperfusion rats via regulating the balance of Treg / γδ T cells


 Much evidence suggests that gut immunity homeostasis plays a vital role in regulating neuroinflammatory response under ischemic stroke. Acupuncture is an effective treatment for post-stroke rehabilitation. However, little is known about the effect of acupuncture on intestinal injury after stroke. Herein, we observed the intestinal inflammatory response and barrier's impairment of the post-stroke rats to explore the mechanism of electroacupuncture (EA) against cerebral ischemia injury from the brain-gut axis. Rats were randomized to the sham operation group (SHAM), the middle cerebral artery occlusion group (MCAO), and the MCAO plus EA treatment group (MEA). Triphenyl tetrazolium chloride (TTC) staining and Longa neurologic score were performed to evaluate the outcomes after ischemic stroke. Inflammatory factors expression levels in the serum, ischemic hemisphere brain, and small intestine were detected. Additionally, the morphology change of small intestine was evaluated via analyzing villus height and smooth muscle thickness. Meanwhile, the expression of tight-junction proteins, including Zonula Occludens-1(ZO-1), Occludin and Claudin-1, was detected to evaluate the impact of EA on mucosal permeability in the small intestine. The percentage of Treg cells (CD45+CD4+Foxp3+) and γδ T cells (CD45+CD4−γδ T +) were measured to assess the effect of EA on T cells. Our data showed that EA could significantly decrease the brain infarction volume and intestine barrier injury of the ischemic stroke rats. At the same time, it effectively suppressed the post-stroke inflammation response of the ischemic brain, small intestine, and peripheral serum. More importantly, EA treatment increased the percentage of Treg cells in the small intestine while reducing the rate of γδ T cells, and ultimately increased the ratio of Treg/ γδ T cells. These results suggested that EA could ameliorate intestinal inflammation damage by regulating the Treg/ γδ T cell polarity shift and improving the intestine barrier integrity post-stroke. It may be one of the mechanisms underlying the anti-ischemic injury effects of acupuncture on stroke.

Electroacupuncture Treatment Ameliorates Post-Stroke Intestinal Inflammation Injury via Regulating the Balance of Treg / γδ T Cells

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Electro-acupuncture treatment inhibits the inflammatory response by regulating γδ T and Treg cells in ischemic stroke

Electro-acupuncture treatment ameliorates intestinal inflammatory injury in cerebral ischemia–reperfusion rats via regulating the balance of Treg / γδ T cells

Electroacupuncture Treatment Ameliorates Post-Stroke Intestinal Inflammation Injury via Regulating the Balance of Treg / γδ T Cells