Acupuncture modulates the balance of excitatory and inhibitory neurotransmission disrupted after stroke, serving as the initial molecular trigger of a multi-level neurorepair cascade. The maintenance of cognitive function relies heavily on intact synaptic connectivity and the efficient transmission of information between neurons within neural circuits (15). Homeostatic regulation of neurotransmitter systems and dynamic modulation of synaptic plasticity are essential for higher-order cognitive processes, including attention, learning, and memory. Following stroke, disturbances in neurotransmitter signaling and structural damage to synapses represent key mechanisms underlying PSCI (16). These changes disrupt excitatory-inhibitory balance, impair synaptic integration, and reduce cognitive reserve. A growing body of evidence indicates that acupuncture can restore neurotransmitter homeostasis and enhance synaptic plasticity via multiple molecular pathways, ultimately contributing to improved cognitive outcomes after stroke (12). ACh is a key neurotransmitter in the central nervous system, primarily synthesized and released by cholinergic neurons. These neurons are predominantly located in the basal forebrain and project to critical cognitive regions such as the hippocampus, neocortex, and brainstem (17). Through extensive synaptic connections, cholinergic circuits support essential cognitive processes, including memory encoding, learning, and attention regulation. ACh plays a central role in maintaining cortical arousal and attentional modulation via the ascending reticular activating system (ARAS) of the brainstem. Disruption of ACh signaling—particularly in the cortex and hippocampus—has been implicated in deficits in spatial learning, memory consolidation, and overall cognitive decline following stroke (8). DA, a catecholaminergic neurotransmitter, plays a critical role in regulating cognition, particularly in domains such as motivation, working memory, and executive function. Stroke-induced degeneration of dopaminergic neurons, particularly in the mesocortical and mesolimbic pathways, has been linked to deficits in attention, executive processing, and reward-based learning (18). NE, predominantly released by neurons in the locus coeruleus, contributes to the modulation of arousal, attention, learning, and memory consolidation. Disruption of noradrenergic pathways following stroke may impair cortical activation and reduce the brain’s capacity for attentional control, thereby exacerbating cognitive impairment (19). 5-HTsynthesized in the raphe nuclei, is another key monoaminergic neurotransmitter that regulates not only mood and emotional stability, but also spatial learning, memory encoding, and circadian rhythm (20). Ischemic damage to serotonergic projections has been shown to impair synaptic plasticity and neurogenesis, thereby contributing to both cognitive and affective dysfunction in stroke survivors. Acupuncture has been shown to significantly modulate central neurotransmitter levels, particularly those implicated in cognitive processes such as learning, memory, and attention. Preclinical studies have demonstrated that acupuncture stimulation at specific acupoints, including GV20and GV24, increases ACh levels in the hippocampus and cortex, enhances cholinergic neurotransmission, and ameliorates memory deficits and attentional impairments following stroke. Moreover, acupuncture has been reported to downregulate acetylcholinesterase (AChE) activity, thereby reducing ACh degradation and promoting cholinergic homeostasis. This balance between ACh synthesis and degradation is crucial for maintaining synaptic plasticity and cognitive integrity, and its restoration through acupuncture contributes to improved learning and memory performance in post-stroke models (9). Synaptic plasticity impairment is considered one of the major causes of cognitive dysfunction following stroke. Neural plasticity encompasses synaptic plasticity, neurogenesis, and the remodeling of axons and dendrites, reflecting the brain’s adaptive response to injury and environmental changes (21). Impaired neuroplasticity can lead to persistent cognitive deficits in patients. In Alzheimer’s disease, structural synaptic alterations such as synaptic loss and reduced synaptic density occur at an early stage (22). In patients with vascular dementia, inadequate cerebral perfusion, accumulation of reactive oxygen species and lactic acid, and inflammatory responses may lead to reduced synapse number, smaller active zones of synaptic connections, and neuronal cell death. Impaired synaptic plasticity is widely recognized as a fundamental contributor to cognitive deficits following stroke (23). Neural plasticity encompasses synaptic remodeling, neurogenesis, and structural modifications of axons and dendrites, reflecting the brain’s intrinsic capacity to adapt to injury and environmental stimuli (24). Disruption of neuroplastic processes may result in long-term impairments in cognitive flexibility, learning capacity, and memory consolidation. In Alzheimer’s disease, structural synaptic alterations—including synaptic loss and reduced synaptic density—emerge early and are strongly associated with cognitive decline. Similarly, in vascular dementia, chronic cerebral hypoperfusion, oxidative stress, and neuroinflammation contribute to synapse loss, shrinkage of active synaptic zones, and progressive neuronal degeneration (4, 5). Ischemic stroke induces microstructural alterations in neural networks, including thickening of postsynaptic density (PSD), reduced extracellular space, decreased dendritic spine density, and diminished mitochondrial number within synapses—factors that collectively impair energy metabolism and hinder efficient synaptic transmission, thereby contributing to PSCI (13). Studies have shown that acupuncture promotes the expression of synapse-associated proteins and facilitates the restoration of synaptic structure and function. Specifically, acupuncture has been shown to upregulate hippocampal expression of key synaptic markers, including synaptophysin (SYN) and PSD-95, thereby enhancing synaptic density, maturation, and structural remodeling. Moreover, acupuncture enhancesLTP in the hippocampus, thereby strengthening synaptic transmission efficiency and providing a physiological basis for improved learning and memory functions (11).

In summary, acupuncture contributes significantly to the reconstruction of post-stroke neural networks through bidirectional modulation of neurotransmitter systems and enhancement of synaptic plasticity. These effects constitute a fundamental mechanism by which acupuncture improves cognitive outcomes in patients with PSCI. By restoring synaptic efficiency and reactivating cholinergic and dopaminergic signaling, acupuncture establishes a neurochemical foundation that subsequently influences neuroinflammatory and neuroimmune responses.

Following the rebalancing of neurotransmission, acupuncture exerts potent regulatory effects on neuroinflammation and immune crosstalk within the injured brain. Neuroinflammation is recognized as a central pathogenic mechanism underlying PSCI. Stroke triggers the activation of the central immune system, resulting in overactivation of microglia and the subsequent release of pro-inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). These cytokines further promote the recruitment of peripheral immune cells—such as monocytes, lymphocytes, and neutrophils—into the ischemic brain tissue (25). The infiltration of inflammatory cytokines and peripheral immune cells exacerbates neuronal damage, impairs synaptic integrity, and disrupts functional neural circuits, thereby accelerating cognitive deterioration. In recent years, accumulating evidence has demonstrated that acupuncture can suppress the activation, infiltration, and proliferation of inflammatory cells in the central nervous system (26). It also helps restore the balance between pro-inflammatory and anti-inflammatory mediators, thereby exerting significant neuroprotective effects in ischemic brain injury. Animal studies have confirmed that acupuncture stimulation at specific acupoints—such as GV20 and Dazhui (GV14)—significantly downregulates the expression of pro-inflammatory cytokines, including IL-1β, TNF-α, and others in brain tissue. In addition, acupuncture inhibits the activity of inflammation-related pathways, particularly the Toll-like receptor 4 (TLR4)/NF-κB signaling cascade, thereby attenuating neuroinflammatory responses. NF-κB, a canonical inflammatory signaling mediator, upon activation induces the transcription of multiple pro-inflammatory cytokines and perpetuates the inflammatory cascade (2). Acupuncture has been shown to inhibit NF-κB phosphorylation and nuclear translocation, thereby suppressing its transcriptional activity and reducing cytokine production at the upstream regulatory level. Microglia, the resident macrophages of the central nervous system, play a dual role in neuroinflammation and can induce neuronal degeneration and death under pathological conditions (1). Acupuncture has been shown to modulate microglial polarization by promoting the phenotypic shift from the pro-inflammatory M1 type to the anti-inflammatory M2 type (27). This shift enhances the secretion of neuroprotective cytokines such as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), while suppressing the pro-inflammatory cytokine cascade, thereby creating a neuroimmune microenvironment conducive to neural repair. Furthermore, acupuncture has been reported to inhibit inflammasome activation, particularly the NOD-like receptor protein 3 (NLRP3) inflammasome, thereby reducing neuronal pyroptosis and preserving the structural integrity of brain tissue after stroke. In addition to its central effects, acupuncture also modulates peripheral immune responses via the neuroimmune axis (28). It has been demonstrated that acupuncture activates the vagus nerve-mediated cholinergic anti-inflammatory pathway, which suppresses the production of inflammatory cytokines in the spleen and peripheral immune organs. These findings highlight the systemic anti-inflammatory effects of acupuncture (29).

In summary, acupuncture alleviates chronic neuroinflammation following stroke through multi-level, multi-target anti-inflammatory mechanisms. These include the suppression of pro-inflammatory cytokine expression, modulation of key signaling pathways, and regulation of glial activation and immune cell polarization. Collectively, these mechanisms attenuate sustained neuroinflammatory damage and establish an immunological foundation for cognitive recovery in post-stroke patients. These anti-inflammatory and immune-modulatory effects not only mitigate secondary neuronal damage but also reduce oxidative burden, paving the way for the activation of antioxidant and anti-apoptotic pathways.

As inflammation subsides, oxidative stress and apoptosis remain key barriers to neural survival and network integrity; acupuncture has been shown to alleviate these processes through multiple signaling pathways. Oxidative stress, caused by an imbalance between pro-oxidant and antioxidant systems, is recognized as a central pathological mechanism contributing to PSCI (6, 7). During cerebral ischemia–reperfusion injury, excessive production of ROS initiates a cascade of oxidative stress responses (3). These reactive species damage membrane lipids, proteins, and nucleic acids, impair mitochondrial function, and ultimately induce neuronal apoptosis and necrosis, all of which contribute significantly to cognitive dysfunction. In addition, oxidative stress indirectly exacerbates neuronal injury by disrupting intracellular signaling pathways, impairing energy metabolism, and further aggravating mitochondrial dysfunction. ROS also disrupt the integrity of the blood–brain barrier (BBB) by damaging endothelial cells, increasing permeability, and facilitating the infiltration of inflammatory cells and cytokines into brain parenchyma, thereby exacerbating tissue injury (30). Sustained oxidative stress may initiate chronic neuroinflammation, characterized by persistent microglial activation, excessive ROS generation, and upregulation of pro-inflammatory cytokines, forming a vicious cycle that further damages neurons and impairs neuroregeneration (31). Recent studies suggest that acupuncture exerts neuroprotective and cognition-enhancing effects by upregulating endogenous antioxidant defenses and modulating apoptosis-related signaling cascades (9). First, acupuncture has been shown to effectively reduce oxidative stress levels in brain tissue following stroke. Experimental studies indicate that acupuncture upregulates the activity of endogenous antioxidant enzymes, including superoxide dismutase (SOD), while concurrently downregulating lipid peroxidation markers such as malondialdehyde (MDA) (20). These effects alleviate free radical-induced cellular damage and contribute to the stabilization of the neural microenvironment. In addition, acupuncture enhances other antioxidant defense systems, including GSH-Px and catalase (CAT), thereby further augmenting the brain’s capacity to counteract oxidative damage (4, 5). Apoptosis, also referred to as programmed cell death, is a genetically regulated and highly orchestrated process of cellular self-destruction (6, 7). It plays essential roles in embryonic development, tissue remodeling, and immune homeostasis. Neuronal apoptosis is a core pathological event in the development of PSCI (32). During cerebral ischemia and hypoxia, cellular energy metabolism collapses, ATP synthesis declines sharply, and membrane ion pumps become dysfunctional, leading to intracellular calcium overload and a cascade of cytotoxic events that culminate in neuronal apoptosis. The Wnt/β-catenin signaling pathway plays a pivotal role in promoting neuronal survival and inhibiting apoptosis (33). Under physiological conditions, stabilized β-catenin translocates to the nucleus, where it interacts with TCF/LEF transcription factors to upregulate anti-apoptotic genes such as Bcl-2 and suppress pro-apoptotic proteins including Bax and caspase-3, thereby preventing neuronal apoptosis. In PSCI, ischemia and hypoxia lead to abnormal activation of GSK-3β, which induces excessive phosphorylation and proteasomal degradation of β-catenin, thereby markedly reducing its cytoplasmic levels (34). This diminishes anti-apoptotic capacity, promotes cytochrome c release, and activates the caspase cascade, culminating in neuronal apoptosis. Extensive neuronal apoptosis leads to severe disruption of neural circuits, particularly in the hippocampal CA1 region and prefrontal cortex, and is considered a pathological hallmark of PSCI (14). Studies have demonstrated that acupuncture mitigates post-stroke neuronal apoptosis through multiple molecular mechanisms. It modulates the expression of Bcl-2 family proteins by upregulating anti-apoptotic Bcl-2 and downregulating pro-apoptotic Bax, inhibits mitochondrial membrane permeability transition, and prevents cytochrome c release—collectively suppressing mitochondria-dependent apoptotic pathways (35). Moreover, acupuncture downregulates the expression and enzymatic activity of caspase-3 and caspase-9—critical downstream effectors of the apoptotic cascade—thereby preserving the structural and functional integrity of brain tissue. Emerging evidence also suggests that acupuncture may regulate endoplasmic reticulum stress and modulate the crosstalk between autophagy and apoptosis following stroke, offering additional molecular targets for neuroprotection (36, 37).

In summary, acupuncture exerts coordinated neuroprotective effects through multiple mechanisms, including enhancement of antioxidant defenses, suppression of free radical accumulation, and modulation of mitochondrial pathways and downstream apoptotic executioners. These mechanisms collectively mitigate oxidative damage and programmed neuronal death following stroke, thereby establishing a crucial cellular foundation for cognitive recovery. The attenuation of oxidative injury and apoptosis creates a favorable intracellular environment for neurotrophic signaling, particularly the up-regulation of BDNF and its downstream cascades.

Building upon the neuroprotective microenvironment established by antioxidant mechanisms, acupuncture activates neurotrophic signaling centered on the brain-derived neurotrophic factor (BDNF) pathway. BDNF is the most abundant neurotrophin in the central nervous system. It plays a pivotal role in neuronal survival, synaptic plasticity, and the regulation of learning and memory (38). BDNF also contributes to neuronal repair following injury and prevents degenerative changes in neural cells, with its highest concentrations found in the hippocampus and cortex. BDNF exerts its biological effects by binding to its high-affinity receptor, tropomyosin receptor kinase B (TrkB), inducing tyrosine phosphorylation and activating downstream signaling cascades (39). The BDNF/TrkB signaling pathway is essential for neuronal survival and proliferation, dendritic and axonal development, and modulation of synaptic plasticity (40). Stroke markedly downregulates BDNF expression and impairs TrkB receptor activity, leading to disrupted synaptic remodeling and diminished neuronal repair capacity. This process represents a key pathological mechanism in the development of PSCI (41). In recent years, the regulatory effect of acupuncture on BDNF and its downstream signaling pathways has gained increasing attention as a potential mechanism underlying its therapeutic effects on PSCI (6, 7). Multiple animal studies have demonstrated that acupuncture significantly upregulates BDNF mRNA and protein expression in post-stroke brain tissue, restores its binding activity with TrkB, and activates a series of neuroprotective downstream pathways (1). Notably, the BDNF–TrkB axis mediates the phosphorylation of cAMP response element-binding protein (CREB), which enhances the expression of plasticity-related proteins such as SYN and growth-associated protein 43 (GAP-43), thereby facilitating synaptic remodeling and memory consolidation (26).

In addition, BDNF activates the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, which inhibits pro-apoptotic protein expression and promotes neuronal survival (21). Acupuncture has also been shown to activate the PI3K/Akt pathway in stroke models, suggesting a potential synergistic neuroprotective effect with BDNF signaling. Additionally, acupuncture modulates other signaling cascades such as MAPK/ERK, further expanding the BDNF-mediated regulatory network. BDNF also plays a pivotal role in mediating bidirectional signaling between neurons and glial cells (42). Acupuncture-induced upregulation of BDNF expression in astrocytes may represent a novel mechanism for restoring neuron–glia interactions post-stroke (4, 5). In summary, acupuncture modulates the BDNF/TrkB signaling axis and its downstream pathways, including CREB and PI3K/Akt, thereby promoting neuronal survival, facilitating synaptic plasticity, and contributing to cognitive recovery (17). This represents a core mechanism through which acupuncture ameliorates post-stroke cognitive impairment. Through these neurotrophic cascades, acupuncture promotes synaptic remodeling, axonal regeneration, and neuronal survival, thereby facilitating large-scale network reorganization and functional integration.

The cumulative effects of neurotransmitter regulation, anti-inflammatory modulation, antioxidative protection, and neurotrophic activation ultimately converge at the systems level, driving neurogenesis and the reconstruction of functional brain networks. After stroke, structural damage in localized brain regions combined with disrupted functional connectivity constitutes the pathological basis of cognitive impairment (8). Stroke not only induces neuronal apoptosis and synaptic disconnection but also compromises the integrity of neural networks, particularly disrupting key cognitive circuits such as the thalamocortical and hippocampal–prefrontal pathways (43). These changes severely impair the brain’s integrative and processing capacity during cognitive tasks (6, 7). Neurogenesis and brain network reorganization represent two central processes in cognitive recovery after stroke, both of which are positively regulated by acupuncture. Regarding neurogenesis, studies have demonstrated that acupuncture promotes the proliferation, differentiation, and migration of neural stem cells (NSCs) in the hippocampal dentate gyrus (DG) and subventricular zone (SVZ) (44). This facilitates the generation of new neurons, thereby providing a cellular foundation for post-stroke brain tissue repair and cognitive recovery. Electroacupuncture at acupoints such as GV20 and Shenting GV24 modulates signaling pathways including Notch and Wnt/β-catenin, thereby enhancing NSC activity. It also upregulates neurogenesis-related markers such as Nestin and doublecortin (DCX), indicating that acupuncture facilitates the generation and integration of newborn neurons (4, 5).

Regarding brain network reorganization, functional magnetic resonance imaging (fMRI) studies have revealed that acupuncture modulates functional connectivity among multiple brain regions (9). Specifically, it enhances synchrony within regions associated with the default mode network (DMN), including the medial prefrontal cortex (mPFC), hippocampus, and posterior cingulate cortex (PCC), suggesting a potential role for acupuncture in restoring high-order cognitive networks disrupted by stroke (45). Additional studies have shown that acupuncture promotes synaptogenesis and remyelination, enhances axonal conduction efficiency, and provides a microstructural basis for neural network functional restoration (3). Notably, acupuncture-induced neurogenesis and functional remodeling exhibit “acupoint-to-central-target” specificity. That is, its regulatory effects are not diffuse or nonspecific, but preferentially target cognition-related brain regions such as the hippocampus and prefrontal cortex (29). This may represent a distinctive mechanistic feature distinguishing acupuncture from other physical therapies. In summary, acupuncture facilitates neurogenesis and functional connectivity remodeling post-stroke, offering dual structural and functional support for brain recovery, and forming a fundamental biological basis for its therapeutic effects on PSCI. This hierarchical progression—from molecular modulation to network reorganization—illustrates the integrative neurobiological mechanism by which acupuncture may restore cognitive function in post-stroke populations.