Sensory and Metabolic Networks in Stroke Offer Investigational Clues for Therapy

A narrative review published in Discover Neuroscience evaluates how sensory afferents, neuropeptides, and metabolic pathways intersect during ischemic stroke and systemic inflammatory diseases, proposing an integrative hypothesis-generating framework rather than establishing sensory signaling as a primary disease driver. Authored by Shiyang Liu, Meixiang Sun, Hui Liu, Yu Wang, Fang Zhang, Nan Li, and Peiyang Sun, the synthesis situates neurogenic activity within the complex multicellular pathophysiology of acute cerebral ischemia. Arterial occlusion initiates immediate cellular energy failure and severe excitotoxicity, which subsequently trigger oxidative stress, neuroinflammation, microvascular dysfunction, and blood-brain barrier disruption within and beyond the neurovascular unit. This pathological cascade engages neurons, astrocytes, microglia, pericytes, endothelial cells, infiltrating leukocytes, and extracellular matrix components, culminating in multiple regulated cell-death programs including apoptosis, necroptosis, pyroptosis, and ferroptosis. Within this broader injury landscape, peripheral and cranial sensory afferents can influence local vascular tone and immune behavior through ion channel activation and neuropeptide discharge. However, the authors stress that sensory-immune interactions represent merely one contributory layer of post-ischemic biology rather than the dominant organizing principle governing stroke outcomes.

The sensory component of this proposed network operates through transient receptor potential channels expressed on peripheral sensory nerve terminals that respond to noxious heat, extracellular acidosis, oxidative stress, lipid mediators, and inflammatory signals. While the non-selective cation channel TRPV1 is frequently highlighted as a polymodal sensor whose activation threshold is lowered by tissue acidosis, capsaicin, bradykinin, prostaglandins, and growth factors through phosphorylation-dependent mechanisms, the review cautions against viewing it as an isolated upstream driver. Ischemic brain injury simultaneously recruits a broader family of transient receptor potential channels, including TRPV4, TRPM2, TRPM4, and TRPM7, which display either protective or injurious actions depending on cellular distribution, timing, and experimental context. Furthermore, because these channel families are distributed across neurons, glia, vascular endothelial cells, and immune cells, attributing functional changes exclusively to peptidergic sensory fibers is biologically unsupported. Existing evidence does not demonstrate that TRPV1-dependent sensory discharge functions as a necessary initiating trigger in human stroke, highlighting the functional redundancy that exists across diverse sensory receptors.

Sensory afferent stimulation can release neuropeptides into damaged tissue through local axon-reflex pathways, but the review emphasizes that their biological consequences cannot be categorized as uniformly pro-inflammatory. Substance P operates predominantly through the neurokinin-1 receptor and possesses substantial preclinical support connecting it to post-ischemic blood-brain barrier permeability, neurogenic inflammation, and progressive cerebral edema. Despite robust experimental evidence, pharmacological antagonists targeting the neurokinin-1 receptor have not successfully translated into approved clinical therapies for acute ischemic stroke. In comparison, calcitonin gene-related peptide functions primarily via the calcitonin receptor-like receptor and receptor activity-modifying protein 1 complex, acting as a potent vasodilator with context-dependent immunomodulatory properties. The net effect of neurogenic signaling in cerebral tissue depends heavily on peptide identity, receptor density, disease phase, and cellular microenvironment. Consequently, the authors state that sensory neuropeptide signaling cannot be reduced to a single self-amplifying cascade of neuroinflammation, particularly given the parallel inflammatory contributions made by cytokines, complement activation, damage-associated molecular patterns, and recruited leukocytes.

The review highlights calcitonin gene-related peptide signaling as an essential case study demonstrating the perils of extrapolating pharmacological success across different neurological conditions. While four monoclonal antibodies and multiple small-molecule receptor antagonists known as gepants have demonstrated robust clinical efficacy for migraine prevention, confirming target tractability in primary headache disorders, no randomized clinical evidence supports their application in ischemic stroke. To the contrary, experimental studies in mice revealed that administering the receptor antagonists olcegepant or rimegepant exacerbated ischemic brain injury and compromised collateral blood flow. Because calcitonin gene-related peptide produces potent vasodilation, endogenous release during acute ischemia may perform a critical neuroprotective function by maintaining microvascular perfusion in the penumbral border zones. Neutralizing this pathway could inadvertently eliminate vital collateral circulation during arterial occlusion. Consequently, the authors caution that inhibiting CGRP receptors could compromise microcirculatory compensation and exacerbate acute tissue infarction. Therapeutic strategies validated for neurovascular disorders cannot be assumed safe or effective in stroke without rigorous preclinical confirmation and dedicated disease-specific clinical trials.

Post-ischemic inflammation is tightly coupled with cellular metabolic reprogramming throughout the neurovascular unit, where activated microglia and infiltrating immune cells alter glycolysis, oxidative phosphorylation, lipid handling, and redox balance, while parenchymal brain cells endure rapid adenosine triphosphate depletion. Within this metabolic landscape, the review examines the regulatory axis formed by sirtuin 1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha. Sirtuin 1 operates as a nicotinamide adenine dinucleotide-dependent deacetylase that activates its transcriptional coactivator partner to coordinate mitochondrial biogenesis, oxidative metabolism, and cellular stress adaptation. Experimental stroke investigations demonstrate that preserving sirtuin 1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha signaling correlates with sustained mitochondrial respiration, improved fission-fusion dynamics, and neuroprotection. However, the authors caution that acute ischemia directly diminishes cofactor availability and escalates reactive oxygen species, meaning suppression of this mitochondrial regulatory pathway cannot be causally attributed to persistent neurogenic inflammation in stroke patients based on current correlative findings. Future experimental work must therefore employ cell-type-specific genetic perturbations and rigorous temporal analyses to distinguish direct sensory influences from general ischemic damage.

The synthesis similarly evaluates lipid peroxidation and ferroptosis as critical metabolic processes that intersect with acute ischemic injury and neuroinflammatory signaling. Ferroptosis represents an iron-dependent form of non-apoptotic regulated cell death characterized by the catastrophic accumulation of toxic phospholipid hydroperoxides following the failure of endogenous antioxidant defenses, specifically the glutathione-dependent glutathione peroxidase 4 system. While cerebral ischemia creates an environment rich in disturbed iron handling, oxidative stress, and polyunsaturated fatty acid-containing phospholipids, the authors emphasize that ferroptosis operates alongside apoptosis, necroptosis, and pyroptosis rather than as an isolated mechanism. Furthermore, inflammatory mediators and sensory signals may theoretically amplify oxidative stress, but clinical investigations have not established a direct linear pathway leading from transient receptor potential channel activation through neuropeptide release to iron dysregulation and human ferroptotic cell death. As a result, theoretical frameworks connecting sensory afferents to downstream ferroptosis must be interpreted as hypothesis-generating conceptual schemes rather than proven causal mechanisms.

Physical neuromodulation strategies, including manual acupuncture and electroacupuncture, represent non-pharmacological interventions investigated for their capacity to influence sensory, inflammatory, and metabolic pathways after cerebral ischemia. A systematic review cited by the authors, encompassing 40 randomized clinical trials with 4,485 stroke patients, identified reported improvements in neurological deficits and disability scores, although the overall certainty of the underlying evidence was rated as moderate to low. Preclinical investigations have suggested that electroacupuncture can reduce neuroinflammation, attenuate oxidative stress, promote microvascular remodeling, and support sirtuin 1-dependent mitochondrial signaling. Outside the stroke setting, research in a rat colitis model demonstrated that applying electroacupuncture at the Zusanli acupoint, designated ST36, attenuated dorsal root ganglion sympathetic-sensory coupling and suppressed neurogenic inflammatory signaling involving transient receptor potential vanilloid 1 and calcitonin gene-related peptide. Nevertheless, the review stresses that such animal findings cannot demonstrate that physical neuromodulation prevents recurrent stroke or restores human mitochondrial dynamics through a validated sensory-immune mechanism.

Pharmacological efforts to modulate ferroptosis have investigated diverse synthetic compounds and naturally derived agents, notably the antimalarial derivative artesunate, which influences cellular redox balance and ferroptotic pathways in experimental disease models. However, the authors caution that natural derivation confers no inherent clinical advantage, emphasizing that candidate molecules frequently exhibit limited target selectivity, suboptimal tissue exposure, reactive metabolite generation, inadequate metabolic stability, or dose-limiting toxicity liabilities. Like synthetic molecules, naturally derived compounds require rigorous pharmacokinetic and pharmacodynamic optimization, target validation, and formal safety profiling before entering clinical testing. Currently, neither artesunate nor any alternative ferroptosis-targeted agent possesses clinical evidence supporting its implementation for acute ischemic stroke therapy or secondary prevention. The review notes that network-level multi-target activity cannot be considered therapeutically superior without definitive proof of efficacy within a defined therapeutic window, reproducible dose-response relationships, and demonstrated safety across diverse model systems and patient cohorts.

To address the temporal and spatial cellular heterogeneity of the neurovascular unit, the authors evaluate high-dimensional computational approaches, including single-cell transcriptomics, spatial transcriptomics, metabolomics, and lipidomics. While integrating multi-omics datasets using machine-learning algorithms, attention architectures, and graph neural networks can help identify candidate relationships across sensory, immune, and metabolic pathways, these analytical technologies remain susceptible to batch effects, sampling bias, and limited longitudinal coverage. Crucially, statistical associations generated by computational profiling cannot replace empirical verification of causal relationships. The review similarly appraises digital twin concepts—theoretical computational frameworks that integrate longitudinal patient data, clinical imaging, vascular risk profiles, and multi-omics measurements into dynamic personalized predictive models. Although digital twins represent an intriguing conceptual direction for future stroke research, there are currently no validated artificial intelligence systems capable of reconstructing neurogenic inflammation, mitochondrial dynamics, or ferroptotic states in individual patients to guide mechanism-specific clinical interventions.

The authors conclude by identifying major methodological limitations and outlining a translational roadmap to guide future investigations into sensory-immune-metabolic biology. They emphasize that their synthesis is a narrative review rather than a preregistered systematic review, meaning publication and selection bias cannot be ruled out. Additionally, findings derived from migraine, colitis, or pain models cannot be presumed directly transferable to ischemic stroke pathology. Current secondary stroke prevention remains firmly established upon antithrombotic therapies and vascular risk factor management, whereas the incremental predictive or clinical value of sensory-immune biomarkers remains unquantified. Future translational success will require establishing causal mechanisms by manipulating defined sensory afferent populations in controlled stroke models, validating sensory and metabolic biomarkers in prospective human cohorts, and conducting adequately powered randomized trials with prespecified mechanistic endpoints. Until such rigorous empirical criteria are met, the sensory-immune-metabolic axis should be treated as an investigational research framework rather than an established foundation for routine stroke care.

Subject of Research: Sensory, immune, and metabolic interactions in ischemic stroke pathophysiology

Article Title: Sensory immune and metabolic interactions in ischemic stroke and inflammatory diseases inform emerging therapeutic strategies

Article References: Liu, S., Sun, M., Liu, H., Wang, Y., Zhang, F., Li, N., & Sun, P. (2026). Sensory immune and metabolic interactions in ischemic stroke and inflammatory diseases inform emerging therapeutic strategies. Discover Neuroscience, 21(1), Article 121. https://doi.org/10.1186/s13064-026-00340-y

Image Credits: AI Generated

DOI: 10.1186/s13064-026-00340-y

Keywords: Ischemic Stroke, Neurovascular Unit, TRP Channels, Neuropeptides, Mitochondrial Dysfunction, Ferroptosis, Neuromodulation, Translational Medicine, Sensory, immune, metabolic, interactions