Journal Article

Deficiency of SARM1 attenuates neuronal injury and improves neurological performance in a photothrombotic stroke model

Cheng, Xiaofeng, Yang, Qingwu, Ma, Yufan, Yan, Ke, Huang, Yanjie, Lin, Sen

2025

Overview

Stroke is a major cause of morbidity and mortality worldwide. There is an urgent need for effective neuroprotective agents to reduce brain injury. SARM1 (sterile alpha and TIR motif-containing 1) has been identified as a key mediator of axonal degeneration. However, its role in stroke and the underlying mechanisms remain insufficiently understood. In the present study, a mouse model of stroke with focal infarction in the cortex was used to investigate the potential relation between SARM1 and post-stroke brain injury. We found that SARM1 expression increased in neurons of the peri-infarct cortex at an early stage after photothrombotic stroke induction (PTI) and was evenly distributed between excitatory and inhibitory neurons. Deficiency of SARM1 improved neurological performance, reduced the infarct volume and the inflammatory response including reactive gliosis and TNF-α level after PTI. Meanwhile, SARM1 deficiency promoted neuronal preservation in the peri-infarct cortex and mitigated axonal degeneration, possibly because of reduced NAD + consumption of neurons in the peri-infarct cortex. Additionally, we found that SARM1 deficiency inhibited glial scar formation and decreased activated microglia. FK866 and DSRM-3716, two recently reported pharmacological inhibitors of SARM1, failed to alleviate brain injury in mice with stroke. Our findings demonstrate that SARM1 deficiency attenuates ischemic neuronal injury and improves neurological performance post PTI, suggesting that the SARM1 signaling pathway could serve as a potential therapeutic target for stroke in the future.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Anesthesia / Animals / Armadillo Domain Proteins - deficiency / Armadillo Domain Proteins - metabolism / Axonal degeneration / Axons - metabolism / Axons - pathology / Biomedical and Life Sciences / Biomedicine / Brain / Brain injury / Carotid arteries / Cerebral infarction / Cortex / Cytoskeletal Proteins - deficiency / Cytoskeletal Proteins - metabolism / Disease Models, Animal / Gliosis / Gliosis - pathology / Health aspects / Inflammation / Injuries / Ischemia / Laboratory animals / Life sciences / Male / Medical research / Mice / Mice, Inbred C57BL / Microglia / Microglia - metabolism / Microglia - pathology / Morbidity / Neurodegeneration / Neurology / Neuron injury / Neurons / Neurons - metabolism / Neurons - pathology / Neuroprotection / Neuroprotective agents / Neurosciences / Psychopharmacology / SARM1 / Signal transduction / Stroke / Stroke - complications / Stroke - metabolism / Stroke - pathology / Stroke - physiopathology / Tenecteplase / Therapeutic targets / Tissues / Tumor necrosis factor-α / Veins & arteries