Continuous Theta Burst Stimulation (cTBS) protects against acute ischemic stroke by modulating calcineurin/AKT/FOXO1 pathway
Background
Ischemic stroke remains a leading cause of death and long-term disability, with current therapies primarily focused on reperfusion rather than neuroprotection. Secondary injury mechanisms, including neuronal apoptosis in the peri-infarct region, significantly contribute to poor outcomes. There's a critical need for strategies that activate endogenous protective pathways and limit this secondary damage. The calcineurin/AKT/FOXO1 signaling pathway is a key regulator of cell survival and apoptosis, making its modulation a promising target for neuroprotective interventions.
Study Design
Researchers induced ischemic stroke in mice using the Longa method (MCAO model). Continuous Theta Burst Stimulation (cTBS) was administered daily for seven days post-stroke. Motor function and limb coordination were assessed through behavioral tests. To elucidate mechanisms, transcriptomic and proteomic analyses were performed on the peri-infarct region. Key proteins in the calcineurin/AKT/FOXO1 pathway were analyzed via immunofluorescence and Western blot, while TUNEL staining quantified neuronal apoptosis. AAV-mediated gene knockdown was employed to validate the pathway's role in apoptosis.
Results
cTBS significantly improved motor performance and reduced infarct volume in the MCAO mouse model. It also preserved the architecture of the peri-infarct tissue. Mechanistically, cTBS suppressed calcineurin expression, leading to enhanced activation of the AKT and FOXO1 components within the calcineurin/AKT/FOXO1 signaling pathway. This modulation ultimately resulted in a marked decrease in neuronal apoptosis in the vulnerable peri-infarct region. The AAV-mediated gene knockdown experiments further confirmed the critical role of this pathway in mediating the observed anti-apoptotic and neuroprotective effects. > cTBS exerted neuroprotection by modulating the calcineurin/AKT/FOXO1 pathway, ultimately inhibiting neuronal apoptosis in the peri-infarct region.
Key Findings
- cTBS improved motor performance and limb coordination in MCAO mice.
- cTBS reduced infarct volume and preserved peri-infarct tissue architecture.
- cTBS suppressed
calcineurinexpression in the peri-infarct region. - cTBS enhanced activation of the
AKT/FOXO1pathway. - cTBS significantly decreased neuronal apoptosis in the peri-infarct area.
Why It Matters
cTBS presents a promising non-pharmacological neuroprotective strategy for acute ischemic stroke, potentially complementing existing reperfusion therapies. By targeting the calcineurin/AKT/FOXO1 pathway, it offers a novel approach to mitigate secondary injury and neuronal apoptosis, which are major drivers of long-term disability. While this is a preclinical animal study, the findings suggest that transcranial magnetic stimulation protocols like cTBS could be developed for clinical use in the acute phase of stroke. Further research is needed to optimize stimulation parameters and confirm efficacy in human trials, but this work highlights a tangible mechanism for cTBS's therapeutic potential.
ctbs
ischemic stroke
neuroprotection
apoptosis
calcineurin
akt