# The Potential Therapeutic Role of Bruton Tyrosine Kinase Inhibition in Neurodegenerative Diseases
## 3 Bruton Tyrosine Kinase's Inhibitors in Neurodegenerative Disease
### Ischemic Stroke  
IS results from the sudden interruption of cerebral blood flow due to arterial occlusion, leading to acute neuronal injury and rapid activation of inflammatory pathways [76]. Stroke is a leading cause of death and disability worldwide, with current treatment options limited to thrombol agents and mechanical thrombectomy, both constrained by narrow therapeutic windows. Neuroinflammation is now recognized as a critical determinant of secondary brain injury following ischemic insult [77]. Within minutes of ischemia, DAMPs released from dying cells activate resident microglia and astrocytes, triggering the production of pro-inflammatory cytokines, chemokines, and matrix metalloproteinases (MMPs), leading to BBB disruption, leukocyte infiltration, and further neuronal injury [78]. Peripheral immune cells, particularly neutrophils, monocytes, and B cells, are rapidly recruited and contribute to post-ischemic inflammation. In murine models of stroke, BTK expression is significantly upregulated in infiltrating immune cells and perilesional microglia [79]. Pharmacological inhibition of BTK has shown neuroprotective effects in rodent models of cerebral ischemia. In mice subjected to middle cerebral artery occlusion (MCAO), brturinib administration reduced brain damage and improved neurological outcomes in diabetic mice with ischemia/reperfusion injury [80]. It enhanced cell viability, decreased oxidative stress, and activated the PI3K/Akt/mTOR pathway, suggesting neuroprotection via reduced inflammation and improved autophagy. These effects were associated with reduced oxidative stress, lower levels of IL-1\(\beta\) and TNF-\(\alpha\), and decreased peripheral cell infiltration. Similar benefits were observed with tolebrturinib, which showed enhanced neuroprotection in a model of chronic cerebral hypoperfusion, with reduced white matter damage and cognitive deficits, by suppressing microglial activation, inflammation, oxidative stress, and ferroptosis, highlighting its therapeutic potential in ischemic demyelination [81]. BTK inhibitors may also exert beneficial effects on stroke recovery by limiting chronic inflammation, inflammasome activation, and secondary injury. Indeed, NLRP3 expression increases up to 20-30 fold within 24 h after stroke, and inhibition of BTK, an upstream regulator of NLRP3, showed reduced infarct volume and related neurological disruption after ischemic stroke [79; 82]. In subacute stroke models, evobrutinib treatment alleviated ischemic injury, reduced gliosis, and promoted anti-inflammatory microglial polarization, suggesting a role for BTKis in promoting CNS repair [83]. Importantly, BTK inhibition does not interfere with clot formation or dissolution, unlike anticoagulants or antiplatelet agents, making it potentially safer in the context of acute ischemia [84]. Additionally, BTKis may be useful adjuncts to reperfusion therapies, extending the therapeutic window and reducing reperfusion injury. Although clinical trials of BTKis in stroke are currently lacking, the mechanistic rationale and robust preclinical data justify their evaluation in human studies. Given the central role of innate immune activation in post-stroke injury, BTK inhibition may represent a promising strategy to mitigate neuroinflammation and improve functional outcomes.