# The Potential Therapeutic Role of Bruton Tyrosine Kinase Inhibition in Neurodegenerative Diseases
## 3 Bruton Tyrosine Kinase's Inhibitors in Neurodegenerative Disease
### Multiple Sclerosis  
MS is a chronic autoimmune demyelinating disease of the CNS characterized by recurrent episodes of neurological dysfunction due to immune-mediated damage to the myelin sheath, axonal degeneration, and neuroinflammation [60]. The disease predominantly affects young adults and is a leading cause of non-traumatic neurological disability in this population [61]. MS is considered a multifactorial disease involving genetic susceptibility and environmental triggers such as Epstein-Barr virus infection and vitamin D deficiency [62; 63]. Immune dysregulation lies at the core of MS pathogenesis. The adaptive immune response, particularly autoreactive CD4+ T cells, plays a central role in initiating inflammation [60]. However, emerging evidence has highlighted the importance of B cells and myeloid cells, including microglia and monocyte-derived macrophages, in perpetuating CNS injury [64]. B cells contribute through antigen presentation, pro-inflammatory cytokine release, and the formation of ectopic follicle-like structures within the meninges, and BTK is a crucial signaling mediator in these cell types [24]. In MS lesions, BTK expression is increased in microglia and infiltrating macrophages, where it promotes inflammatory responses via activation of the NF-kB and NLRP3 inflammasome pathways [65]. In vitro studies using human microglia have shown that BTK inhibition reduces LPS-induced TNF-\(\alpha\), IL-6, and IL-19 production, highlighting its role in modulating innate immune responses [27; 43]. Preclinical studies using experimental autoimmune encephalomyelitisitis, the prototypical animal model of MS, have demonstrated the efficacy of BTK inhibitors such as byturinib and evobrutinib in reducing disease severity [43; 66]. In a recent study, the effects of three BTK inhibitors (i.e., evobrutinib, fenebrutinib, and tolebrutinib) were evaluated on neutrophil activity [67]. All inhibitors attenuated neutrophil activation triggered by the bacterial peptide fMLF and CXCL8, reducing reactive oxygen species production, neutrophil extracellular trap formation, and the secretion of CXCL8 and IL-19 in response to inflammatory stimuli. These effects were independent of toxicity and were accompanied by prolonged neutrophil survival in inflammatory conditions. These findings highlight a novel role for BTK inhibitors in modulating innate immune functions beyond B cells [67]. Also, treatment with fenebrutinib leads to reduced spinal cord inflammation, demyelination, and axonal damage [13]. Importantly, BTK inhibition dampens both peripheral and CNS-resident immune responses [68]. Inhibition of BTK in B cells limits the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-6, crucial cytokines in T-cell activation, while microglial inhibition reduces local cytokine storms and cytotoxicity [69]. Moreover, in vitro BTK inhibition with evobrutinib in iron-loaded human microglia reduces proinflammatory gene expression and iron importer levels while increasing ferroportin, suggesting that BTK blockade modulates both inflammation and iron homeostasis in microglia, key features of chronic lesions in MS [70]. Clinical translation of these findings is underway. Evobrutinib has been evaluated in a phase II trial (ID: NCT02975349) involving 267 patients with relapsing-remitting MS, demonstrating significant reductions in gadolinium-enhancing lesions on MRI and favorable safety and tolerability profiles [71]. These findings have prompted phase III trials (IDs: NCT04338022 and NCT04338061) to assess long-term clinical benefits. However, evobrutinib did not distinguish itself from terifulunomide, an MS drug, in reducing the annualized relapse rate, causing the termination of these studies with no further support for evobrutinib application in MS [72]. Other BTK inhibitors are also in advanced stages of clinical development and exhibit promising CNS penetrance and immunomodulatory activity.