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Advanced Neurology BTKi in brain diseases

4.3. Ischemic stroke have not yet been adequately elucidated. Importantly,
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Ischemic stroke is a major global cause of neurological elevated BTK expression was discovered in brain autopsies
impairment and mortality. Plasminogen activator (t-PA) from Alzheimer’s disease patients and 5xFAD mice
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is currently approved worldwide for the treatment of (a rodent model of Alzheimer’s disease).
ischemic stroke; however, the window of opportunity for Ibrutinib holds promise as a potential treatment for
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t-PA therapy is limited to 4.5 h following the onset of the Alzheimer’s disease, according to a study by Lee et al.
stroke. An effective treatment that can be used in a broader Ibrutinib modifies cognitive function and Alzheimer’s
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time window is required. The pathophysiology of ischemic disease-associated pathology. The researchers examined
stroke is characterized by post-ischemic inflammation. 69,70 how ibrutinib affected two Alzheimer’s disease mice
Inflammatory cytokines secreted by myeloid cells, such as models. Ibrutinib injection significantly decreased
interleukin (IL)-1β, TNF-α, and IL-23, aggravate brain Aβ-induced neuroinflammatory responses, Aβ plaque
tissue injury, therefore serving as potential targets for levels, and tau phosphorylation in 5xFAD mice by
therapy after ischemic stroke. 71-73 A type of tissue damage activating the non-amyloidogenic pathway of amyloid
sensor known as an inflammasome is required for the β protein precursor cleavage and decreasing levels of
transformation of IL-1β preform into the mature, active phosphorylated cyclin-dependent kinase-5 (p-CDK5). It
form and is also connected to pyroptosis, a type of cell also reduced tau-mediated neuroinflammation and tau
death. 74-77 In mouse models of ischemia brain injury, it phosphorylation in PS19 animals. Furthermore, ibrutinib
has also been reported that IL-1β and NLR family, pyrin also enhanced long-term memory and the amount of
domain containing 3 (NLRP3) play important roles. 78-80 dendritic spines in 5xFAD mice. However, it presented less
effect on short- or long-term memory in PS19 mice but
As reported by Ito et al., BTK is a crucial part did stimulate dendritic spinogenesis. Inhibiting microglial
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of the NLRP3 inflammasome. Activation of the BTK may also enhance cognition in Alzheimer’s disease by
NLRP3 inflammasome is significantly hampered by halting synaptic degeneration and microglial activation.
pharmacological or genetic inhibition of BTK, and Hence, reducing BTK expression in microglia is a potential
ibrutinib effectively prevents the development of infarct strategy for managing Alzheimer’s disease.
volume and neurological impairment in a mouse brain
ischemic/reperfusion (I/R) paradigm. This research 5. Conclusions and future perspectives
highlighted the importance of BTK in the activation of the In summary, therapeutic targeting of BTK in brain illness is
NLRP3 inflammasome, which could represent a promising a promising, emerging strategy that can augment existing
therapeutic target for ischemic stroke. According to medicines. BTK inhibition can affect cell types other than B
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another study, ibrutinib can successfully treat cerebral cells, such as macrophages in the periphery and microglia
pathological dysregulation and ischemia/reperfusion in the CNS. This integration of adaptive and innate
injury in diabetic rats by reducing inflammatory response immunity emphasizes the superiority of BTK inhibition
and oxidative stress and enhancing autophagy via the over other currently available B cell-targeted treatments.
PI3K/AKT/mTOR signaling pathway. Considering all The limitations and challenges of BTK inhibitors mainly
the evidence above, BTK inhibitors could be promising lie in the side effects of the drugs. The more severe side
therapeutic approaches in the treatment of ischemic brain effects of the first-generation BTK inhibitors (ibrutinib)
injury. seriously limited its clinical usage. A new generation
4.4. Alzheimer’s disease of highly selective BTK inhibitors continues to emerge.
Second-generation BTK inhibitors improved potency and
Alzheimer’s disease is a neurological disease that typically meanwhile presented fewer off-target effects. The safety data
worsens over time but progresses slowly in the early stage from clinical trials testing BTK inhibitors have been largely
of the disease. Neurofibrillary tangles (NFTs) and amyloid reassuring, but common adverse events such as reversible
beta (Aβ) plaques are two neuropathological characteristics liver enzyme and lipase elevations have been reported. In
that define Alzheimer’s disease. Memory impairment, addition, BTK inhibitors have the potential to treat specific
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reduced dendritic spine development, increased brain diseases. In ischemic stroke, BTK inhibition can
neuroinflammation, and tauopathy are all consequences suppress inflammation and protect against neurological
of Aβ plaque accumulation. 84,85 Drugs that reduce and/ damage. In Alzheimer’s disease, BTK inhibitors can
or prevent the buildup of Aβ and hyperphosphorylation reduce Aβ plaque levels, decrease neuroinflammatory
of tau may still be helpful for target-based treatment of responses, and alleviate tau-mediated neuroinflammation
Alzheimer’s disease even if the molecular processes by and phosphorylation. Further studies are required to yield
which Aβ and NFTs alter synaptic and cognitive function clinical and experimental findings supporting the use of

Volume 3 Issue 1 (2024) 6 https://doi.org/10.36922/an.2184