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Advanced Neurology BTKi in brain diseases

Figure 1. Diagram of the structure of Bruton’s tyrosine kinase (BTK). BTK has five domains and 659 amino acids in total. The pleckstrin homology
domain, proline-rich TEC homology domain, SRC homology domains such as Src homology 3 and Src homology 2, and the catalytic kinase domain are
the domains in the BTK structure from N-terminal to C-terminal.

that clear away cell waste and injured neurons, playing a PLC2 is part of the BTK substrate. Two-second messengers,
significant role in neuroprotection in the healthy brain. 13,14 i.e., inositol 1,4,5-trisphosphate (IP3) and diacylglycerol
Interleukin-1β (IL-1β), IL-6, tumor necrosis factor- (DAG), are produced when PLC2 is activated. Ca
2+
alpha (TNF-α), cyclooxygenase-2, and inducible nitric mobilization is initiated by IP3, which then activates the
oxide synthase are just a few of the pro-inflammatory NFAT pathway. Protein kinase C is activated by DAG,
cytokines and mediators are released by abnormally which also activates the nuclear factor-κB (NF-κB) and
activated microglia, which can significantly speed up MAPK pathways 20,21 (Figure 2).
neuroinflammatory and neurotoxic responses. These In addition, BTK is part of the signaling downstream of
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neuroinflammatory reactions have a high correlation with TLRs, specifically TLR3, 4, 7, 8, and 9, in both B cells and
both neurodegenerative diseases (e.g., Alzheimer’s disease) other hematological cell types. Within these signaling
22
and neuroinflammation diseases such as multiple sclerosis pathways, BTK has been demonstrated to primarily
(MS). Therefore, controlling the neuroinflammatory serve as a linker protein for the recruitment of myeloid
16
response offers a potential therapeutic approach for these differentiation primary response 88 (MyD88) and MyD88
diseases.
adaptor-like (MAL) to the receptor (Figure 2).
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In both innate and adaptive immunological responses, FcR (fragment, crystallizable receptor) signaling also
BTK plays a critical mediating role, in linking activated involves BTK. 24,25 Many immune cell types, including B
immunoreceptors to subsequent signaling processes. It is cells, macrophages, mast cells, and neutrophils, express FcR.
activated in numerous acute and chronic inflammatory These receptors recognize the Fc region of immunoglobulin
conditions. As a result, efforts have been put into the G, which is located in the immunoglobulin G’s constant area.
development of pharmacological inhibitors of BTK as For example, BTK is substantially activated in mast cells by
potential immunomodulatory drugs for the control of the Fc epsilon receptor (FCRI)-mediated crosslinking, 26-28
autoimmune and inflammatory disorders. 17
suggesting the pivotal role of BTK in many FcRs. When the
In this review, we present an overview of current insights FcR is activated, histamine is released more readily by mast
on BTK inhibitors in brain diseases. First, we present the cells, and this process also increases myeloid cells’ ability to
signaling pathway involved in BTK and its important role present antigens and the generation of pro-inflammatory
in immune cells; second, we review the BTK inhibitors cytokines (Figure 2).
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currently in clinical application or ongoing experiments; Studies have shown that the inhibition of BTK in B cells
finally, we summarize the current experimental studies may alter not only the activation and cytokine production
of inhibitors in brain diseases to discover the potential of but also the expression of chemokine receptors, resulting
BTK inhibitors in the treatment of brain diseases.
in impaired lymphocyte homeostasis and humoral
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2. BTK signaling pathways immunity. So far, the involvement of BTK in chemokine
receptor signaling pathways has been well studied
BTK is involved in BCR signaling, FcR signaling, TLR (Figure 2). 31,32
signaling, and chemokine receptor signaling. The BCR
signaling pathway is essential in regulating B cells to 3. BTK inhibitors
survive, mature, adhere, and produce antibodies after Many BTK inhibitors are used in animal experiments or
differentiating into plasma cells. In BCR signaling, BTK
9,18
activation starts with transphosphorylation at position clinical trials or clinics, including ibrutinib, acalabrutinib,
Tyr551 by SYK and LYN after it is recruited to the membrane. zanubrutinib, evobrutinib, tolebrutinib, fenebrutinib,
This action results in BTK autophosphorylation at position orelabrutinib, Remibrutinib, and BIIB091.
Tyr223 in the SH3 domain. B-cell linker protein BLNK, Ibrutinib (Imbruvica, PCI-32765), is the first
19
which SYK phosphorylates after activation, functions as a BTK inhibitors approved by the U.S. Food and Drug
bridge connecting BTK and phospholipase C-2 (PLC2). Administration (FDA) in 2013 for the treatment of mantle

Volume 3 Issue 1 (2024) 2 https://doi.org/10.36922/an.2184