Bruton's tyrosine kinase (BTK) is a crucial part of the B-cell receptor signaling pathway that has been extensively studied in various types of malignancies. Recent studies have extended our knowledge on its role in metabolism as well as neurological disorders. It may play an important role in the pathophysiology of neurological diseases, such as multiple sclerosis, Alzheimer's disease, brain injury, and several others. Activation of inflammasomes, mainly NLRP3, is one of the core mechanisms by which it promotes inflammation in the brain related to aging and diseases. In this paper, we provide an overview of the less explored roles of BTK in several brain diseases and discuss the potential of its inhibition to become a therapeutic target for neurological diseases.

Institute of Pharmacology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic Institute of Pharmacology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Zobrazit více v PubMed

Wu J, Liu C, Tsui ST, et al. Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol. 2016;9(1):80. doi: 10.1186/s13045-016-0313-y. PubMed DOI PMC

Estupiñán HY, Berglöf A, Zain R, et al. Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects. Front Cell Dev Biol. 2021;9:630942. doi: 10.3389/fcell.2021.630942. PubMed DOI PMC

Jongstra-Bilen J, Puig Cano A, Hasija M, et al. Dual Functions of Bruton’s Tyrosine kinase and tec kinase during fcγ receptor-induced signaling and phagocytosis. J Immunol. 2008;181(1):288–298. doi: 10.4049/jimmunol.181.1.288. PubMed DOI

Ringheim GE, Wampole M, Oberoi K. Bruton’s Tyrosine Kinase (BTK) Inhibitors and Autoimmune Diseases: Making Sense of BTK Inhibitor Specificity Profiles and Recent Clinical Trial Successes and Failures. Front Immunol. 2021;12:662223. doi: 10.3389/fimmu.2021.662223. PubMed DOI PMC

Montalban X, Arnold DL, Weber MS, et al. Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. N Engl J Med. 2019;380(25):2406–2417. doi: 10.1056/NEJMoa1901981. PubMed DOI

Smith CIE, Burger JA. Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway. Front Immunol. 2021;12:689472. doi: 10.3389/fimmu.2021.689472. PubMed DOI PMC

Wen T, Wang J, Shi Y, et al. Inhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances. Leukemia. 2021;35(2):312–332. doi: 10.1038/s41375-020-01072-6. PubMed DOI PMC

Tasso B, Spallarossa A, Russo E, et al. The Development of BTK Inhibitors: A Five-Year Update. Molecules. 2021;26(23):7411. doi: 10.3390/molecules26237411. PubMed DOI PMC

Dolgin E. BTK blockers make headway in multiple sclerosis. Nat Biotechnol. 2021;39(1):3–5. https://doi.org/10.1038/s41587-019-0381-y https://doi.org/10.1038/s41587-020-00790-7 https://doi.org/10.1038/d41587-021-00025-3 . PubMed DOI

Zhang D, Gong H, Meng F. Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases. Molecules. 2021;26(16):4907. doi: 10.3390/molecules26164907. PubMed DOI PMC

Woyach JA, Furman RR, Liu T-M, et al. Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib. N Engl J Med. 2014;370(24):2286–2294. doi: 10.1056/NEJMoa1400029. PubMed DOI PMC

Young WB, Barbosa J, Blomgren P, et al. Discovery of highly potent and selective Bruton’s tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability. Bioorg Med Chem Lett. 2016;26(2):575–579. doi: 10.1016/j.bmcl.2015.11.076. PubMed DOI

Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood. 2017;129(16):2224–2232. doi: 10.1182/blood-2016-10-747345. PubMed DOI PMC

Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010;107(29):13075–13080. doi: 10.1073/pnas.1004594107. PubMed DOI PMC

Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507–516. doi: 10.1056/NEJMoa1306220. PubMed DOI PMC

Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42. doi: 10.1056/NEJMoa1215637. PubMed DOI PMC

Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström’s macroglobulinemia. N Engl J Med. 2015;372(15):1430–1440. doi: 10.1056/NEJMoa1501548. PubMed DOI

Miklos D, Cutler CS, Arora M, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130(21):2243–2250. doi: 10.1182/blood-2017-07-793786. PubMed DOI PMC

Levade M, David E, Garcia C, et al. Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions. Blood. 2014;124(26):3991–3995. doi: 10.1182/blood-2014-06-583294. PubMed DOI

Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. N Engl J Med. 2019;381(5):432–443. doi: 10.1056/NEJMoa1817073. PubMed DOI PMC

Munir T, Brown JR, O’Brien S, et al. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019;94(12):1353–1363. doi: 10.1002/ajh.25638. PubMed DOI PMC

Nicolson PLR, Hughes CE, Watson S, et al. Inhibition of Btk by Btk-specific concentrations of ibrutinib and acalabrutinib delays but does not block platelet aggregation mediated by glycoprotein VI. Haematologica. 2018;103(12):2097–2108. doi: 10.3324/haematol.2018.193391. PubMed DOI PMC

Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020;136(18):2038–2050. doi: 10.1182/blood.2020006844. PubMed DOI PMC

Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278–1291. doi: 10.1016/S0140-6736(20)30262-2. PubMed DOI PMC

Ghia P, Pluta A, Wach M, et al. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020;38(25):2849–2861. doi: 10.1200/JCO.19.03355. PubMed DOI

Hillmen P, Eichhorst B, Brown JR, et al. Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial. JCO. 2023;41(5):1035–1045. doi: 10.1200/JCO.22.00510. PubMed DOI PMC

Bye AP, Unsworth AJ, Desborough MJ, et al. Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib. Blood Adv. 2017;1(26):2610–2623. doi: 10.1182/bloodadvances.2017011999. PubMed DOI PMC

Ma B, Metrick CM, Gu C, et al. Optimization of a novel piperazinone series as potent selective peripheral covalent BTK inhibitors. Bioorganic & Medicinal Chemistry Letters. 2022;60:128549. doi: 10.1016/j.bmcl.2022.128549. PubMed DOI

Elamin G, Aljoundi A, Alahmdi MI, et al. Battling BTK mutants with noncovalent inhibitors that overcome Cys481 and Thr474 mutations in Waldenström macroglobulinemia therapy: structural mechanistic insights on the role of fenebrutinib. J Mol Model. 2022;28(11):355. doi: 10.1007/s00894-022-05345-y. PubMed DOI

Brullo C, Villa C, Tasso B, et al. Btk Inhibitors: A Medicinal Chemistry and Drug Delivery Perspective. Int J Mol Sci. 2021;22(14):7641. doi: 10.3390/ijms22147641. PubMed DOI PMC

Dickson EJ, Hille B. Understanding phosphoinositides: rare, dynamic, and essential membrane phospholipids. Biochemical Journal. 2019;476(1):1–23. doi: 10.1042/BCJ20180022. PubMed DOI PMC

Solvason N, Wu WW, Kabra N, et al. Transgene Expression of bcl-xL Permits Anti-immunoglobulin (Ig)-induced Proliferation in xid B Cells. Journal of Experimental Medicine. 1998;187(7):1081–1091. doi: 10.1084/jem.187.7.1081. PubMed DOI PMC

Schaeffer EM, Debnath J, Yap G, et al. Requirement for Tec Kinases Rlk and Itk in T Cell Receptor Signaling and Immunity. Science. 1999;284(5414):638–641. doi: 10.1126/science.284.5414.638. PubMed DOI

Smith CIE, Islam TC, Mattsson PT, et al. The Tec family of cytoplasmic tyrosine kinases: mammalian Btk, Bmx, Itk, Tec, Txk and homologs in other species. Bioessays. 2001;23(5):436–446. doi: 10.1002/bies.1062. PubMed DOI

Basile N, Danielian S, Oleastro M, et al. Clinical and Molecular Analysis of 49 Patients With X-linked Agammaglobulinemia From A Single Center in Argentina. J Clin Immunol. 2009;29(1):123–129. doi: 10.1007/s10875-008-9227-y. PubMed DOI

Väliaho J, Smith CIE, Vihinen M. BTKbase: the mutation database for X-linked agammaglobulinemia. Hum Mutat. 2006;27(12):1209–1217. doi: 10.1002/humu.20410. PubMed DOI

Rawlings DJ, Saffran DC, Tsukada S, et al. Mutation of Unique Region of Bruton’s Tyrosine Kinase in Immunodeficient XID Mice. Science. 1993;261(5119):358–361. doi: 10.1126/science.8332901. PubMed DOI

Cancro MP, Sah AP, Levy SL, et al. xid mice reveal the interplay of homeostasis and Bruton’s tyrosine kinase-mediated selection at multiple stages of B cell development. International Immunology. 2001;13(12):1501–1514. doi: 10.1093/intimm/13.12.1501. PubMed DOI

Torke S, Pretzsch R, Häusler D, et al. Inhibition of Bruton’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease. Acta Neuropathol. 2020;140(4):535–548. doi: 10.1007/s00401-020-02204-z. PubMed DOI PMC

Middendorp S, Dingjan GM, Hendriks RW. Impaired Precursor B Cell Differentiation in Bruton’s Tyrosine Kinase-Deficient Mice. The Journal of Immunology. 2002;168(6):2695–2703. doi: 10.4049/jimmunol.168.6.2695. PubMed DOI

Cariappa A, Tang M, Parng C, et al. The Follicular versus Marginal Zone B Lymphocyte Cell Fate Decision Is Regulated by Aiolos, Btk, and CD21. Immunity. 2001;14(5):603–615. doi: 10.1016/S1074-7613(01)00135-2. PubMed DOI

Lünemann JD, Malhotra S, Shinohara ML, et al. Targeting Inflammasomes to Treat Neurological Diseases. Ann Neurol. 2021;90(2):177–188. doi: 10.1002/ana.26158. PubMed DOI

Rip J, Van Der Ploeg EK, Hendriks RW, et al. The Role of Bruton’s Tyrosine Kinase in Immune Cell Signaling and Systemic Autoimmunity. Crit Rev Immunol. 2018;38(1):17–62. doi: 10.1615/CritRevImmunol.2018025184. PubMed DOI

DiSabato D, Quan N, Godbout JP. Neuroinflammation: The Devil is in the Details. J Neurochem. 2016;139(Suppl 2):136–153. doi: 10.1111/jnc.13607. PubMed DOI PMC

Chen F, Ghosh A, Lin J, et al. 5-lipoxygenase pathway and its downstream cysteinyl leukotrienes as potential therapeutic targets for Alzheimer’s disease. Brain Behav Immun. 2020;88:844–855. doi: 10.1016/j.bbi.2020.03.022. PubMed DOI

Zheng Z-H, Tu J-L, Li X-H, et al. Neuroinflammation induces anxiety- and depressive-like behavior by modulating neuronal plasticity in the basolateral amygdala. Brain Behav Immun. 2021;91:505–518. doi: 10.1016/j.bbi.2020.11.007. PubMed DOI

Subramanian J, Savage JC, Tremblay M-È. Synaptic Loss in Alzheimer’s disease: mechanistic insights provided by two-photon in vivo imaging of transgenic mouse models. Frontiers in Cellular Neuroscience [Internet] 2020 doi: 10.3389/fncel.2020.592607. [cited 2023 Mar 6];14. PubMed DOI PMC

Zhang Y, Chen K, Sloan SA, et al. An RNA-Sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34(36):11929–11947. doi: 10.1523/JNEUROSCI.1860-14.2014. PubMed DOI PMC

Zhang Y, Sloan SA, Clarke LE, et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron. 2016;89(1):37–53. doi: 10.1016/j.neuron.2015.11.013. PubMed DOI PMC

Keaney J, Gasser J, Gillet G, et al. Inhibition of Bruton’s tyrosine kinase modulates microglial phagocytosis: therapeutic implications for Alzheimer’s disease. J Neuroimmune Pharmacol. 2019;14(3):448–461. doi: 10.1007/s11481-019-09839-0. PubMed DOI PMC

Lee H, Jeon SG, Kim J, et al. Ibrutinib modulates Aβ/tau pathology, neuroinflammation, and cognitive function in mouse models of Alzheimer’s disease. Aging Cell [Internet] 2021;20(3) doi: 10.1111/acel.13332. [cited 2023 Apr 15] PubMed DOI PMC

Dybowski S, Torke S, Weber MS. Targeting B cells and microglia in multiple sclerosis with bruton tyrosine kinase inhibitors: a review. JAMA Neurol. 2023;80(4):404. doi: 10.1001/jamaneurol.2022.5332. PubMed DOI

Fusco R, Siracusa R, Genovese T, et al. Focus on the role of NLRP3 inflammasome in diseases. Int J Mol Sci. 2020;21(12):4223. doi: 10.3390/ijms21124223. PubMed DOI PMC

Guo H, Callaway JB, Ting JP-Y. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21(7):677–687. doi: 10.1038/nm.3893. PubMed DOI PMC

Youm Y-H, Grant RW, McCabe LR, et al. Canonical Nlrp3 inflammasome links systemic low grade inflammation to functional decline in aging. Cell Metab. 2013;18(4):519–532. doi: 10.1016/j.cmet.2013.09.010. PubMed DOI PMC

Jin L, Mo Y, Yue E-L, et al. Ibrutinib ameliorates cerebral ischemia/reperfusion injury through autophagy activation and PI3K/Akt/mTOR signaling pathway in diabetic mice. Bioengineered. 2021;12(1):7432–7445. doi: 10.1080/21655979.2021.1974810. PubMed DOI PMC

Ito M, Shichita T, Okada M, et al. Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. Nat Commun. 2015;6:7360. doi: 10.1038/ncomms8360. PubMed DOI PMC

Bittner ZA, Liu X, Mateo Tortola M, et al. BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity. J Exp Med. 2021;218(11):e20201656. doi: 10.1084/jem.20201656. PubMed DOI PMC

Ghosh S, Mohammed Z, Singh I. Pharmacological Inhibition of BTK reduces neuroinflammation and stress induced anxiety in vivo [Internet] bioRxiv. 2021 [cited 2023 Mar 6] 2021.01.11.426241. Available from: https://www.biorxiv.org/content/10.1101/2021.01.11.426241v1 https://doi.org/10.1101/2021.01.11.426241. DOI

Franke M, Bieber M, Kraft P, et al. The NLRP3 inflammasome drives inflammation in ischemia/reperfusion injury after transient middle cerebral artery occlusion in mice. Brain Behav Immun. 2021;92:221–231. doi: 10.1016/j.bbi.2020.12.009. PubMed DOI

Ghosh S, Mohammed Z, Singh I. Bruton’s tyrosine kinase drives neuroinflammation and anxiogenic behavior in mouse models of stress. J Neuroinflammation. 2021;18(1):289. doi: 10.1186/s12974-021-02322-9. PubMed DOI PMC

Cui Y, Yu H, Bu Z, et al. Focus on the Role of the NLRP3 Inflammasome in Multiple Sclerosis: Pathogenesis, Diagnosis, and Therapeutics. Front Mol Neurosci. 2022;15:894298. doi: 10.3389/fnmol.2022.894298. PubMed DOI PMC

Hanslik KL, Ulland TK. The Role of Microglia and the Nlrp3 Inflammasome in Alzheimer’s Disease. Front Neurol. 2020;11:570711. doi: 10.3389/fneur.2020.570711. PubMed DOI PMC

Lassmann H. Pathogenic mechanisms associated with different clinical courses of multiple sclerosis. Front Immunol. 2018;9:3116. doi: 10.3389/fimmu.2018.03116. PubMed DOI PMC

Milo R. Therapies for multiple sclerosis targeting B cells. Croat Med J. 2019;60(2):87–98. doi: 10.3325/cmj.2019.60.87. PubMed DOI PMC

Touil H, Li R, Zuroff L, et al. Cross-talk between B cells, microglia and macrophages, and implications to central nervous system compartmentalized inflammation and progressive multiple sclerosis. eBioMedicine. 2023;96:104789. doi: 10.1016/j.ebiom.2023.104789. PubMed DOI PMC

Comi G, Bar-Or A, Lassmann H, et al. Role of B cells in multiple sclerosis and related disorders. Ann Neurol. 2021;89(1):13–23. doi: 10.1002/ana.25927. PubMed DOI PMC

Li R, Tang H, Burns JC, et al. BTK inhibition limits B-cell-T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy. Acta Neuropathol. 2022;143(4):505–521. doi: 10.1007/s00401-022-02411-w. PubMed DOI PMC

Pellerin K, Rubino SJ, Burns JC, et al. MOG autoantibodies trigger a tightly-controlled FcR and BTK-driven microglia proliferative response. Brain. 2021;144(8):2361–2374. doi: 10.1093/brain/awab231. PubMed DOI

Hopkins BT, Bame E, Bajrami B, et al. Discovery and preclinical characterization of BIIB091, a reversible, selective BTK inhibitor for the treatment of multiple sclerosis. J Med Chem. 2022;65(2):1206–1224. doi: 10.1021/acs.jmedchem.1c00926. PubMed DOI

Saez-Atienzar S, Masliah E. Cellular senescence and Alzheimer disease: the egg and the chicken scenario. Nat Rev Neurosci. 2020;21(8):433–444. doi: 10.1038/s41583-020-0325-z. PubMed DOI

Peters R. Ageing and the brain. Postgrad Med J. 2006;82(964):84–88. doi: 10.1136/pgmj.2005.036665. PubMed DOI PMC

Ekpenyong-Akiba AE, Poblocka M, Althubiti M, et al. Amelioration of age-related brain function decline by Bruton’s tyrosine kinase inhibition. Aging Cell. 2020;19(1):e13079. doi: 10.1111/acel.13079. PubMed DOI PMC

Mendez MF. The Relationship Between Anxiety and Alzheimer’s Disease. J Alzheimer’s Dis Rep. 2021;5(1):171. https://doi.org/10.3233/ADR-219003 https://doi.org/10.3233/ADR-210294 . PubMed DOI PMC

Limorenko G, Lashuel HA. Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies. Chem Soc Rev. 2022;51(2):513–565. doi: 10.1039/D1CS00127B. PubMed DOI

Schaff LR, Grommes C. Primary central nervous system lymphoma. Blood. 2022;140(9):971–979. doi: 10.1182/blood.2020008377. PubMed DOI PMC

Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011;470(7332):115–119. doi: 10.1038/nature09671. PubMed DOI PMC

Schaff LR, Grommes C. Update on novel therapeutics for primary CNS lymphoma. Cancers. 2021;13(21):5372. doi: 10.3390/cancers13215372. PubMed DOI PMC

Goldwirt L, Beccaria K, Ple A, et al. Ibrutinib brain distribution: a preclinical study. Cancer Chemother Pharmacol. 2018;81(4):783–789. doi: 10.1007/s00280-018-3546-3. PubMed DOI

Lionakis MS, Dunleavy K, Roschewski M, et al. Inhibition of B cell receptor signaling by Ibrutinib in primary CNS lymphoma. Cancer Cell. 2017;31(6):833–843.e5. doi: 10.1016/j.ccell.2017.04.012. PubMed DOI PMC

Zhai Y, Zhou X, Wang X. Novel insights into the biomarkers and therapies for primary central nervous system lymphoma. Ther Adv Med Oncol. 2022;14:175883592210937. doi: 10.1177/17588359221093745. PubMed DOI PMC

Grommes C, Pastore A, Palaskas N, et al. Ibrutinib unmasks critical role of bruton tyrosine kinase in primary CNS lymphoma. Cancer Discovery. 2017;7(9):1018–1029. doi: 10.1158/2159-8290.CD-17-0613. PubMed DOI PMC

Soussain C, Choquet S, Blonski M, et al. Ibrutinib monotherapy for relapse or refractory primary CNS lymphoma and primary vitreoretinal lymphoma: Final analysis of the phase II ‘proof-of-concept’ iLOC study by the Lymphoma study association (LYSA) and the French oculo-cerebral lymphoma (LOC) network. European Journal of Cancer. 2019;117:121–130. doi: 10.1016/j.ejca.2019.05.024. PubMed DOI

Grommes C, Tang SS, Wolfe J, et al. Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. Blood. 2019;133(5):436–445. doi: 10.1182/blood-2018-09-875732. PubMed DOI PMC

Houillier C, Chabrot CM, Moles-Moreau M-P, et al. Rituximab-Lenalidomide-Ibrutinib combination for relapsed/refractory primary CNS lymphoma: A Case Series of the LOC Network. Neurology. 2021;97(13):628–631. doi: 10.1212/WNL.0000000000012515. PubMed DOI

Munakata W, Tobinai K. Tirabrutinib hydrochloride for B-cell lymphomas. Drugs Today. 2021;57(4):277. doi: 10.1358/dot.2021.57.4.3264113. PubMed DOI

Okita Y, Kano-Fujiwara R, Nakatsuka S-I, et al. Histological verification of the treatment effect of tirabrutinib for relapsed/refractory primary central nervous system lymphoma. Exp Hematol Oncol. 2021;10(1):29. doi: 10.1186/s40164-021-00222-5. PubMed DOI PMC

Yang C, Cui Y, Ren X, et al. Orelabrutinib combined with Lenalidomide and immunochemotherapy for relapsed/refractory primary central nervous system lymphoma: a retrospective analysis of case series. Front Oncol. 2022;12:901797. doi: 10.3389/fonc.2022.901797. PubMed DOI PMC

Yu CG, Bondada V, Iqbal H, et al. Inhibition of Bruton Tyrosine Kinase Reduces Neuroimmune Cascade and Promotes Recovery after Spinal Cord Injury. Int J Mol Sci. 2021;23(1):355. doi: 10.3390/ijms23010355. PubMed DOI PMC

Liu Y, Huang Z, Zhang T-X, et al. Bruton’s tyrosine kinase-bearing B cells and microglia in neuromyelitis optica spectrum disorder. J Neuroinflammation. 2023;20(1):309. doi: 10.1186/s12974-023-02997-2. PubMed DOI PMC

Zheng C, Li W, Ali T, et al. Ibrutinib Delays ALS Installation and Increases Survival of SOD1G93A Mice by Modulating PI3K/mTOR/Akt Signaling. J Neuroimmune Pharmacol. 2023;18(3):383–396. doi: 10.1007/s11481-023-10068-9. PubMed DOI

Li K, Ran B, Wang Y, et al. PLCγ2 impacts microglia-related effectors revealing variants and pathways important in Alzheimer’s disease. Front Cell Dev Biol. 2022;10:999061. doi: 10.3389/fcell.2022.999061. PubMed DOI PMC

Vastrad B, Vastrad C. Screening of the key genes and signaling pathways for schizophrenia using bioinformatics and next generation sequencing data analysis [Internet] 2023. [cited 2024 Dec 20].Available from: http://biorxiv.org/lookup/doi/10.1101/2023.10.24.563759 https://doi.org/10.1101/2023.10.24.563759. DOI

Roussou IG, Papanikolopoulou K, Savakis C, et al. Drosophila Bruton’s tyrosine kinase regulates habituation latency and facilitation in distinct mushroom body neurons. J Neurosci. 2019;39(44):8730–8743. doi: 10.1523/JNEUROSCI.0633-19.2019. PubMed DOI PMC

Reich DS, Arnold DL, Vermersch P, et al. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2021;20(9):729–738. doi: 10.1016/S1474-4422(21)00237-4. PubMed DOI PMC

Mali AS, Novotny J. Opioid receptor activation suppresses the neuroinflammatory response by promoting microglial M2 polarization. Mol Cell Neurosci. 2022;121:103744. doi: 10.1016/j.mcn.2022.103744. PubMed DOI

Martin E, Aigrot M-S, Grenningloh R, et al. Bruton’s Tyrosine Kinase Inhibition Promotes Myelin Repair. Brain Plast. 2020;5(2):123–133. doi: 10.3233/BPL-200100. PubMed DOI PMC