Traumatic brain injury (TBI) is a generally serious public health and social problem. Traffic incidents, falls, violence, and sports injuries are the major causes. In China alone, TBI results in 50,000 deaths annually [1], while in the US, similar trends are observed [2]. The cost of TBI adds up to 400 billion dollars, accounting for 0.5% of the gross world product [3]. The classification of TBI can divide this disease into different conditions to help therapeutic interventions exert the best effect. The courses of TBI are divided into three periods: acute phase (within 3 days), subacute phase (3 days to 3 weeks), and chronic phase (over 3 weeks). The severity of TBI is classified based on Glasgow Coma Scale (GCS) into mild (GCS 13–15), moderate (9–12), and severe (3–8) [3]. The primary injury and secondary injury of TBI are complex due to their diverse pathological processes. Primary injury directly relates to the external force of the brain damaging normal brain structures. Macroscopic and microscopic changes as hemorrhage, extrinsic compression from hematoma, contusion, traumatic axonal injury (TAI), neuronal injury, microvascular thrombosis, and demyelination deteriorate the injury. The harmful effect induced by primary injury will not terminate in a short time [2] and also trigger the secondary injury [4]. The secondary injury involves multiple biological responses leading to further brain injury. The injured neuronal cells will release excitatory neurotransmitters and toxic cytokines that aggravate the mitochondrial damage and neuron necroptosis [2]. The dysregulated mitochondria induce excessive reactive oxygen species (ROS) and elevate intracellular calcium. The calcium activates enzymes involved in kinase cascades like receptor-interacting protein kinases (RIPKs) 1 and 3 activated by tumor necrosis factor (TNF) linked to the progress of necroptosis [5]. Not only the increasing inflammatory cytokines but also the activated astrocytes and microglia play an important role in the disruption of the blood-brain barrier (BBB) and further brain edema [6]. The assorted mechanisms of secondary injury link to the neuron’s death and symptoms as cognitive deficits in patients.

The current treatment measures include hyperventilation, prophylactic hypothermia, hyperosmolar therapy, barbital coma therapy, and surgery, which can inhibit the progression of the disease. The complicated pathology and BBB primarily limit the therapeutic effect of the present treatments [7]. Nowadays, many other existing methods intended to mediate the above mechanisms have been applied in the TBI treatment. The changes of kinases have a strong link to pathological responses. Kinase inhibitors that regulate the activity of changed kinase after TBI have shown great neuroprotection in preclinical research.

Kinases regulate many cellular signaling cascades involved in cell growth, differentiation, proliferation, metabolism, transcription, angiogenesis, and apoptosis. 518 protein kinases and nearly 20 lipid kinases have been observed in humans. There are over 250 kinases expressed in the human brain [8]. The eukaryotic protein kinase (ePK) domain, which contains the ATP and substrate binding sites, is the shared highly conversed domain in many protein kinases. The main structures of ePK are the N-terminal lobe (N-lobe), C-lobe, and a linker that separates the lobes and contains important residues binding to ATP. The serine, threonine, or tyrosine residue in protein kinases can be phosphorylated. In the active state, the activation loop Asp-Phe-Gly (DFG) motif located on the C-lobe is lengthened from the ATP-binding site. The phosphate-binding loop of the N-lobe binds a phosphate [9, 10]. Many activated kinases are involved in the pathology of TBI. Kinase inhibitors have been applied in the study of neurodegenerative diseases. Today, kinase inhibitors treating TBI in preclinical research show a superior therapeutic effect. In the following, we will discuss preclinical research of kinase inhibitors approved by the Food and Drug Administration (FDA) applied in TBI and explore the possibility of further application in clinical practice.

The changes of kinases induce more detrimental biological consequences than favorable results after injury. In acute TBI, activated protein kinase B (Akt/PKB) and PKC affect the normal neuronal function by reducing the expression of glutamate transporter-1 (GLT-1) that mainly in astrocytes which clears glutamate from the synapse to maintain the extracellular glutamate homeostasis [11]. Activated homeodomain interacting protein kinase 2 (HIPK2) participates in neuron apoptosis [12]. Src family kinases (SFK) in the early phase directly bind N-methyl-D-aspartic acid (NMDA) receptors and mediate brain edema. Nuclear factor kappa B (NF-κB) activation in the acute phase induces neuroinflammation through the elevation of interleukin (IL)-1β, IL-6, and TNF-α [13]. In the chronic course, upregulated death-associated protein kinase 1 (DAPK1) mediates a conformation-specific cis-phosphorylated form of tau induction which contributes to neurodegeneration [14]. Necroptosis mediated by activated RIPK1 and RIPK3 is mainly linked to chronic trauma brain damage [15]. Repetitive mild or moderate TBI is the underlying mechanism of chronic traumatic encephalopathy (CTE). The activation of c-Jun N-terminal kinase (JNK), Akt, extracellular signal-regulated protein kinase 1/2 (ERK1/2) [16], and glycogen synthase kinase-3β (GSK-3β) [17] are associated to the accumulation of p-tau that initiates the neurological deficits and cognitive impairment. Figure 1 shows the kinases linked to the increased p-tau in CTE.

In the mild TBI (mTBI), elevated GSK-3β may induce depressive behavior [18]. Activated dual leucine zipper kinase (DLK) is responsible for the death of layer V neurons [19]. Mesenchymal to epithelial transition factor (MET) activation promotes microglia activation and inflammatory cytokines release [20]. The distribution of spleen tyrosine kinase (SYK) is mainly consistent with microglia which may induce neuroinflammation [21]. Kinase alterations display different biological functions in moderate TBI. Increasing PTEN-induced putative kinase 1 (PINK-1) associates with mitochondrial dysfunction [22] after the injury. Activated PKA promotes tau hyperphosphorylation [23] and impairs autophagic flux with ERK2 [24] which results in harming recognition memory. Increased PKC disrupts the BBB integrity [25]. Activated Fyn, c-Src, Rho-associated coiled-coil-containing protein kinase (ROCK) influences hippocampal neuronal cell death linked to spatial memory loss [26]. Leucine-rich repeat kinase 2 (LRRK2) and ERK are involved in depression after moderate injury [27, 28]. Rho kinase degenerates nerve cells in moderate TBI [29]. The activated Janus kinase (JAK)/STAT pathway regulates γ-aminobutyric acid (GABA) type A receptor (GABA_AR) related to memory and vestibular motor dysfunction [30] in severe TBI. Activated JNK in injured axons accelerates p-tau [31]. Increasing NF-κB activated by MAPK is related to inflammation in the injured brain [32]. The change of kinases is vital for the development of TBI so that the kinase inhibitors targeted on specific mechanisms have enormous prospects in TBI therapy.

Many kinase inhibitors are often classified into two types: ATP-competitive and non-ATP-competitive. The high intracellular levels of ATP and the highly conversed ATP-binding site restrict the binding affinity of ATP competitive kinase inhibitors which hinders the expected selective effect. To overcome this limitation, researchers are exploring novel targets beyond the ATP-binding site to develop non-ATP-competitive inhibitors that may offer greater selectivity [9]. Protein kinases as targets have been researched for 40 years. In the 1990s, fasudil inhibiting ROCK1 and ROCK2 was approved in Japan and sirolimus reached the market in the US. Imatinib approved by the FDA in 2001 was the breakthrough in the kinase inhibitors research [33].

Many kinase inhibitors have been applied in cancer therapy but there are no FDA-approved inhibitors applied for the clinical treatment of TBI [34]. The mechanism of TBI is complex which involves many kinase pathways and needs more research to find the medicine that can exert the maximum effect. Recently, many preclinical studies have shown better prognosis of TBI animal models after the treatment of kinase inhibitors. Compared to the other various kinase inhibitors, sirolimus [35–40], dasatinib [15, 41–43], imatinib [44–46], pexidartinib [47, 48], ruxolitinib [13, 49], abrocitinib [50], sunitinib [50], and trametinib [51–53] have shown great application potential as attenuating inflammation, promoting prognosis, increasing neurons in the preclinical research.

Rapamycin (sirolimus) is an inhibitor of the mammalian target of rapamycin (mTOR), which was approved by FDA in 1999. mTOR is a rapamycin sensitive serine/threonine protein kinase involved in cellular homeostatic functions such as translation, transcription, and metabolism which is composed of mTOR complex 1 (mTORC1) and mTORC2 [36, 37]. Rapamycin binds to FKBP12 as a result that allosterically inhibits mTORC1. mTORC2 is not sensitive to rapamycin but prolonged treatment of rapamycin (> 12 h) may block mTORC2 assembly [36]. The downstream molecule toll-like receptor 4 (TLR4), activated by mTOR, mediates glial phagocytic activity and inflammatory cytokines production resulting in neuroinflammatory response and brain damage post-TBI [37]. Phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling pathway leads to neuroinflammation by increasing the expression of IL-1β and TNF-α [38]. Rapamycin can suppress the activation of nucleotide-binding domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome after TBI to block caspase-1 activation and reduce downstream inflammatory factors [39]. The neuroprotective effects of rapamycin extend beyond TBI, demonstrating potential therapeutic benefits in other neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s [40].

Dasatinib, approved by FDA in 2006, mainly inhibits Src, a kinase important to cell growth, cycle progression, development, and survival signaling pathways [41]. In TBI, oxidized delayed rectifier potassium (K⁺) channel KCNB1 can activate Src, leading to increased release of ROS [42]. Besides dasatinib, bosutinib and ponatinib are also Src inhibitors approved by FDA. RIPK1, RIPK3, and the downstream RIPK3-mediated phosphorylation of mixed lineage kinase domain-like protein (MLKL) involve in necroptosis. The neuroinflammation induced by RIPK connects with TBI. Emerging research indicates that dasatinib, foretinib, poziotinib, and pexmetinib can inhibit RIPK3 activity following TBI [15, 43].

Imatinib mainly inhibits platelet-derived growth factor receptor (PDGFR) related to Ras, MAPK, PI3K, Akt, PLCγ, and others [44, 45]. PDGF signaling pathway may compromise the integrity of BBB and lead to brain edema, neuroinflammation, neuronal death, and cognitive impairment [46]. Imatinib inhibits the activation of the cascade via binding to the ATP-binding pocket of the receptor [44]. Sunitinib, sorafenib, pazopanib, and nilotinib are also PDGFR inhibitors [45].

Pexidartinib (PLX3397) exhibits high selectivity for stem cell factor and colony stimulating factor 1 receptor (CSF1R) belonging to the PDGFR family. CSF1R required for the development, and survival of microglia, neurogenesis, and neuronal survival [47] binds to CSF1 and IL-34 which are highly expressed in the brain. Pexidartinib can attenuate neuroinflammation by eliminating the elevated CSF1R post-TBI through modulating microglial activity [48].

Ruxolitinib, the first selective inhibitor of JAK1 and JAK2 approved by FDA, demonstrates neuroprotective effects [49]. Abrocitinib, approved by FDA in 2022, promotes fluid percussion injury (FPI) mice recovery through JAK inhibition [13]. Sunitinib exhibits protection in TAI models by inhibiting DLK and leucine zipper kinase (LZK) in recent research [50]. Trametinib is the highly specific ATP non-competitive inhibitor of mitogen-activated protein kinase kinase (MEK), the essential component of the MAPK signaling cascade. Trametinib can mitigate the neuroinflammation and cognitive deficits associated with elevated MEK expression following TBI [51–53].

In addition to the mentioned drugs, other medicines also have the application prospect based on their preclinical research findings. Midostaurin has demonstrated the ability to attenuate neuroinflammation and improve functional outcomes after spinal cord injury (SCI) [54]. Retinal pathology after brain injury is mostly identical to retinal detachment (RD). AR-13503, the active metabolite netarsudil, which is a ROCK inhibitor, has shown protection in RD [55]. There is also clinical research to demonstrate the effect of kinase inhibitors.

The kinase inhibitors in clinical trauma research are less. Baricitinib, a JAK inhibitor, is being studied in a phase II trial (NCT06065046) for the treatment of moderate and severe traumatic intracerebral hemorrhage and contusions. Imatinib has been explored the clinical effects on cervical SCI (NCT02363361). Rapamycin may be an optional interference for posttraumatic stress disorder (NCT01449955).

According to our investigation by searching on PubMed and Web of Science, there have been preclinical studies of kinase inhibitors approved by FDA on TBI. We discuss these medicines based on their effect as follows.

The dosage of the mentioned medicine is different due to the reference content. The previous study is the main reference source. The appearances of post-injury are mainly identical to neurodegenerative diseases and the mechanism may be consistent. Researchers conducted the above experiments with reference to neurodegenerative diseases. The molecular mechanism research can provide the basic evidence for further research. The dose of pexidartinib is based on the associated mechanism experiment [75].

Unlike cancer therapy, the specific target kinase has not precisely been observed in TBI patients. The complex kinase cascades exert different influences in the early or late phase of disease. The mentioned kinases are not involved in just one pathway, as a result that diverse downstream kinases may induce converse biological results. Finding the most suitable target kinase in the development of TBI is a challenging problem. Multiple kinase inhibitors may need further research to confirm the most suitable one [34].

The highly selective BBB combined with protective efflux systems limits many xenobiotics penetrating into the brain parenchyma [76]. Imatinib showed effect in the brain cancer preclinical study but failed in clinical research due to poor brain intake to a certain extent [77]. Nowadays, only a small number of kinase inhibitors have been reported that are BBB permeable in neurodegenerative disease. Many companies have reformed kinase inhibitors with BBB penetration for which there may be higher medicine concentration in the lesion [78] to lessen the inhibition of BBB.

The safety and side effects of kinase inhibitors have been verified in cancer, autoimmune diseases, hematological disorders, and so on. The previous studies indicate that side effects such as gastrointestinal events, fluid retention, muscle cramps, fatigue, and hepatotoxicity may appear when patients are on long-time treatment of imatinib. Dasatinib may also cause pleural effusion, pulmonary hypertension, headache, and dyspnea [79]. Sunitinib has been proved to increase RGCs after TAI [50] but also relates to cognitive deficit, memory decrease, cortical and hippocampal neuronal degeneration, and hippocampal autophagic machinery in the normal experimental models [80]. The associated contents have not been fully confirmed in the nervous system diseases. TBI patients are in vulnerable condition. The clinical symptoms may be identical to the adverse events of these drugs. The clear classification between clinical appearance and adverse drug reaction needs more exploration. Further experiments are needed to avoid side effects in the treatment of kinase inhibitors.

The complex progression of TBI inhibits the excessive production of drug efficacy. Multiple target kinase inhibitors require more exploration to achieve better effects. Various drug delivery methods, such as biomaterials, have been used in many diseases. Improving the levels of kinase inhibitors in the injured brain tissue may promote the regeneration of neurons and alleviate neuroinflammation. The new delivery methods have been studied in many diseases, especially cancers. The novel ways which deliver medicine to brain tumors are the templates for TBI. Certain nanomaterials can be employed as a carrier for medicine [81]. The combination of kinase inhibitors and nanomaterial may have great prospects in clinical practice. Improving outcomes and avoiding untoward reactions meanwhile may be a considerable question. Further efficacy needs more studies to confirm. Compared to the current conservative treatment, the cost of kinase inhibitors is higher. The more clinical practice may help to determine the most affordable price.

Compared to their application in the acute phase, the use of kinase inhibitors in chronic and subacute TBI is less. More research is needed to determine the optimal timing and duration of administration. The kinase inhibitors mentioned in the research are mainly those approved by the FDA over 10 years ago. The newly confirmed drug that targets the same kinases can be considered for preclinical research.

The pathology of TBI is complex, involving many biological processes. Kinases link pathological changes together as they are involved in many cascades that are activated after the primary or secondary injury. The mentioned drugs such as sirolimus, dasatinib, imatinib, pexidartinib, ruxolitinib, abrocitinib, sunitinib, and trametinib have shown promise in preclinical models, and their translational application in clinical practice remains untested. Additionally, the variability in kinase pathways across TBI severities is complex. The most suitable kinase inhibitor needs more studies to find and confirm. The treatment with kinase inhibitors is supported by animal experiments, and more research is needed to test the medicine’s efficacy in humans.