The preclinical research of kinase inhibitors in traumatic brain injury (TBI)

DrugAuthor/dateInjury modelTreatmentPathological outcomeClinical outcome
SirolimusSong et al. [38], 2015WDI mice2 mg/kg, i.p. 30 min after TBINeurons↑, IL-1β and TNF-α↓, microglial activation↓The NSS score↓, the score in the grip test↑
Chen et al. [39], 2019WDI mice3 mg/kg, i.p. 3 h after TBINLRP3 inflammasome↓, mitochondrial dysfunction↓, cortical neuron↑, IL-1β↑, IL-18↓mNSS scores↓, brain edema↓
Jiang et al. [37], 2018CCI rats2 mg/kg, i.p. 1 h before TBITNF-α↑, IL-1β↑, IL-6↑mNSS score↑, brain edema↑
Nikolaeva et al. [71], 2016CCI mice1 mg/kg, i.p. 1h after TBIDamaged neurons↓, astrogliosis↓, C-side GFAP positive cells↓Latency time of MWM↑
Ding et al. [70], 2015WDI mice2 mg/kg, i.p. 30 min after TBINeurons↑, apoptosis index↓NSS score↓
Wang et al. [68], 2017WDI rats for daily 5 days3 mg/kg, i.p. 4 h after each WDIApoptosis↓, autophagy↑, mitophagy↑Footslips in the beam walking↓
Fan et al. [69], 2018cTBI miceDaily 0.5 mg/kg, i.p. at 1 h after cTBIThe infarct volume↓, glial scar↓, axon regeneration↑Footslips in the beam walking test↓
Daily 1.5 mg/kg, i.p. at 1 h after cTBIGFAP+ cell↓Latency in rotarod↑
Zhu et al. [35], 2014CHI mice4 μL 1.25 mmol/L or 12.5 mmol/L, ICV before CHI-12.5 mmol/L worsened the performance in the hidden platform and probe trials↓
Berdichevsky et al. [66], 2013Accelerated in vitro model of post-traumatic epilepsyAt 3 days in vitroLactate↓, LDH↓, axon sprouting in CA3 and DG↓, surviving CA3 and CA1 neurons↑, ictal event↓-
Guo et al. [64], 2013CCI mice6 mg/ kg, i.p. 1 h after TBI and continued once daily for 4 weeksNeuronal death in the hippocampus↓, seizure frequency↓-
Butler et al. [67], 2016CCI mice3 mg/kg, 20–30 min after injury and continued once dailysIPSC frequency↓, synaptic inhibition current↑, THIP-induced tonic current↑-
DasatinibSun et al. [43], 2024WDI mice5 mg/kg, i.p. right after WDIIL-6↓, RIPK3↓, necrosis↓-
Wang et al. [59], 2023CCI miceD 5 mg/kg + Q 50 mg/kg 1 month after CCI for 13 weeksIL-1β↓, IL-6↓, p16+ and p21+ astrocytes↓, p16+ and p21+ microglia↓, NeuN+ cell↑Defect in the Barnes maze test↓, depressive-like behavior in the Forced Swim↓
Yu et al. [42], 2016FPI mice25 mg/kg, i.p. 2 h after FPIPositive cells in the typical lesion↓Latency in the rotarod↑
Van Houcke et al. [72], 2023Stab-wound injury killifishD 5 mg/kg + Q 50 mg/kg, i.p.Progenitors↑, NGPs↑, mature neurons↑-
ImatinibSu et al. [46], 2015CCI mice200 mg/kg, p.o. 45 min after TBI twice daily for 5 daysBBB leakage↓, lesion size↓, edema↓, tissue loss↓Deficit in MWM↓, the performance in probe trial↑
Sakai et al. [60], 2021CCI mice200 mg/kg, p.o. 12 h and 2 h before CCI and twice daily for 4 days after CCIIba1 immunoreactivity↓, pilocarpine-induced seizure severity↓, pilocarpine-induced seizure interval↓-
PexidartinibWang et al. [61], 2020FPI mice290 mg/kg, p.o. for 21 days before FPI and continued after FPIMicroglia↓, infiltrated immune cells↓, apical dendritic spines↑, synaptic proteins↑, cell apoptosis↓, ER stress↓, neurite sprouting↑-
Wang et al. [47], 2022CCI mice290 mg/kg, p.o. 90 min after CCI for 5 days or 30 days5 days: CD68+ M/M↓, GFAP+ astrocytes↓, Iba1+ M/M↓, apoptosis marker Bax↓, Ki67 cells↓Weight↓, NSS↓
30 days: brain tissue loss↓, NeuN+ neurons↑ in male mice, gene of immune processes and phagocytosis in male↑NSS↑ in male, motor deficits in rotarod test↑ in female
RuxolitinibChen et al. [73], 2021CCI mice0.44 mg/kg, i.p. 30 min after TBICOX2↓, TfR1↓, GPX4↓, the shrinkage and hyperchromatic morphology of the Nissl bodies↑, degenerating cells↓, brain edema↓, iron-positive cells↓Motor dysfunction in the wire-grip test↓, latency in MWM↓, total distance in open field test↓
Peng et al. [49], 2023CCI mice0.44 mg/kg, i.p. 15 min or 6 h after TBILesion volume↓, caspase-1↓, caspase-3↓, caspase-8↓, IL-1β↓, neurodegeneration↓, maintain the homeostasis of cathepsin B (↑ in the early, ↓ in the following)Vestibulomotor dysfunction↓, latency in MWM↓, total distance in open field test↓
SunitinibWelsbie et al. [50], 2019IA mice60 mg/kg, i.p. 24 h and 4h before IA, immediately once and daily for 3 weeks after IARetinal ganglion cells↑-
TrametinibHuang et al. [51], 2020CCI mice1 mg/kg for 7 days after CCIOligo2-positive cells↑, myelin basic protein↑, myelin oligodendrocyte glycoprotein↑, IL-1β↓, CD86↓, TNF-α↓, NOS2↓, IL-12↓, GM-CSF↓, microglia↓Revisiting error time in eight-arm radial maze assay↓, latency in MWM↓, latency in rotarod assay↑
AbrocitinibLi et al. [13], 2022FPI mice10 mg/kgThe lesion size↓, hematoma↓, BBB integrity↑, cortical cerebral blood flow↑, neurons↑, apoptosis↓, neutrophils↓, microglia↓, M1 polarization↓, M2 polarization↑, IL-6↓, TNF-α↓, NF-κB↓, NLRP3↓, ASC↓, caspase-1↓, GSDMD↓, IL-1β↓, IL-18↓, pyroptosis↓mNSS score↓

↑: increase or promote; ↓: decrease or reduce; -: no relevant experiment. WDI: weight drop injury; IL: interleukin; TNF: tumor necrosis factor; NSS: neurological severity score; NLRP3: nucleotide-binding domain leucine-rich repeat and pyrin domain-containing protein 3; mNSS: modified NSS; CCI: controlled cortical impact; GFAP: glial fibrillary acidic protein; MWM: Morris water maze; cTBI: cryogenic TBI; ICV: intracerebroventricular; CHI: closed head injury; LDH: lactate dehydrogenase; CA: cornu ammonis; sIPSC: spontaneous inhibitory post-synaptic current; RIPK3: receptor-interacting protein kinase 3; D: dasatinib; Q: quercetin; FPI: fluid percussion injury; NGPs: non-glial progenitors; BBB: blood-brain barrier; Iba1: ionized calcium binding adapter molecule 1; ER: endoplasmic reticulum; M/M: microglia/macrophage; Bax: B-cell lymphoma 2-associated X protein; COX2: cyclooxygenase 2; GPX4: glutathione peroxidase 4; IA: impact acceleration; NF-κB: nuclear factor kappa B; i.p.: intraperitoneal; p.o.: oral; DG: dentate gyrus; NeuN: neuronal nuclear antigen