Table 2.

Treatment with modern drugs of entering clinical trials in animal models post-TBI

Multipotential modern treatment strategies	Models	Species	Sample size	Gender	Mode of action	Effects on post-TBI consequences
Corticosteroids [8-11]	CCI	Rat	36	Male	↓ the number of CD31+ cells and circulating EPCs	↓ neuronal cell loss and impaired neurofunction
	CCI	Rat	296	Male	↑ MR; ↓GR	↓apoptosis and cell loss, and impaired spatial memory
	CCI	Rat	Unknown	Male	↓ TGF-β1, IL-1β, TNF-α,↑ IL-10) ；↓ Bax, ↑Bcl-2	↓cavity size;↑neuronal cell survival and improved motor functional recovery
	CCI	Rat	24	Male	↓NeuN+ and apoptotic cells; ↓ activated microglia/infiltrated macrophages ; ↓ IL-1β, TGF-β1, TNF-α, and IFN-γ	↓lesion volume; ↑motor and cognitive function
Citicoline [23-25]	WDI	Rat	30	Male	↓S-100β and NES	↑nerval protection effect
	WDI	Rat	40	Male	↓S-100β and IL-6	↑brain functional recovery
	WDI	Rat	40	Male	↓neurological severity score, balance test;↑slanting board test	↑ the recovery of neural dysfunction
β-blockers [20, 21]	CCI	Mouse	64	Male	↓leukocyte rolling; ↑GNT	↓edema
	WDI	Mouse	100	Both sexes	↓p-tau	↓learning and memory deficit
Statins (atorvastatin, simvastatin, lovastatin) [28-30, 32]	WDI	Mouse	36	Male	↓TNF-α, IL-1β, TBK1,TLR4; ↓microglia activation	↓edema; ↓cognitive deficit
	WDI	Rat	18	Male	↓TNF-α, IL-1β, NF-κB, CD40	↓TBI-induced intestinal injury
	FPI	Rat	30	Male	↓ TLR4,NF-KB p65,p-IκB,cleaved Caspase-3, IL-6, TNF-α and IL-1β	↑neurological function
	FPI	Rat	32	Male	↓GRP78, P-PERK,P-eif2α, ATF6,Caspase12,CHOP, Nrf2 and Caspase3	↓edema; ↑neurological function
Tranexamic acid [39-42]	WDI	Mouse	60	Male	↓ MCP-1 , IL-6, TNF-α, p-tau and NSE; ↑ MIP-1α	↓ neuroinflammatory response
	CCI	Pig	20	Female	↓ p-tau and IL-1β	↑neurological function
	CCI	Mouse	Unknown	Male	↑immune activation at the 72 h, altere several myeloid and lymphoid cell populations	↑immune-modulatory properties
	CCI	Mouse	Unknown	Both sexes	↓ blood neutrophils in male mice 3 h post-TBI, ↑ monocyte subsets and dendritic cells	protective effects post-TBI but only in male mice
Erythropoietin [46-49]	WDI	Rat	15	Male	↑BDNF and SDF-1; ↓NSE	↑anti-inflammatory properties
	CCI	Rat	76	Unknown	↓NF-κB and GR; ↑GPX, SOD, GSH/GSSG and HIF-1α	↓apoptosis and cell loss
	WDI	Mouse	Unknown	Male	↓GFAP and S100; ↑MAPK, cAMP, CREB and NOR	↑memory response, hippocampal neuroprotection, and neurogenesis
	WDI	Rat	20	Male	↑AQP4, ↓GFAP	↓brain edema
Progesterone [13-17]	CCI	Rat	121	Both sexes	↑NOR, EAAT-3 and NaVβ3; ↓EPSCs,IPSCs, frequency and EPSC amplitude	↑motor and memory functional recovery
	CCI	Rat	36	Female	↓ICP;↑CPP	↓ cerebral edema; ↓learning and memory deficit
	WDI	Rat	48	Male	↓Bcl-2; ↑BAX	↑motor and cognitive function
	WDI	Rat	210	Female	↑SOCS-3, p-STAT-3, NFκB-P52, p-NFκB-P65 and p-IκBα	↓ brain edema
	WDI	Rat	Unknown	Female	↑NGF; ↓ IL6	↓ cerebral edema
Amantadine [54, 55]	CCI	Rat	60	Male	↓ the numbers of degenerating neurons	↓brain lesion; ↓learning and memory deficit
	WDI	Rat	Unknown	Male	↓ DNA fragmentation	↓ neuronal cell loss and impaired neurofunction
Caffeine [62-64]	FPI	Rat	180	Male	↓lethal apnea (an acute bolus of caffeine)	↑motor function
	WDI	Rat	56	Male	↑spine density in OFC, mPFC and NAc; ↓telomere length	↓motor and cognitive function
	WDI	Rat	64	Both sexes	↑Drd1, Drd2, Gfap, Dnmt3a and longer telomeres	↓anxiolytic-like behaviors

CCI controlled cortical impact, WDI weight drop injury, FPI fluid percussion injury, EPCs endothelial progenitor cells, MR mineralocorticoid receptor, GR glucocorticoid receptor, GNT garcia neurologic test, p-tau phosphorylated tau, NF-κB nuclear transcription factor-κB, IκB inhibitor of NF-κB, NSE neuron-specific enolase, GRP78 glucose-regulated protein 78, PERK proteinkinaseR—likeERkinase, eIF2α eukaryotic tanslation initiation factor 2α, ATF6 activating transcription factor, Caspase 3 cysteme aspartate specific protease 3, Caspase 12 cysteme aspartate specific protease 12, CHOP CAAT/enhancer binding protein homologous protein, Nrf2 nuclear factor (erythroidderived 2)-like 2, MCP-1 monocyte Chemoattractant Protein-1, MIP-1α macrophage inflammatory protein 1α, SDF-1 stromal cell-derived factor 1, GPx glutathione peroxidase, GSH reduced glutathione, GSSG oxidized glutathione, GR glutathione reductase, SOD superoxide dismutase, NOR novel object recognition, MAPK mitogen-activated protein kinase, cAMP cyclic adenosine monophosphate, AQP4 aquaporin 4, GFAP glial fibrillary acidic protein, EPSCs excitatory post-synaptic currents, IPSCs inhibitory post-synaptic currents, EAAT3 excitatory amino acid transporter 3, NaVβ3 β subunit of the voltage-gated sodium channel, ICP Intracranial pressure, CPP cerebral perfusion pressure, SOCS-3 suppressor of cytokine signaling-3, STAT-3 signal transducer and activator of transcription-3