Table 1.

Summary of the pathophysiology, therapeutic targets and potential therapies in traumatic brain injuries.

Pathophysiology	Therapeutic targets	Potential therapies	Clinical trials	Treatment efficacy
Excitotoxicity	Glutamate receptors, Ca2+ channels, calpains/caspases	Glutamate receptor antagonists HU211 (Dexanbionol; Nadler et al., 1993, 1995; Shohami et al., 1995), MK 801 (Goda et al., 2002; Imer et al., 2009), NBQX (Follett et al., 2000)	Dexanbionol: NCT00129857	Neuroprotective effect in experimental TBI but not efficacious in clinical trials (Maas et al., 2006)
		Ca2+ channel inhibitors (S)-emopamil (Okiyama et al., 1992, 1994), SNX-111 (Ziconotide; Samii et al., 1999) and SNX-185 (Lee et al., 2004; Shahlaie et al., 2009), Nimodipine (Veng et al., 2003), Nicarpine (Compton et al., 1990)
		Calpain/caspase inhibitors MDL 28170 (Kawamura et al., 2005), Z DEVD-fmk (Knoblach et al., 2004)
Mitochondrial dysfunction	ROS, mPTP components, cytochrome c	Neuroprotectants Cyclosporine A (Okonkwo and Povlishock, 1999; Sullivan et al., 1999)	NeuroSTAT: NCT01825044; EudraCT 2012-000756-34	Anti-oxidative effect reduces axonal damage and mitochondrial dysfunction in animal TBI. Phase IIa trial confirmed drug safety and BBB permeability (Kelsen et al., 2019)
Oxidative stress	ROS	Anti-inflammatory agents Methylprednisolone (Hall, 1992) Neuroprotectants Cyclosporine A (Turkoglu et al., 2010)	Methylprednisolone: ISRCTN74459797; NCT00004759	Anti-inflammatory and anti-oxidative effects. Early administration of methyl-prednisolone is associated with higher risk of death in patients with head injury (Thompson and Bakshi, 2005)
Neuroinflammation	Pro-inflammatory chemokines, complement factors	Anti-inflammatory agents Minocycline (Tikka and Koistinaho, 2001; Bye et al., 2007; Filipovic and Zecevic, 2008; Ng et al., 2012)	Minocycline: NCT01058395; NCT02802631	Anti-inflammatory and anti-apoptotic effects. Erythropoietin shows no beneficial effect in moderate or severe TBI patients (Nichol et al., 2015)
		Anti-apoptosis Erythropoietin (Yatsiv et al., 2005; Chen et al., 2007)	Erythropoietin: NCT00987454; NCT00313716
Axonal degeneration	Calpains, NOS	Glutamate receptor antagonists NBQX (Follett et al., 2000; Goda et al., 2002)		Anti-apoptotic, anti-inflammatory, neuroprotection
		Calpain inhibitors MDL 28170 (Buki et al., 2003; Ai et al., 2007; Czeiter et al., 2009)
		Anti-inflammatory agents Minocycline (Siopi et al., 2011)
		Neuroprotectants Cyclosporine A (Okonkwo and Povlishock, 1999; Okonkwo et al., 1999)
		Anti-apoptosis Erythropoietin (Yatsiv et al., 2005)
		Stem cells therapy Marrow stromal cells (Mahmood et al., 2004b), mesenchymal stem cells (Kim et al., 2009), fetal stem cells (Riess et al., 2002; Skardelly et al., 2011)
		Neurotrophic factors BDNF, NGF (Kromer, 1987; Dixon et al., 1997; Sinson et al., 1997), bFGF (Dietrich et al., 1996), EGF (Laskowski et al., 2005)
Apoptosis	Caspases, calpains, cytochrome c	Calpain/caspase inhibitors MDL 28170 (Kawamura et al., 2005; Thompson et al., 2010), Z DEVD-fmk (Clark et al., 2000; Knoblach et al., 2004)		Anti-apoptosis
		Anti-apoptosis Erythropoietin (Yatsiv et al., 2005; Liao et al., 2008)
		Stem cells therapy Mesenchymal stem cells (Kim et al., 2009)
Impaired autophagy-lysosomal pathway	mTOR	Rapamycin (Erlich et al., 2007; Zhang Y. B. et al., 2008), Luteolin (Xu et al., 2014)		Neuroprotection
Myelin-derived inhibitors	Nogo and NgR, MAG, OMgp, RhoA	Myelin inhibitors IN-1 antibody against Nogo-A (Yu et al., 2008), DNA vaccine against myelin inhibitors (Zhang et al., 2009)	IN-1 antibody: NCT03935321	Intrathecal administration of anti-Nogo-A to SCI patients is well-tolerated in phase I trial (Kucher et al., 2018)
		RhoA inhibitors C3 transferase (Tan et al., 2007; Höltje et al., 2009; Boato et al., 2010)	Cethrin (BA-210: NCT00500812; VX-210: NCT02669849)	Treatment of SCI patients with Cethrin is well-tolerated in phase I/IIa trial (McKerracher and Anderson, 2013)
Glial scar	CSPGs, tenascins, semaphorins	Glial scar Chondrotinase ABC (Bradbury et al., 2002; Barritt et al., 2006; Lin et al., 2008)		Chondrotinase ABC promotes axon outgrowth and regeneration in SCI animals
		RhoA inhibitor C3 transferase (Monnier et al., 2003)