Traumatic Brain Injury and Immunological Outcomes: the double-edged Killer

Figures & data

Table 1. Some promising targeted therapeutics, and approaches in TBI.

Pathways	Major targets	Promising therapeutics	Preclinical Effect	Ref.
Glutamatergic Pathways, neuroptosis, autophagy, lysosomal pathway, excitotoxicity pathway, GABAnergic pathway	NMDA receptor, neuronal synapse receptor, autophagy receptor, caspase enzyme	MK801, Ro25 6981, Memantine, 3-methyladenosine, Levetirecetam, Caspase-1 inhibitor	Prevent excitotoxicity, and neuronal death	[75–81]
RAGE pathway, BBB permeability, cytokine releasing pathway	HMGB-1, IL-6, intracranial pressure, sulphonylurea receptor	Anti-HMGB1 monoclonal antibody, ethylpyruvate, mannitol, glycyrohizin, barbiturates, glibenclamide	Reduce brain edema	[82–91]
Redox regulatory pathway, oxidative phosphorylation, electron transport chain, apoptotic pathway	MPTP, TIR-4, HMGB1, HMG-CoA reductase enzyme	Antioxidant as PEG-SOD enzyme, U83836E, edaravone, MPTP inhibitors, SS-31 peptides, Mito-Q, GS-nitroxide as redox regulators, rosuvastatin, dimethyl fumerate, glatiramer acetate as scavenger of cytotoxic molecules, low hanging fruit, neutraceuticals	Mitochondrial regulation, oxidative stress reduction, neuroprotection	[92–97]
Cytoskeleton stabilization, cytochrome P450 pathway, mitochondrial calcium channel pathway, Rho GTPase and kinase pathway	Chemical depolymerisation, membrane disruption, calpain, calcinurin, NO synthase, arachidonic acid metabolite formation, calcium overload	Depolymerization inhibitor Kollidon VA64, citicoline as calpain inhibitor, FK506, VAS203, inhaled NO as vasodilator, ET-1 antagonist, CsA, DNA Vaccine against myelin-derived axonal growth inhibitors	Traumatic axonal injury reduction	[98–102]
Dopaminergic pathway, neuroinflammatory pathway promoting astrogliosis	D2 receptor, dopamine transporter, neuronal transport	Perfluorocarbon-enhanced oxygen delivery, methylphenidate, dopaminergic drug amantidine, D2 receptor agonist as bromocriptine	Reduce inflammation, cerebral ischemia, cognitive enhancement	[103–105]
Cellular neuroprotective pathways, augmentation of endogenous pathways	VEGF, BDNF, NGF, bFGF, EGF	Stress regulation by RBM3 inhibition, exogenous bone marrow derived stem cells enhancing neurogenesis, bone marrow derived stromal cells, intracranial human bone marrow stromal cells in collagen scaffold, adipose-derived stem cells, neuroprotective agent P730-A20	Cellular therapies, neurotropic factor enhancement therapies	[106–109]
Cerebral blood flow, tissue perfusion, routed drug delivery	Augmented agent for blood flow	PNPH resuscitation solution, drag reducing polymers, colloid small molecules, albumin, vesicular delivery, small penetrating peptide based delivery, nanocarriers and osmotic pump based delivery	TBI resuscitation, tissue perfusions, ICP reduction, edema reduction, and better targeted drug delivery	[47,110–115]

BBB: Blood–brain barrier; ICP: Intracranial pressure; TBI: Traumatic brain injury.

Table 2. Ongoing clinical trials in TBI.

Conditions	Therapeutics/therapy	Trial phase	Clinical registry ID
Mild TBI	Hyperbaric oxygen therapy	III	NCT02089594
Lower limb or upper limb spasticity associated to TBI	NT 201 (botulinum toxin)	III	NCT03992404
Minor TBI	S100B protein	III	NCT03780062
TBI	Umbillical cord-derived MSC	I	NCT05018832
TBI	PNT001	I	NCT04677829
TBI	Autologous MSC	I, II	NCT04063215
Mild TBI	Exercise as concussion therapy	II	NCT04578743
TBI	Hyperbaric oxygen treatment	II	NCT02407028
Adult severe TBI	Antisecretory factor given as a food supplement	III	NCT03339505
Post TBI vasogenic pericontusional edema	Dexamethasone	III	NCT04303065
Severe TBI	Antisecretory factor (Salovum)	II	NCT04117672
TBI	Amantadine	IV	NCT04527289
TBI associated fatigue and cognitive impairment	Growth hormone therapy (Somatropin)	III	NCT03554265
TBI	Human C1 inhibitor (@Fter)	II	NCT04489160
Epileptic trauma in TBI	VPA	I	NCT02027987
Mild TBI	NeuroAiD II™ (MLC901)	III	NCT04861688
TBI-PTSD comorbidity	Cannabidiol	II	NCT04550377
TBI	Autologous stem cell therapy	II	NCT02525432
Concussion associated to TBI	Ghrelin (OXE-103)	II	NCT04558346
Mild adult TBI	Tranexamic acid	III	NCT04521881
Pediatric TBI	Nucleo CMP forte	III	NCT04499755
TBI	Dexmedetomidine	IV	NCT04006054
Pain, seizures, stress associated to chronic TBI	Cannabis	II	NCT03944447
Memory deficits associated to TBI	Donepezil	III	NCT02255799
TBI related pain	Ketamine adjunct therapy	IV	NCT05097261
Post pediatric TBI concussion syndrome, headache	Nortriptyline	IV	NCT04226365
TBI	Anodal transcranial direct current stimulation	II	NCT02849223
Un- consciousness related to TBI	Methylphenidate	I	NCT03814356
Adult upper limb spasticity related to TBI	IPN10200	I, II	NCT04752774
Alcohol use disorder and stress related to TBI	repetitive transcranial magnetic stimulation	II	NCT03995173
TBI	Aerobic exercise and rehabilitation	I	NCT03407924
TBI related headache	Prazosin hydrochloride	I, II	NCT02266329
Functional disability related to mild TBI	Magventure MagProX100 with MagOption stimulator and Magpro Cool Coil B65 A/P device	II	NCT04043442
Concussion related TBI in retired football players	Growth hormone therapy	II	NCT04121780
TBI	Biperiden Lactate	III	NCT01048138
Moderate to severe TBI	MLC901	IV	NCT04487275
Spasticity related to TBI	Rimabotulinum toxin B	II, III	NCT04099667
Moderate TBI	Dietary supplement: MLC901	IV	NCT04766281
TBI	Vegal nerve stimulation	IV	NCT04437498
TBI	Nitric oxide	III	NCT03260569
Post-concussion syndrome related to TBI	Adipose-derived stem cell infusion	I	NCT04744051
Mild to severe TBI	Beta blocker propranolol	IV	NCT04508244
Non-penetrating moderately severe TBI	Cytoflavin (inosine + nicotinamide + riboflavin + succinic acid)	III	NCT04631484
Thromboembolic issues related to TBI	Dalteparin	III	NCT03559114
Critically ill penetrating TBI	Epoetin alfa	III	NCT04588311

TBI: Traumatic brain injury.

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