Table 1.

Selected list of neurotherapeutics that have been evaluated for the treatment of brain injury in preclinical and clinical trials.

Drug Category (Neurotherapeutic)	Mechanism of Action/Outcome(s)
Hormone therapy (17β estradiol, E2)	• exerts neuroprotective effects via genomic mechanisms (delayed onset and prolonged duration via nuclear estrogen receptors) and non-genomic mechanisms (rapid onset and short duration via estrogen receptors in the plasma membrane resulting in the activation of signaling cascades such as kinase pathways—ERK/MAPK and PI3K/Akt, CREB, etc.) [207-209]; exerts neurotrophic effects [210] • regulates ion channels, second messengers, and kinase signaling pathways and reduces intracellular calcium overload to promote neuronal viability [207, 211] • promotes energy metabolism and mitochondrial function in metabolically compromised states to exert neuroprotection [212, 213] • attenuates glutamate-induced calcium overload in primary rat hippocampal neuron cultures [214] • attenuates abnormal excitation of neurons following perturbations in cerebral blood flow [215] • attenuates glutamate-induced calcium overload in primary rat hippocampal neuron cultures [214] and the accumulation of extracellular excitatory amino acids [216] • improves outcomes after cerebral ischemia and promotes cerebral blood flow recovery in experimental models [217-219]
Hormone therapy (estrogen sulfate, E2-SO4)	• exerts both genomic and non-genomic effects; increases cerebral perfusion pressure; stabilizes the blood-brain barrier; decreases neuronal degeneration, apoptosis, and reactive astrogliosis; edema and intracranial pressure; increases cerebral glycolysis in a rat TBI model [220]
Hormone therapy (progesterone)	• modulates excitotoxicity [160] • downregulates TBI-induced inflammation and cerebral edema [158, 160, 162, 221]; attenuates TBI-induced activation of the TLR/NF-κB signaling pathway to improve outcomes [222]; reconstitutes the blood-brain barrier [161] • clinical trials [153, 163, 223]
Tetracycline antibiotics (e.g., minocycline, doxycycline)	• exhibit anti-inflammatory and anti-apoptotic properties; reduce TBI-mediated tissue injury and caspase-1 activity; improve spatial memory and neurological outcome after TBI [224, 225]
Acetylcholinesterase Inhibitors (e.g., donepezil, rivastigmine, galantamine)	• increase synaptic acetylcholine by inhibiting acetylcholinesterase breakdown in the synapse; reduce edema and improve cognitive outcomes [3, 19]
Immunosuppressant Cyclosporin A	• maintains the mitochondrial membrane homeostasis by inhibiting the opening of the mitochondrial permeability transition pore; maintains calcium homeostasis [3, 5, 226, 227]
Erythropoietin	• attenuates glutamate toxicity; have anti-apoptotic, antioxidant, and anti-inflammatory effects; increases hematocrit level; stimulates neurogenesis [3]
ROCK Inhibitors (e.g., fasudil [HA-1077])	• reduce neuronal focal swelling after neuronal injury in vitro [114]; improves neurological functions after ischemia stroke, subarachnoid hemorrhage and other central nervous system disorders, observed in clinical trials [228-230]
Antioxidants (e.g., Cu/Zn SOD, PEG-SOD, tirilazad, dexanabinol)	• inhibit free radical-induced oxidative damage and lipid peroxidation and its effects in potentiating cellular injury [135, 136]
Antioxidant nanoparticles (e.g., ceria)	• reduces free radical damage, calcium dysregulation and neuronal death in vitro and in vivo [231, 232] • preserves the lifespan of mixed organotypic cultures of brain cells and pure neurons, while preserving normal calcium signaling during the extended lifespan [233, 234] • radical scavenging activity of ceria is regenerative under biological conditions permitting sustained activity [132, 233, 235-237]
Nootropics (e.g., BMY-21502, cerebrolysin, pyrrolidine derivatives)	• known to improve cognitive functions in rat TBI models [26, 132, 138]
Drug Category (Neurotherapeutic)	Mechanism of Action/Outcome(s)
Nutraceuticals (e.g., vitamins, creatine, nicotinamide, resveratrol, curcumin)	• nutritional agents/food supplements known to protect the brain [132, 238]
Gasotransmitters (e.g., NO therapeutics, molecular H2, H2S)	• these gases are synthesized endogenously and act as key modulators on intracellular pathways to exert certain regulatory functions such as vasoactivity, signal transmission and neurotransmitter release [132, 239, 240]; and antioxidant, anti-inflammatory and anti-apoptotic effects [241-243]. The role of NO seems debatable as it can act as both a signaling molecule and a neurotoxin [244]. In particular, NO derived from endothelial nitric oxide synthase (eNOS) is thought to possess neuroprotective properties whereas NO derived from inducible nitric oxide synthase (iNOS) appears to have neurotoxic properties [240]. Accordingly, iNOS inhibitors have been evaluated for their neuroprotective properties [245, 246].