Medicinal plants in traumatic brain injury: Neuroprotective mechanisms revisited

Traumatic brain injury (TBI) is the most prevalent health problem affecting all age groups, and leads to many secondary problems in other organs especially kidneys, gastrointestinal tract, and heart function. In this review, the search terms were TBI, fluid percussion injury, cold injury, weight drop impact acceleration injury, lateral fluid percussion, cortical impact injury, and blast injury. Studies with Actaea racemosa, Artemisia annua, Aframomum melegueta, Carthamus tinctorius, Cinnamomum zeylanicum, Crocus sativus, Cnidium monnieri, Curcuma longa, Gastrodia elata, Malva sylvestris, Da Chuanxiong Formula, Erigeron breviscapus, Panax ginseng, Salvia tomentosa, Satureja khuzistanica, Nigella sativa, Drynaria fortune, Dracaena cochinchinensis, Polygonum cuspidatum, Rosmarinus officinalis, Rheum tanguticum, Centella asiatica, and Curcuma zedoaria show a significant decrease in neuronal injury by different mechanisms such as increasing superoxide dismutase and catalase activities, suppressing nuclear factor kappa B (NF‐κB), interleukin 1 (IL‐1), glial fibrillary acidic protein, and IL‐6 expression. The aim of this study was to evaluate the neuroprotective effects of medicinal plants in central nervous system pathologies by reviewing the available literature.


| INTRODUCTION
One of the major causes of morbidity and mortality in both developed and developing countries is traumatic brain injury (TBI) especially people under the age of 45 years. TBI attributes to approximately 10 million deaths and/or hospitalizations annually. Biomechanical and neurochemical damage following TBI usually leads to deficits in behavioral, cognitive, neuropsychiatric, and physical functions. 1,2 Systemic insults of TBI include both hypoxia and hypotension mechanistically. In addition, acute cell death and delayed apoptosis have a relative contribution. Mechanisms of cell damage in TBI include free radical production, excitotoxicity, oxidative stress, inflammation, and apoptosis. Genetic factors are also associated with the pathophysiology of TBI. In addition, myelin and multifocal axonal abnormalities are also attributed to posttraumatic cognitive impairments. [3][4][5][6] Various aspects of human TBI have been studied in a variety of animal models over the decades to have a better understanding of pathophysiology and potential treatments. The models of TBI include cortical impact injury (CCI), fluid percussion injury (FPI), blast injury, and weight drop impact acceleration injury (WDIAI) ( Table 1). 7 Various traditional supplements and herbal medicine therapies for TBI have been developed recently. These include both crude extracts and isolated compounds from plants and have shown to exert neuroprotective effects due to their antioxidant and anti-inflammatory actions on nerve function. The medicinal plants included in this review are Aframomum melegueta (A. melegueta), Carthamus tinctorius (C. tinctorius), Cinnamomum zeylanicum (C. zeylanicum), Crocus sativus (C. sativus), Da Chuanxiong Formula (DCXF), Erigeron breviscapus (E. breviscapus), Panax ginseng (P. ginseng), Salvia tomentosa (S. tomentosa), Nigella sativa (N. sativa), Dracaena cochinchinensis (D. cochinchinensis), Polygonum cuspidatum (P. cuspidatum), Rosmarinus officinalis (R. officinalis), Centella asiatica (C. asiatica), and Curcuma zedoaria (C. zedoaria). To date, there are no reviews about the neuroprotective function of medicinal plants in TBI. In view of the increasing number of studies conducted in the recent years, we reviewed the literature to assess the potential neuroprotective role of herbal plants in TBI including active components, experimental methodologies, and mechanisms of action (Table 2).

| METHODS
Online literature resources were searched using search engines such as ISI Web of Knowledge, PubMed, Medline, Scopus, and Google Scholar from 1976 to August 2018 to identify studies, editorials, and reviews about the effect of medicinal plants on TBI and their possible mechanisms. We used appropriate keywords such as TBI, medicinal plants, FPI, cold injury (CI), CCI, lateral fluid percussion (LFP), WDIAI, and blast injury. All of T A B L E 1 The summary of TBI animal models 7

Animal model Description
Fluid percussion injury (FPI) models The fluid pressure pulse insult is caused by a pendulum striking the piston of a reservoir of fluid to the intact dura through a craniotomy, which is made either centrally around the midline, or laterally over the parietal bone, between bregma and lambda. Brief displacement and deformation of brain tissue produce following the percussion, and the severity of injury depends on the strength of the pressure pulse.
Cortical impact injury (CCI) model The exposed intact dura will be under effect of pneumatic or electromagnetic impact device to create a rigid impactor. This method can mimic cortical tissue loss, acute subdural hematoma, axonal injury, concussion, blood-brain barrier (BBB) dysfunction, and even coma.
Penetrating ballistic-like brain injury (PBBI) A temporary cavity in the brain is produced by transmission of projectiles with high energy and a leading shockwave. The projectile's anatomical path and degree of energy transfer can affect on the outcome in this model.

Weight drop models
After exposing the skull (with or without a craniotomy), a falling weight guided to it. Injury severity in these models can be altered by adjusting the mass of the weight and the height from which it falls. This model also divided to some subdivisions such as Feeney's weight drop model and Marmarou model. these keywords were searched for each of these plants and its constituents.

| Actaea racemosa
Actaea racemosa (A. racemosa), commonly called black cohosh, is a perennial rhizomatous forest herb with white to yellow flowers, belonging to the Ranunculaceae family. The chemical constituents of A. racemosa are caffeic acid, ferulic acid, phenylpropanoids, triterpenoids, cimigenol, and formononetin. 48 This plant has been shown to have several therapeutic effects including anti-inflammatory, 49 antioxidant, 50 antidepressant, 51 and immunomodulatory 52 effects. The effect of formononetin orally was evaluated for 7 days after the induction TBI by a WDIAI model in rat. There was a significant improvement in neurological severity score (NSS) and increased cortical neuronal numbers in Nissl-special and DAPI-labeled stains with formononetin. Formononetin also reduced the levels of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) and increased the IL-10 levels in serum and cerebral cortex. 8 In another study, intraperitoneal injection of formononetin for 5 days after the induction TBI by WDIAI rat model showed that formononetin improved NSS, reduced brain edema, and inhibited neuronal apoptosis. Additionally, formononetin upregulated the expression of microRNA-155 (miR-155) and heme oxygenase 1 (HO-1) and downregulated the expression of BACH1 in the brain tissue of TBI rats. 9

| Aframomum melegueta
A. melegueta, commonly known as grains of paradise, ossame, alligator pepper, melegueta pepper, efom wisa, Guinea grains, or Guinea pepper, is a flowering plant belonging to the family Zingiberaceae. It has been used traditionally in African folk medicine to treat several conditions including stomach ache, diarrhea, and hypertension, and is also used as purgative, galactagogue, anthelmintic, and hemostatic agents. 53 The main components of this plant include cardiac glycosides, alkaloids, sterols, tannins, triterpenes, flavonoids, and oils. 54 This plant also exhibits various pharmacological effects including antimicrobial, 55 antiulcer and cytoprotective, 56 antioxidant, 57 antidiabetic, 58 antifungal, 59 and antihypertensive 60 activities.
A. melegueta seeds possess significant anti-inflammatory and antinociceptive activity. The antinociceptive activity of this plant has been investigated using the Randall-Selitto paw pressure, formalin-induced paw edema, and hot plate models of nociception. This plant extract showed antiinflammatory effect with the formalin test and reduced response to nociceptive stimuli evoked by squeezing of the inflamed hind paw of rats. 61 A. melegueta seeds' ethanolic extract and pure compounds including 6-paradol, 6-shogaol, and 6-gingerol have been studied in vitro on pro-inflammatory gene expression and inflammatory enzymes such as lipoxygenases (LOX) and cyclooxygenase-2 (COX-2), and they are found to have anti-inflammatory effects. 62 Aqueous seed extract of A. melegueta (50-200 mg/kg, i.p.) has been investigated in vivo by formaldehyde and nystatin-induced subchronic inflammatory conditions in rats and is found to have anti-inflammatory effects. 63 The effect of the hydroethanolic extract of A. melegueta seeds on male rats was evaluated in an FPI model of TBI. Eleven days after injury, rats were sacrificed and their brains were collected for assessment of microglial activation. Immunohistochemical analysis of injured rat brain sections using an antibody to CD11b (a marker of activated microglia) showed that this extract reduced microglial activation in the rat cortex and hippocampus. It also showed that the administration of A. melegueta extract after injury reduced the number of Fluoro-Jade (a marker for neuronal injury) positive neurons in the CA1/2 and CA3 regions on the hippocampus of ipsilateral side. 10

| Allium sativum
Allium sativum (A. sativum), or garlic, is a bulbous plant belonging to the Amaryllidaceae family. In Ayurvedic medicine, this is used to treat respiratory conditions, dyspepsia, colic, and flatulence. 64 This plant is also shown to have antinociceptive, 65 anticonvulsant, 66 anti-inflammatory, immunomodulatory, 67 and antioxidant 68 properties.
The effect of allicin (an organosulfur compound obtained from garlic) on a CCI model of TBI showed that allicin reduced contusion volume and water content of brain, neurological deficit scores, Bcl-2/Bax ratio, malondialdehyde (MDA), protein carbonyl, TNFα, and IL-1β levels. It increased the activities of catalase (CAT), superoxide dismutase (SOD), and GST levels of IL-10 and transforming growth factor beta 1 (TGF-β1). It also activated Akt and endothelial nitric oxide synthase (eNOS) as well as inhibited the activation of caspase-3 and poly(ADP-ribose) polymerase (PARP). 69

| Artemisia annua
Artemisia annua (A. annua), or sweet wormwood, is an annual, aromatic herb, belonging to the Asteraceae family and has been used in China to treat fevers for centuries. 70 It is often used in the tropics as an affordable and effective antimalarial agent. 71 Leaves of A. annua have been used as antiseptic, digestive, and febrifuge. 72,73 A leaf infusion of this plant is used as a remedy for colds, fevers, and diarrhea. 73,74 The main ingredients of the essential oil of A. annua are beta-pinene, alphapinene, camphor, camphene, 1,8-cineole, artemisia ketone, myrcene, borneol, linalool, and beta-caryophyllene. 75 The pharmacological effects of A. annua include its antimalarial, 76 antioxidant, anti-inflammatory, antimicrobial, 77 immunomodulatory, 78 and anticancer 79 properties. A variety of compounds have been isolated from A. annua such as coumarins, flavonoids, sesquiterpenoids, triterpenoids, phenolics, and artemisinin. 80 The effect of atesunate, a more stable derivative of its precursor artemisin, on a CCI model of TBI showed that atesunate reduced tissue damage and inflammation in histological studies. Additionally, it reduced the expression of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), glial cell line-derived neurotrophic factor (GDNF), and inflammasome components (NLRP3, ASC, and caspase-1) as well as Il-1β, TNFα, and iNOS levels. 11 3.5 | Carthamus tinctorius C. tinctorius, also known as Safflower, is a thistle-like annual plant with yellow, orange, or red flowers, belonging to the Compositae or Asteraceae family, cultivated mainly for its seed, which is used as edible oil and as birdseed. Traditionally, the crop was grown for its flowers, used for coloring and flavoring foods and making dyes, and in medicines. 81 Several pharmacological effects have been described for C. tinctorius such as its anti-inflammatory, 82 cardioprotective, 83 antioxidant and neuroprotective, 84 and anticancer 85 properties. The standardized safflower flavonoid extract (SAFE) (35 and 70 mg/kg, p.o.) and the compounds isolated from safflower, including kaempferol 3-O-rutinoside (K3R), anhydrosafflor yellow B (AYB), (50, 100, and 200 μM), were evaluated for their neuroprotective effects in vitro and in vivo using Parkinson's disease (PD) models employing 6-hydroxydopamine (6-OHDA) lesioning in rats and rotenoneinduced damage to differentiated PC12 cells, respectively. The results showed that K3R and AYB inhibited microtubule destabilization and decreased cell area and SAFE improved behavioral performances, partially via the suppression of α-synuclein overexpression or aggregation, as well as the suppression of reactive astrogliosis. 86 However, some studies reported the toxic effects of C. tinctorius on renal and brain tissues. 87 C. tinctorius extract has been shown to reduce the cerebral infarction area and neurological deficits as well as expression of TNFα and IL-1β in ischemiareperfusion (I/R) brain injury in rats. 88 The effect of hydroxysafflor yellow A (HSYA), a constituent of the flower petals of Carthamus tinctorius, on a CCI model of TBI showed that HSYA increased the activities of SOD and CAT, the level of glutathione (GSH) and the GSH/glutathione disulfide (GSSG) ratio, and decreased the levels of MDA and GSSG. 12 3.6 | Cinnamomum zeylanicum C. zeylanicum is commonly known as cinnamon, belonging to the Lauraceae family. The major components of the essential oil of C. zeylanicum are trans-cinnamaldehyde, eugenol, and linalool. 89 C. zeylanicum is used as part of Ayurvedic medicine as a remedy for a variety of digestive, respiratory, and gynecological symptoms. 90 Various pharmacological effects of cinnamon have been reported including antibacterial, 91 antifungal, 92 antioxidant, 93 antidiabetic, 94 anti-inflammatory, 95 and immunomodulatory 96 effects. When administered orally in experimental allergic encephalomyelitis in mice, cinnamon powder suppressed the expression of iNOS and IL-1β in vivo in the spinal cord and cerebellum, suggesting anti-inflammatory effects. 97 In addition, cinnamon suppressed neuronal apoptosis, inhibition of glial activation, and reduced amyloid beta in the hippocampus and protected memory as well as learning in an animal model of Alzheimer disease. 98 In an animal model of Parkinson disease, it also protected the nigrostriatum, normalized striatal neurotransmitters, and improved motor functions. 99 The effect of cinnamon polyphenol extract on the CI model of TBI in mice showed that the extract reduced infarct and edema formation in the brain by suppressing the expression of nuclear factor kappa B (NF-κB), IL-1, IL-6, glial fibrillary acidic protein (GFAP), neuronal cell adhesion molecule (NCAM), and nuclear factor erythroid 2-related factor 2 (Nrf2) in brain. 13
Administration of osthole, a coumarin compound, isolated from C. monnieri intraperitoneally, 30 min before TBI, reduced neurological deficits, cerebral edema, and hippocampal neuron loss. It also increased SOD activity, GSH and MDA levels, the ratio of Bcl-2/Bax, the expression of active caspase-3, and the number of apoptotic cells in the WDIAI-induced TBI in rat. 14
In a rat model of stroke, administration of crocin during induction of ischemia showed protective effects against I/R injury and cerebral edema. It also decreased brain edema and infarct volume. 110 In addition, administration of crocin before TBI activated the notch signaling pathway by upregulation of notch intracellular domain and basic helix-loop-helix (bHLH) transcription factor 1 (HES1) mRNA. In CCI-induced TBI in mice, it also reduced microglial activation, cell apoptosis, and release of IL-1β and TNFα, as well as improved brain edema and NSS. 15 3.9 | Da Chuanxiong Formula DCXF in Chinese traditional medicine consists of two dried rhizomes of Ligusticum chuanxiong and Gastrodia elata (G. elata) at a ratio of 4:1 (w/w). 111 Studies have shown that DCXF possesses therapeutic effects on stroke, dementia, vertigo, and headache, and is mediated by improvement of blood vessel elasticity and cerebral blood supply, reduction of bloodbrain barrier (BBB) disruption, intracellular free calcium concentration, and edema formation. It also inhibits inflammation and nerve cell apoptosis. 112 In lipopolysaccharide (LPS)-incited RAW 264.7 cells, DCXF inhibited the productions of NO and PGE2 by suppressing COX-2 and iNOS expressions. 111 Treatment with DCXF aqueous extract 1 week before and 11 days after the induction TBI by a CCI model in rat improved the learning ability, memory retention, and proliferation of neural stem cells (NSCs). Results also showed that DCXF reduced activation of astrocytes and microglia, BBB permeability, brain edema, and neuronal loss in the brain with TBI. 16 3.10 | Erigeron breviscapus E. breviscapus known as "Dengzhanxixin," belonging to the Asteraceae family, is a plant species endemic to southwestern China. It has been used in traditional Chinese medicine for various conditions including digestive disorders, heart disease, cerebral infarction, and apoplexy. 113 The chemical constituents of E. breviscapus are flavonoids, triterpenes, caffeoyl derivatives, and steroids. 114 It has been shown to have antifungal, antimicrobial, 115 antioxidant, 116 and antiinflammatory 117 activities.
Injection of 75 μg breviscapine (a flavonoid extracted from E. breviscapus) via the right lateral ventricle after induction of TBI by CCI model remarkably improved NSS score and reduced expression of IL-6 in the injured cortex and IL-6-positive cell number in injured brain tissue. 17

| Gastrodia elata
G. elata is a saprophytic perennial herb from the Orchidaceae family. The dried rhizome of G. elata is used as a traditional Chinese medicine for remedy of neurological disorders such as Alzheimer, general paralysis, headache, convulsions, vertigo, stroke, and tetanus. 118 The main components with neuropharmacological properties are 4-hydroxybenzaldehyde, gastrodin, vanillin, and vanillyl alcohol. 119 It has been shown to have various pharmacological effects including antimicrobial, 120 antimutagenic, 121 antioxidative, 122 and anti-inflammatory 123 properties.
The effects of G. elata aqueous extract on the CCI model of TBI in rat showed that G. elata improved locomotor functions in the rotarod test and reduced the number of astrocytes in immunohistochemical staining and the expression of IL-6 and TNFα in the brain tissue. 18

| Malva sylvestris
Malva sylvestris (M. sylvestris), or common mallow, belongs to the Malvaceae family. The main components of M. sylvestris are polysaccharides malvin, flavonoids, scopoletin, coumarins, polyphenols, niacin, folic acid, tannins, and vitamins A, C, and E. 124 M. sylvestris is used as bacteriostatic, antinociceptive, anti-inflammatory, antioxidant, and anticholinesterase agent in Chinese medicine. 24 The preventive effect of M. sylvestris methanolic extract orally on TBI-induced CCI model in rat showed improved cognitive functions in the MVM test and reduced neuronal loss and GFAP-positive cells in hippocampus. Additionally, it also increased levels of SOD and decreased ROS production as well as lipidperoxides (LPO), IL-1β, IL-6, and TNFα levels in the brain tissue. 24 3.13 | Panax ginseng P. ginseng is a perennial herb from the Araliaceae family, native to Korea and China. Ginseng, the root of P. ginseng, has been traditionally used as an herbal remedy. 125 The main components of ginseng are ginseng oils, phytosterol, saponins, organic acids, nitrogenous substances, enzymes, vitamins, and minerals. 126 It has been shown to have antimicrobial, 127 antifungal, 128 antioxidant, 129 antiviral, 130 anti-inflammatory and antifatigue, 131 and anti-asthmatic activities. 132 Oral administration of ginsenoside Rb1, which is the main bioactive component in ginseng, significantly increased cell survival in the dentate gyrus and hippocampus, which could be potentially related to its effects on memory and learning. 133 In addition, ginsenoside Rg downregulated calpain I and caspase-3 and attenuated neuronal apoptosis induced by cerebral I/R injury. 134 Oral administration of P. ginseng aqueous extract on WDIAI model of TBI in rat improved its neurological functions. In addition, P. ginseng reduced the levels of MDA, nitrite, acetylcholinesterase (AChE), TNFα, and IL-6 and increased GSH, SOD, and CAT in hippocampus and cerebral cortex. 19 The major ingredient of P. ginseng, ginseng total saponins (GTS), is shown to have neuroprotective effects against TBI. GTS when administered intraperitoneally significantly reduced neuronal loss in the hippocampal regions of CA1, CA2, and CA3, contusion volume, and percentage of contusion, as well as improved neurological deficits on TBIinduced CCI model in rat. 20 In a similar study, assessment of the preventive effects of GTS on TBI-induced CCI model in rat showed that treatment with GTS after induction of TBI improved NSS score and reduced brain water content, neuronal loss in the hippocampus. This increased the activity of SOD; downregulated IL-1β, IL-6, and TNFα; and upregulated IL-10. This also inhibited the apoptotic cell death and expression of caspase-3, bax, and Bcl-2. 21 Similarly, the effect of administration of GTS on the CI model of TBI rats was shown to have improved recovery of neurological functions, including learning and memory and reduced cell loss in the hippocampus. 22 In another study, GTS improved NSS score, increased SOD activity, and reduced brain water content, MDA level, and expression of IL-1β and TNFα. 135 In addition, administration of GTS after induction of TBI improved neurological function and histological morphology of brain tissue in rats. 23

| Rheum tanguticum
Rheum tanguticum (R. tanguticum), also known as rhubarb in Chinese, belongs to the Polygonaceae family. Traditionally, the roots and rhizomes of R. tanguticum have been used as a poultice for their antispasmolytic, antineoplastic, antibacterial, and antipyretic properties and also to reduce obesity, lipid, and blood pressure. 136 The effect of rhubarb aqueous extract (3, 6, and 12 mg/kg, p.o.) was evaluated after the induction of TBI by CCI model in rat. Rhubarb significantly ameliorated brain edema and BBB injury and increased SOD, CAT activities, GSH level, and GSH/GSSG ratio. It also decreased the levels of MDA and GSSG. Rhubarb also prevented the gp91 phox subunit of NADPH oxidase activation-induced ROS production. Additionally, this inhibited ERK/MMP-9 pathway both in vivo and in vitro as well as downregulated GFAP in vitro. 25,26 Oral administration of polysaccharide extracted from R. tanguticum (RTP) for 5 days exhibited marked protective effects on oxidative stress and brain edema on the WDIAI model of TBI in rats by reduction of water content and MDA levels. This also resulted in the enhancement of SOD and Na+K+ATPase activity after injury. 27 3.15 | Salvia tomentosa S. tomentosa belongs to the Lamiaceae family. It has used in traditional Chinese medicine to manage various conditions including stomatitis, glossitis, gingivitis, pharyngitis, flatulent dyspepsia, galactorrhea, and hyperhidrosis. 137 The major components of the essential oil from S. tomentosa include β-pinene, α-pinene, trans-pinocarveol, myrtenol, caryophyllene oxide, and d-camphor. 138 The reported effects of this herb include antioxidant, 139 and antibacterial, 140,141 activities.
The effect of luteolin, which is a flavone, isolated from the aromatic flowering plant of S. tomentosa on the CCI model of TBI in mice showed that it significantly reduced levels of TNFα and IL-1β in blood and brain tissue of mice. 28

| Nigella sativa
N. sativa is a grassy plant from the Ranunculaceae family, which grows in cold and temperate climates. The seeds of N. sativa contain thymoquinone (TQ) and monoterpenes including p-cymene, a-pinene, 141 nigellidine, 142 nigellimine, 143 and a saponin. 144 The seeds have different pharmacological effects including anti-asthmatic, antidyspnea, 145 antinociceptive, antidiabetes, antihypertensive, 146 anti-inflammatory, immunomodulatory, 147 anticonvulsant, 148 anxiolytic, 149 and antinociceptive effects. 150 It has been shown that N. sativa improved neurological functions and reduced the infarct volume in middle cerebral artery-occluded rats. 151 Treatment with thymoquinone orally for 1 week after the induction TBI by WDIAI model in mice reduced lactate dehydrogenase (LDH) activity and plasma copeptin level in the brain tissue. 29 3.17 | Dracaena cochinchinensis D. cochinchinensis belongs to the Asparagaceae family and is widely cultivated in different provinces of China. The main components of D. cochinchinensis are flavonoids, terpenes, steroids, saponins, and phenols. 152 Resina Draconis (RD), which is a resin obtained from D. cochinchinensis, is a popular traditional Chinese medicine widely used for the management of various conditions including cerebral arterial thrombosis, ischemic heart disease, 153 and trauma and allergic dermatitis. 154,155 Several therapeutic effects of RD has been described including its antitumor, 156 antidiabetes, 157 analgesic, anti-inflammatory, 119 and immunomodulatory 158 activities.
Administration of RD aqueous extract intraperitoneally for 5 days after the induction TBI by WDIAI model in rat reduced the serum levels of MDA, IL-1β, TNFα, and IL-6. It also reduced the amount of neuronal cell apoptosis in brain tissue as well as increased the serum SOD activity. 159 3.18 | Polygonum cuspidatum P. cuspidatum also known as Hu Zhang in Chinese belongs to the Polygonaceae family. It has been used as a traditional Chinese medicine for the management of inflammatory conditions, infections, jaundice, skin burns, and hyperlipidemia. 30 The reported therapeutic effects include anti-inflammatory, 160 analgesic, antibacterial, antiviral analgesic, 161 immunomodulatory, 162 and anticancer 163 activities. The major compounds of P. cuspidatum are polydatin, resveratrol, torachryson-8-O-glucoside, and emodin. 164 The effect of oral administration of emodin after the induction TBI by WDIAI model in rat significantly ameliorated brain edema after TBI, improved NSS, and reduced BBB permeability. Emodin also inhibited the expression of aquaporins (AQPs), including AQP-1, AQP-4, and AQP-9, hypoxia-inducible factor-1α, and matrix metalloprotein-9. 165 Injection of resveratrol intraperitoneally after induction of TBI by WDIAI model remarkably improved NSS and reduced escape latency in MVM, brain edema, and levels of the autophagy marker proteins. 31

| Rosmarinus officinalis
R. officinalis, known as rosemary, belongs to the Lamiaceae family. It has been shown to have different therapeutic effects including antibacterial (Huhtanen), 166 168 and vascular smooth muscle relaxant properties (Aqel). 169 The main constituents of the essential oil of R. officinalis are gamma-terpinene, p-cymene, linalool, eucalyptol, thymol, alpha-pinene, and beta-pinene. 32 The neuroprotective effects of R. officinalis in the transient model of focal cerebral ischemia have shown to be related to its ability to decrease subcortical and cortical infarct volumes, NSS, cerebral edema, and BBB permeability. 170 Oral administration of R. officinalis after induction of TBI by LFP model reduced the latency to find platform and increased time spent in target quadrants in morris water maze (MWM). Additionally, it reduced neuronal degeneration and GFAP-positive cells. It also reduced the levels of TNFα, IL-1β, and IL-6 in hippocampus and increased activity of glutathione peroxidase (GPx), SOD, and CAT. 171 3.20 | Centella asiatica C. asiatica is a perennial plant belonging to the Umbelliferae family. 33 The main components of C. asiatica are saponins, brahmoside, brahminoside, glycosides isothankuniside and hankuniside, sterols, and flavonoids. 172 This plant has been shown to have several pharmacological effects including antiinflammatory, 173 wound healing, 174 sedative, anxiolytic, 175 antidepressant, 176 anticonvulsant, 177 and antioxidant 178 activities.
C. asiatica when administered orally improved memory and learning flexibility deficits and ameliorated neuronal damage in the dorsal hippocampus when mild chronic cerebral hypoperfusion was induced by right common carotid artery occlusion in rats. 179 It has also been shown that after the induction TBI by WDIAI model in rat, administration of C. asiatica hydroethanolic extract intraperitoneally increased the activation of Krox-20, the expression of neuregulin-1 (NRG-1), and the distribution of phospholipids and improved neurological functions. 180
The effect of curcumin when evaluated after the induction TBI by FPI model in rat showed that it improved the memory retention and learning ability in MVM test, reduced oxidative stress, and increased BDNF levels, as well as protected synaptic proteins and mitochondria. [186][187][188][189] Treatment with curcumin intraperitoneally before the induction TBI by WDIAI model in rat reduced the cerebral damage and brain levels of MDA. It also improved various neurological functions in the rotarod and inclined-plane tests. 42 In addition, administration of curcumin before TBI and 30 min after TBI reduced cerebral edema, AQP4 expression within the pericontusional cortex, NF-κB activation, and IL-1β expression. It also improved neurological functions in the rotarod and open-field tests in the CCI-induced TBI in mice. 190 In a similar study, assessing the preventive effect of curcumin after the induction TBI by WDIAI model in mice showed that curcumin reduced TNFα, MCP-1, IL-1β, IL-6, and RANTES (regulated upon activation, normal T cells expressed and secreted), TLR4 expression, and neuronal and apoptotic cell death. It also reduced microglial activation and improved NSS. 191 3.22 | Curcuma zedoaria C. zedoaria, known as zedoary and white turmeric, belongs to the Zingiberaceae family. The main ingredients of the essential oil of C. zedoaria are curzerenone, germacrone, curdione, 1,8-cineole, cumene, α-phellandrene, β-turmerone, β-elemene, 1,8-cineole, and zingiberene. 45 Different therapeutic effects include antipeptic ulcer, 192 anti-inflammatory, antinociceptive, 193 antioxidant, 194 and anticancer 195 properties.
The effect of curdione after the induction middle cerebral artery occlusion surgery by cerebral I/R model in rat showed that curdione reduced the NSS and infarct size. It also improved cognitive function and neuronal morphologic damage. In addition, it decreased MDA content and enhanced the activities of GSH-PX, CAT, and SOD. 196 Treatment with β-elemene after the induction TBI by WDIAI model in rat improved NSS, and reduced TNFα, IL-1β, apoptosis index, and expression of toll-like receptor (TLR4), and casepase-3. It also increased the expression of inhibitor of kB (IkB). 46

| Salvia miltiorrhiza
Salvia miltiorrhiza (S. miltiorrhiza), commonly known as red sage or Chinese sage belongs to the Lamiaceae family. It is used in traditional medicine for prevention and treatment of various cardiovascular diseases such as stroke and myocardial infarction. 197 The chemical composition of S. miltiorrhiza are tanshinone I, tanshinone IIA, salvianolic acid (or salvianolic acid B), and dihydrotanshinone. 47 Injection of salvianolic acid B (SalB) intraperitoneally after the induction of TBI by CCI model remarkably reduced brain water content, lesion volume, Iba-1 (an activated microglia marker), IL-1β, and TNFα. It also increased TGF-β1 and IL-10 as well as improved neurological function in wire-grip and MVM tests. 198

| Satureja khuzistanica
Satureja khuzistanica (S. khuzistanica) or jamzad is a herb belonging to the Lamiaceae family. The major constituents of S. khuzistanica are p-cymene, carvacrol, and γ-terpinene. 43 In folk medicine, S. khuzistanica is used as an analgesic and antiseptic. 44 Several therapeutic effects for saffron including antidiarrhea and antispasmodic, 199 antiinflammatory, antinociceptive, 200 and antioxidant 201 properties have been described.
It has been shown that after the induction TBI by WDIAI model in rat, administration of S. khuzistanica essential oil intraperitoneally ameliorated veterinary coma scale (VCS) scores, damage to BBB, and brain edema. There was a reduction in IL-6, IL-1β, and TNFα levels. There was also a reduction in intracranial pressure, BBB permeability, and neuronal death and an increase in IL-10 level and numbers of viable astrocytes in the treated groups. 202

| Scutellaria baicalensis
Scutellaria baicalensis (S. baicalensis) is a plant belonging to the Lamiaceae family. S. baicalensis has been used in traditional medicine for managing various inflammatory conditions, hypertension, and cardiovascular diseases. 203 Treatment with baicalin (a major bioactive compound of S. baicalensis) after the induction TBI by CCI model in rat reduced the number of degenerating neurons in fluoro-jade B (FJB) staining, contusion volume of brain, and mRNA and protein expression of IL-1β, IL-6, and TNFα. It also improved neurological functions in rotarod, tactile adhesive removal, and beam walk tests. 204

| Drynaria fortune
Drynaria fortune (D. fortune), or gu-sui-bu, is a fern of the Polypodiaceae family. D. fortune has been used in traditional medicine for the treatment of various bone conditions. 205 Effect of Rhizoma drynariae (R. drynariae) aqueous extract from the dried roots of D. fortune after the induction TBI by WDIAI model in rat showed that R. drynariae significantly reduced the level of CD8 T cells without affecting the levels of IL-2 and CD4 cells. 206 Administration of R. drynariae aqueous extract orally significantly reduced the brain lesion volume and blood levels of IL-6. It also ameliorated anxiety and depression-like behaviors, and improved cognitive function and NSS. In addition, in the CCI model of TBI in rats, blood monocyte numbers, IL-10, and the percentage of blood CD3 and CD4 T lymphocytes increased. This also inhibited macrophage and microglial activation. 207

| MOLECULAR MECHANISMS UNDERLYING THE NEUROPROTECTIVE EFFECTS ON TBI
It was shown that the therapeutic effects of medicinal plants on TBI are mainly mediated by anti-inflammatory, antioxidant, and immunomodulatory mechanisms. We have reviewed the main molecular mechanisms related to these effects in this section.
The protective effect of formononetin on neurobehavioral disorders after or before TBI may be associated with its inhibition of pro-inflammatory cytokines and oxidative stress as well as activation of Nrf2-dependent antioxidant pathways. 8,9 It has been shown hydroethanolic extract of A. melegueta on TBI normalized the genes that are implicated in the chemokine, cytokine, oxidative stress, and NF-κB signaling pathways induced by TBI. 10 Protective effect of allicin on TBI is potentially associated with its antioxidative and anti-inflammatory properties through the Akt/eNOS pathway. 69 The protective effects of artesunate in TBI also occur through inhibition of pro-inflammatory cytokines and apoptosis process by reducing the Bax expression and increasing Bcl2 expression, as well as modulation of various neurotrophic factors. 11 When the antioxidant effect of C. tinctorius was studied, it was shown that HSYA by reduction of oxidant markers and enhancement of antioxidant markers could be a potential neuroprotective medication in the cases of TBI. 12 In a CI model of TBI, it was shown that cinnamon could play an important role in reducing infarct and edema formation through modulation of Nfr2 and cytokine expression. This also reduces oxidative stress and could exert neuroprotective activity through these mechanisms. 13 The protective effect of osthole on TBI may be associated with its antiapoptotic and antioxidative activities. 14 Crocin has also shown to inhibit the production of proinflammatory cytokines and suppress notch signaling activation. 15 In a CCI model of TBI, it was shown that DCXF aqueous extract improved the proliferation of NSCs and reduced BBB damage as well as brain edema. This also alleviated the neuronal loss and improvement in neurological functions including learning, memory, and motor abilities mainly through inhibition of inflammation process. 16 The protective effect of breviscapine on neurobehavioral disorders after TBI may be associated with its mechanism of improving energy metabolism, free radical scavenging, inhibition of intracellular Ca 2+ , overload, excitatory amino acid toxicity, inflammatory suppression, regulation of brain blood vessel activity, and suppression of IL-6 expression. 17,208,209 The protective effect of G. elata on TBI could be associated with the reduction of pro-inflammatory cytokines, inflammation, and astrocytes' accumulation. 18 Treatment with M. sylvestris prevented neurodegeneration after TBI by reducing astrocytosis, pro-inflammatory cytokines, and oxidative stress in the brain tissue. 24 The potential therapeutic effects of P. ginseng could be due to inhibition of inflammatory mediators, reactive oxygen species (ROS) production, and microglial activation. 19 Ginsenosides have been shown to protect neurons from ischemic damage and rescue hippocampal neurons from ischemic damage by free radicals' scavenging. 20 GTS F I G U R E 1 Summary of neuroprotective mechanisms of medicinal plants against traumatic brain injury administration after TBI has been shown to reduce secondary injuries by reducing oxidative and nitrative stress as well as attenuating the expression of pro-inflammatory cytokines and apoptotic cell death. 21 The protective effect of GTS on neurobehavioral disorders after TBI was related to regulating the expression of nerve growth-related factors and improving neural stem/progenitor cells' proliferation. 22 The underlying mechanisms of GTS on TBI induced and modified Feeney's method could be potentially mediated through various mechanisms including reducing MDA level, expression of TNFα and IL-1β, generation of reactive oxygen species (ROS), and elevating the activity of SOD and inflammatory reactions. 135 R. tanguticum has been shown to have neuroprotective effects on TBI by inhibiting oxidative stress. [25][26][27] The potential mechanism for protective effects of luteolin could be due to the inhibition of the release of inflammatory cytokines. 28 The possible mechanisms of TQ on TBI are by improving the redox balance, abating the inflammatory cytokines, and restoring the balance between apoptotic and antiapoptotic factors. 29 Another study demonstrated the antioxidant and antiinflammatory effects of RD aqueous extract through its effects on SOD, MDA, IL-1β, TNFα, and IL-6 levels in TBI rat. 159 It has been shown that emodin attenuated brain edema and BBB disruption after TBI and mediated via inhibition of HIF-1α/AQPs and HIF-1α/MMP-9 pathways. 165 The protective effect of resveratrol was shown to have a protective effect on TBI by upregulation of postsynaptic density protein 95, synaptophysin, and by suppressing neuronal autophagy. 31 R. officinalis has shown to improve cognitive deficits in TBI by inhibiting inflammation and oxidative stress. 171 C. asiatica extract has been shown to have a neuroprotective effect on TBI potentially by activation of Krox-20 gene, thereby triggering the formation of new phospholipids in nerve cells. 180 The proposed mechanism of curcumin on TBI includes inhibition of pro-inflammatory cytokines, oxidative stress, and TLR4 and NF-κB pathways. 42,[186][187][188][189][190][191] β-elemene had a protective effect on TBI that is most likely mediated via reduction of caspase-3 enzyme activity and expression of TLR4 and inflammatory cytokines. 46 The neuroprotective effect of SalB against TBI was associated with its anti-inflammatory activities. 198 R. drynariae has been shown to have a protective role in TBI-induced brain damage, potentially mediated by its immune-promoting, antiinflammatory, and neuroprotective effects. 206,207 In a WDIAI model of TBI, S. khuzistanica has been shown to play a crucial role in reducing edema formation and infarct through its anti-inflammatory action and by reducing neuronal loss. 202 The neuroprotective effect of baicalin in TBI-induced brain injury could be potentially mediated via inhibition of pro-inflammatory cytokines. 204

| CONCLUSIONS
This review discussed the growing evidence on the protective effects and molecular mechanisms of medicinal plants and their constituents on TBI (Figure 1). Although these studies were mostly conducted in animal models of TBI, potentially similar effects could be expected in human TBI patients. This shows that natural compounds have great therapeutic potential for reducing neurodegeneration and improving functional outcomes in TBI patients. However, further studies are required to establish the clinical effects of medicinal plants and their extracts on TBI and their molecular mechanisms.