REVIEW ARTICLE Medicinal plants in traumatic brain injury: Neuroprotective mechanisms revisited Zakieh Keshavarzi 1,2† | Farzaneh Shakeri 1† | George E. Barreto 3,4 | Bahram Bibak 1,2 | Thozhukat Sathyapalan 5 | Amirhossein Sahebkar 6,7,8 1 Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran 2 Department of Physiology, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran 3 Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia 4 Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile 5 Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull HU3 2JZ, UK 6 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran 7 Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 8 School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran Correspondence Amirhossein Sahebkar, PharmD, PhD, Department of Medical Biotechnology, School of Medicine, Mashhad University of Abstract 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. KEYWORDS brain, medicinal plants, signaling mechanisms, TBI, trauma Abbreviations: AChE, Acetylcholinesterase; AE, Aqueous extract; AEE, Aqueous ethanolic extract; AQP-1, Aquaporin-1; BBB, Blood brain barrier; Bcl-2, B-cell lymphoma 2; BDNF, Brain-derived neurotrophic factor; BrdU, 5-Bromo-2 0 -deoxy-uridine; CAT, Catalase; CCI, Cortical impact injury; CI, Cold injury; Conc, Concentration; EO, Essential oil; Exp, Experimental; Ext, Extract; FPI, Fluid percussion injury; GDNF, Glial cell line-derived neurotrophic factor; GFAP, Glial fibrillary acidic protein; GPx, Glutathione Peroxidase; GSH, Glutathione; GSH/GSSG, Glutathione /Glutathione disulfide; GTS, Ginseng total saponins; HIF-1α, Hypoxia-inducible factor-1α; HO-1, heme oxygenase 1; HSYA, Hydroxysafflor yellow A; IkB, Inhibitor of kB; IL-1β, Interleukin-1β; LDH, Lactate dehydrogenase; LFP, Lateral fluid percussion; MDA, Malondialdehyde; miR-155, microRNA-155; MMP-9, Matrix metalloprotein-9; NCAM , Neural cell adhesion molecule; NF-κβ, Nuclear factor kappa B; NGF, nerve growth factor; NO, nitric oxide; Nogo-A, Neurite outgrowth inhibitor A; NOSs, Nitric oxide synthases; Nrf2, Nuclear factor erythroid 2-related factor 2; NRG-1, Neuregulin-1; NSCs, Neural stem/progenitor cells; NSS, Neurological severity score; RANTES, Regulated on activation normal T cell expressed and secreted; Ref, Reference; ROS, Reactive oxygen species; SalB, Salvianolic acid B; SOD, Superoxide dismutase; TBI, Traumatic brain injury; TGF-β1, Transforming growth factor beta 1; TN-C, Tenascin-C; TNF-α, Tumor necrosis factor-α; TLR4, Toll-like receptor4; TQ, Thymoquinone; TUNEL, Terminal deoxynucleotidyl transferase dUTP nick end labeling; VEGF, Vascular endothelial growth factor; WDIAI, Weight drop–impact acceleration injury. † Equally contributed as the 1 st author. Received: 27 March 2019 Accepted: 5 May 2019 DOI: 10.1002/biof.1516 © 2019 International Union of Biochemistry and Molecular Biology BioFactors. 2019;1–19. wileyonlinelibrary.com/journal/biof 1