Traumatic Brain Injuries: Pathophysiology and Potential Therapeutic Targets

Si Yun Ng, Alan Yiu Wah Lee, Si Yun Ng, Alan Yiu Wah Lee

Abstract

Traumatic brain injury (TBI) remains one of the leading causes of morbidity and mortality amongst civilians and military personnel globally. Despite advances in our knowledge of the complex pathophysiology of TBI, the underlying mechanisms are yet to be fully elucidated. While initial brain insult involves acute and irreversible primary damage to the parenchyma, the ensuing secondary brain injuries often progress slowly over months to years, hence providing a window for therapeutic interventions. To date, hallmark events during delayed secondary CNS damage include Wallerian degeneration of axons, mitochondrial dysfunction, excitotoxicity, oxidative stress and apoptotic cell death of neurons and glia. Extensive research has been directed to the identification of druggable targets associated with these processes. Furthermore, tremendous effort has been put forth to improve the bioavailability of therapeutics to CNS by devising strategies for efficient, specific and controlled delivery of bioactive agents to cellular targets. Here, we give an overview of the pathophysiology of TBI and the underlying molecular mechanisms, followed by an update on novel therapeutic targets and agents. Recent development of various approaches of drug delivery to the CNS is also discussed.

Keywords: CNS trauma; biopolymers; cell penetrating proteins; controlled drug release; neuronal regeneration; secondary injuries.

Copyright © 2019 Ng and Lee.

Figures

Figure 1
Figure 1
Schematic representation of pathophysiology of traumatic brain injury (TBI). BBB dysfunction caused by TBI insult allows transmigration of activated leukocytes into the injured brain parenchyma, which is facilitated by an upregulation of cell adhesion molecules. Activated leukocytes, microglia and astrocytes produce ROS and inflammatory molecules such as cytokines and chemokines that contribute to demyelination and disruption of axonal cytoskeleton, leading to axonal swelling and accumulation of transport proteins at the terminals, hence compromising neuronal activity. Progressive axonal damage results in neurodegeneration. In addition, astrogliosis at the lesion site causes glial scar formation, which creates a non-permissive environment that impedes axonal regeneration. On the other hand, excessive accumulation of glutamate and aspartate neurotransmitters in the synaptic space due to spillage from severed neurons, glutamate-induced aggravated release from pre-synaptic nerve terminals and impaired reuptake mechanisms in traumatic and ischemic brain activate NMDA and AMDA receptors located on post-synaptic membranes, which allow the influx of calcium ions. Together with the release of Ca2+ ions from intracellular store (ER), these events lead to the production of ROS and activation of calpains. As a result of mitochondrial dysfunction, molecules such as apoptosis-inducing factor (AIF) and cytochrome c are released into the cytosol. These cellular and molecular events including the interaction of Fas-Fas ligand ultimately lead to caspase-dependent and -independent neuronal cell death. BBB, blood-brain-barrier; ROS, reactive oxygen species; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-d-aspartate; ER, endoplasmic reticulum.

References

    1. Ahn M. J., Sherwood E. R., Prough D. S., Lin C. Y., Dewitt D. S. (2004). The effects of traumatic brain injury on cerebral blood flow and brain tissue nitric oxide levels and cytokine expression. J. Neurotrauma 10, 1431–1442. 10.1089/neu.2004.21.1431
    1. Ai J., Liu E., Wang J., Chen Y., Yu J., Baker A. J. (2007). Calpain inhibitor MDL-28170 reduces the functional and structural deterioration of corpus callosum following fluid percussion injury. J. Neurotrauma 24, 960–978. 10.1089/neu.2006.0224
    1. Aktories K., Wilde C., Vogelsgesang M. (2005). Rho-modifying C3-like ADP-ribosyltransferases. Rev. Physiol. Biochem. Pharmacol. 152, 1–22. 10.1007/s10254-004-0034-4
    1. Alessandri B., Rice A. C., Levasseur J., Deford M., Hamm R. J., Bullock M. R. (2002). Cyclosporin A improves brain tissue oxygen consumption and learning/memory performance after lateral fluid percussion injury in rats. J. Neurotrauma 19, 829–841. 10.1089/08977150260190429
    1. Alvarez-Erviti L., Seow Y., Yin H., Betts C., Lakhal S., Wood M. J. (2011). Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 29, 341–345. 10.1038/nbt.1807
    1. Anderson J. M., Shive M. S. (1997). Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv. Drug Deliv. Rev. 28, 5–24. 10.1016/s0169-409x(97)00048-3
    1. Andriessen T. M., Jacobs B., Vos P. E. (2010). Clinical characteristics and pathophysiological mechanisms of focal and diffuse traumatic brain injury. J. Cell. Mol. Med. 14, 2381–2392. 10.1111/j.1582-4934.2010.01164.x
    1. Ansari M. A., Roberts K. N., Scheff S. W. (2008a). Oxidative stress and modification of synaptic proteins in hippocampus after traumatic brain injury. Free Radic. Biol. Med. 45, 443–452. 10.1016/j.freeradbiomed.2008.04.038
    1. Ansari M. A., Roberts K. N., Scheff S. W. (2008b). A time course of contusion-induced oxidative stress and synaptic proteins in cortex in a rat model of TBI. J. Neurotrauma 25, 513–526. 10.1089/neu.2007.0451
    1. Antoniou X., Borsello T. (2010). Cell permeable peptides: a promising tool to deliver neuroprotective agents in the brain. Pharmaceuticals 3, 379–392. 10.3390/ph3020379
    1. Asher R. A., Morgenstern D. A., Fidler P. S., Adcock K. H., Oohira A., Braistead J. E., et al. . (2000). Neurocan is upregulated in injured brain and in cytokine-treated astrocytes. J. Neurosci. 20, 2427–2438. 10.1523/jneurosci.20-07-02427.2000
    1. Asher R. A., Morgenstern D. A., Moon L. D. F., Fawcett J. W., Castellano Lopez B. M. N.-S. (2001). Chondroitin sulphate proteoglycans: inhibitory components of the glial scar. Prog. Brain Res. 132, 611–619. 10.1016/s0079-6123(01)32106-4
    1. Asher R. A., Morgenstern D. A., Shearer M. C., Adcock K. H., Pesheva P., Fawcett J. W. (2002). Versican is upregulated in CNS injury and is a product of oligodendrocyte lineage cells. J. Neurosci. 22, 2225–2236. 10.1523/jneurosci.22-06-02225.2002
    1. Au A. K., Aneja R. K., Bayir H., Bell M. J., Janesko-Feldman K., Kochanek P. M., et al. . (2017). Autophagy biomarkers beclin 1 and p62 are increased in cerebrospinal fluid after traumatic brain injury. Neurocrit. Care 26, 348–355. 10.1007/s12028-016-0351-x
    1. Bailey I., Bell A., Gray J., Gullan R., Heiskanan O., Marks P. V., et al. . (1991). A trial of the effect of nimodipine on outcome after head injury. Acta Neurochir. 110, 97–105. 10.1007/bf01400674
    1. Bales J. W., Ma X., Yan H. Q., Jenkins L. W., Dixon C. E. (2009). Expression of protein phosphatase 2B (calcineurin) subunit a isoforms in rat hippocampus after traumatic brain injury. J. Neurotrauma 27, 109–120. 10.1089/neu.2009.1072
    1. Barritt A. W., Davies M., Marchand F., Hartley R., Grist J., Yip P., et al. . (2006). Chondroitinase ABC promotes sprouting of intact and injured spinal systems after spinal cord injury. J. Neurosci. 26, 10856–10867. 10.1523/jneurosci.2980-06.2006
    1. Bazarian J. J., Cernak I., Noble-Haeusslein L., Potolicchio S., Temkin N. (2009). Long-term neurologic outcomes after traumatic brain injury. J. Head Trauma Rehabil. 24, 439–451. 10.1097/htr.0b013e3181c15600
    1. Beer R., Franz G., Srinivasan A., Hayes R. L., Pike B. R., Newcomb J. K., et al. . (2000). Temporal profile and cell subtype distribution of activated caspase-3 following experimental traumatic brain injury. J. Neurochem. 75, 1264–1273. 10.1046/j.1471-4159.2000.0751264.x
    1. Berman R. F., Verweij B. H., Muizelaar J. P. (2000). Neurobehavioral protection by the neuronal calcium channel blocker Ziconotide in a model of traumatic diffuse brain injury in rats. J. Neurosurg. 93, 821–828. 10.3171/jns.2000.93.5.0821
    1. Black K. L., Hanks R. A., Wood D. L., Zafonte R. D., Cullen N., Cifu D. X., et al. . (2002). Blunt versus penetrating violent traumatic brain injury: frequency and factors associated with secondary conditions and complications. J. Head Trauma Rehabil. 17, 489–496. 10.1097/00001199-200212000-00001
    1. Blaha G. R., Raghupathi R., Saatman K. E., Mcintosh T. K. (2000). Brain-derived neurotrophic factor administration after traumatic brain injury in the rat does not protect against behavioral of histological deficits. Neuroscience 99, 483–493. 10.1016/s0306-4522(00)00214-1
    1. Boato F., Hendrix S., Huelsenbeck S. C., Hofmann F., Grosse G., Djalali S., et al. . (2010). C3 peptide enhances recovery from spinal cord injury by improved regenerative growth of descending fiber tracts. J. Cell Sci. 123, 1652–1662. 10.1242/jcs.066050
    1. Brabeck C., Beschorner R., Conrad S., Mittelbronn M., Bekure K., Meyermann R., et al. . (2004). Lesional expression of RhoA and RhoB following traumatic brain injury in humans. J. Neurotrauma 21, 697–706. 10.1089/0897715041269597
    1. Bradbury E. J., Moon L. D. F., Popat R. J., King V. R., Bennett G. S., Patel P. N., et al. . (2002). Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 636–640. 10.1038/416636a
    1. Brines M. L., Ghezzi P., Keenan S., Agnello D., De Lanerolle N. C., Cerami C., et al. . (2000). Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc. Natl. Acad. Sci. U S A 97, 10526–10531. 10.1073/pnas.97.19.10526
    1. Bruns J., Jr., Hauser W. A. (2003). The epidemiology of traumatic brain injury: a review. Epilepsia 44, 2–10. 10.1046/j.1528-1157.44.s10.3.x
    1. Brustovetsky T., Bolshakov A., Brustovetsky N. (2010). Calpain activation and Na+/Ca2+ exchanger degradation occur downstream of calcium deregulation in hippocampal neurons exposed to excitotoxic glutamate. J. Neurosci. Res. 88, 1317–1328. 10.1002/jnr.22295
    1. Buki A., Farkas O., Doczi T., Povlishock J. T. (2003). Preinjury administration of the calpain inhibitor MDL-28170 attenuates traumatically induced axonal injury. J. Neurotrauma 20, 261–268. 10.1089/089771503321532842
    1. Büki A., Povlishock J. T. (2006). All roads lead to disconnection? Traumatic axonal injury revisited. Acta Neurochir. 148, 181–194. 10.1007/s00701-005-0674-4
    1. Burke M. A., Mobley W. C., Cho J., Wiegand S. J., Lindsay R. M., Mufson E. J., et al. . (1994). Loss of developing cholinergic basal forebrain neurons following excitotoxic lesions of the hippocampus: rescue by neurotrophins. Exp. Neurol. 130, 178–195. 10.1006/exnr.1994.1197
    1. Buttram S. D., Wisniewski S. R., Jackson E. K., Adelson P. D., Feldman K., Bayir H., et al. . (2007). Multiplex assessment of cytokine and chemokine levels in cerebrospinal fluid following severe pediatric traumatic brain injury: effects of moderate hypothermia. J. Neurotrauma 24, 1707–1718. 10.1089/neu.2007.0349
    1. Bye N., Carron S., Han X., Agyapomaa D., Ng S. Y., Yan E., et al. . (2011). Neurogenesis and glial proliferation are stimulated following diffuse traumatic brain injury in adult rats. J. Neurosci. Res. 89, 986–1000. 10.1002/jnr.22635
    1. Bye N., Habgood M. D., Callaway J. K., Malakooti N., Potter A., Kossmann T., et al. . (2007). Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration. Exp. Neurol. 204, 220–233. 10.1016/j.expneurol.2006.10.013
    1. Cafferty W. B., Yang S. H., Duffy P. J., Li S., Strittmatter S. M. (2007). Functional axonal regeneration through astrocytic scar genetically modified to digest chondroitin sulfate proteoglycans. J. Neurosci. 27, 2176–2185. 10.1523/JNEUROSCI.5176-06.2007
    1. Carlos T. M., Clark R. S., Franicola-Higgins D., Schiding J. K., Kochanek P. M. (1997). Expression of endothelial adhesion molecules and recruitment of neutrophils after traumatic brain injury in rats. J. Leukoc. Biol. 61, 279–285. 10.1002/jlb.61.3.279
    1. Cernak I., Noble-Haeusslein L. J. (2009). Traumatic brain injury: an overview of pathobiology with emphasis on military populations. J. Cereb. Blood Flow Metab. 30, 255–266. 10.1038/jcbfm.2009.203
    1. Chamoun R., Suki D., Gopinath S. P., Goodman J. C., Robertson C. (2010). Role of extracellular glutamate measured by cerebral microdialysis in severe traumatic brain injury. J. Neurosurg. 113, 564–570. 10.3171/2009.12.jns09689
    1. Chau C. H., Shum D. K., Li H., Pei J., Lui Y. Y., Wirthlin L., et al. . (2004). Chondroitinase ABC enhances axonal regrowth through Schwann cell-seeded guidance channels after spinal cord injury. FASEB J. 18, 194–196. 10.1096/fj.03-0196fje
    1. Chaudhry N., Filbin M. T. (2006). Myelin-associated inhibitory signaling and strategies to overcome inhibition. J. Cereb. Blood Flow Metab. 27, 1096–1107. 10.1038/sj.jcbfm.9600407
    1. Chen X., Katakowski M., Li Y., Lu D., Wang L., Zhang L., et al. . (2002). Human bone marrow stromal cell cultures conditioned by traumatic brain tissue extracts: growth factor production. J. Neurosci. Res. 69, 687–691. 10.1002/jnr.10334
    1. Chen G., Shi J. X., Hang C. H., Xie W., Liu J., Liu X. (2007). Inhibitory effect on cerebral inflammatory agents that accompany traumatic brain injury in a rat model: a potential neuroprotective mechanism of recombinant human erythropoietin (rhEPO). Neurosci. Lett. 425, 177–182. 10.1016/j.neulet.2007.08.022
    1. Chen X., Zhang B., Chai Y., Dong B., Lei P., Jiang R., et al. . (2011). Methylprednisolone exacerbates acute critical illness-related corticosteroid insufficiency associated with traumatic brain injury in rats. Brain Res. 1382, 298–307. 10.1016/j.brainres.2011.01.045
    1. Chen X., Zhang K., Yang S., Dong J., Zhang J. (2009). Glucocorticoids aggravate retrograde memory deficiency associated with traumatic brain injury in rats. J. Neurotrauma 26, 253–260. 10.1089/neu.2007.0504
    1. Cherian L., Goodman J. C., Robertson C. (2007). Neuroprotection with erythropoietin administration following controlled cortical impact injury in rats. J. Pharmacol. Exp. Ther. 322, 789–794. 10.1124/jpet.107.119628
    1. Chiaretti A., Antonelli A., Mastrangelo A., Pezzotti P., Tortorolo L., Tosi F., et al. . (2008). Interleukin-6 and nerve growth factor upregulation correlates with improved outcome in children with severe traumatic brain injury. J. Neurotrauma 25, 225–234. 10.1089/neu.2007.0405
    1. Chiaretti A., Barone G., Riccardi R., Antonelli A., Pezzotti P., Genovese O., et al. . (2009). NGF, DCX and NSE upregulation correlates with severity and outcome of head trauma in children. Neurology 72, 609–616. 10.1212/01.wnl.0000342462.51073.06
    1. Choi Y., Kim H. S., Shin K. Y., Kim E. M., Kim M., Kim H. S., et al. . (2007). Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer’s disease models. Neuropsychopharmacology 32, 2393–2404. 10.1038/sj.npp.1301377
    1. Chopp M., Zhang Z. G. (2015). Emerging potential of exosomes and noncoding microRNAs for the treatment of neurological injury/diseases. Expert Opin. Emerg. Drugs 20, 523–526. 10.1517/14728214.2015.1061993
    1. Clark R. S., Bayir H., Chu C. T., Alber S. M., Kochanek P. M., Watkins S. C. (2008). Autophagy is increased in mice after traumatic brain injury and is detectable in human brain after trauma and critical illness. Autophagy 4, 88–90. 10.4161/auto.5173
    1. Clark R. S., Kochanek P. M., Chen M., Watkins S. C., Marion D. W., Chen J., et al. . (1999). Increases in Bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury. FASEB J. 13, 813–821. 10.1096/fasebj.13.8.813
    1. Clark R. S., Kochanek P. M., Watkins S. C., Chen M., Dixon C. E., Seidberg N. A., et al. . (2000). Caspase-3 mediated neuronal death after traumatic brain injury in rats. J. Neurochem. 74, 740–753. 10.1046/j.1471-4159.2000.740740.x
    1. Compton J. S., Lee T., Jones N. R., Waddell G., Teddy P. J. (1990). A double blind placebo controlled trial of the calcium entry blocking drug, nicardipine, in the treatment of vasospasm following severe head injury. Br. J. Neurosurg. 4, 9–15. 10.3109/02688699009000676
    1. Cox C. S., Baumgartner J. E., Harting M. T., Worth L. L., Walker P. A., Shah S. K., et al. . (2011). Autologous bone marrow mononuclear cell therapy for severe traumatic brain injury in children. Neurosurgery 68, 588–600. 10.1227/NEU.0b013e318207734c
    1. Czeiter E., Büki A., Bukovics P., Farkas O., Pál J., Kövesdi E., et al. . (2009). Calpain inhibition reduces axolemmal leakage in traumatic axonal injury. Molecules 14, 5115–5123. 10.3390/molecules14125115
    1. Das M., Mayilsamy K., Mohapatra S. S., Mohapatra S. (2019). Mesenchymal stem cell therapy for the treatment of traumatic brain injury: progress and prospects. Rev. Neurosci. [Epub ahead of print]. 10.1515/revneuro-2019-0002
    1. Deng Y., Thompson B. M., Gao X., Hall E. D. (2007). Temporal relationship of peroxynitrite-induced oxidative damage, calpain-mediated cytoskeletal degradation and neurodegeneration after traumatic brain injury. Exp. Neurol. 205, 154–165. 10.1016/j.expneurol.2007.01.023
    1. Deshpande L. S., Sun D. A., Sombati S., Baranova A., Wilson M. S., Attkisson E., et al. . (2008). Alterations in neuronal calcium levels are associated with cognitive deficits after traumatic brain injury. Neurosci. Lett. 441, 115–119. 10.1016/j.neulet.2008.05.113
    1. Dewan M. C., Rattani A., Gupta S., Baticulon R. E., Hung Y. C., Punchak M., et al. . (2018). Estimating the global incidence of traumatic brain injury. J. Neurosurg. 130, 1039–1408. 10.3171/2017.10.JNS17352
    1. De Winter F., Oudega M., Lankhorst A. J., Hamers F. P., Blits B., Ruitenberg M. J., et al. . (2002). Injury-induced class 3 semaphorin expression in the rat spinal cord. Exp. Neurol. 175, 61–75. 10.1006/exnr.2002.7884
    1. Dietrich W. D., Alonso O., Busto R., Finklestein S. P. (1996). Posttreatment with intravenous basic fibroblast growth factor reduces histopathological damage following fluid-percussion brain injury in rats. J. Neurotrauma 13, 309–316. 10.1089/neu.1996.13.309
    1. Ding K., Xu J., Wang H., Zhang L., Wu Y., Li T. (2015). Melatonin protects the brain from apoptosis by enhancement of autophagy after traumatic brain injury in mice. Neurochem. Int. 91, 46–54. 10.1016/j.neuint.2015.10.008
    1. Diskin T., Tal-Or P., Erlich S., Mizrachy L., Alexandrovich A., Shohami E., et al. . (2005). Closed head injury induces upregulation of Beclin 1 at the cortical site of injury. J. Neurotrauma 22, 750–762. 10.1089/neu.2005.22.750
    1. Dixon C. E., Flinn P., Bao J., Venya R., Hayes R. L. (1997). Nerve growth factor attenuates cholinergic deficits following traumatic brain injury in rats. Exp. Neurol. 146, 479–490. 10.1006/exnr.1997.6557
    1. Domb A. J., Turovsky L., Nudelman R. (1994). Chemical interactions between drugs containing reactive amines with hydrolyzable insoluble biopolymers in aqueous solutions. Pharm. Res. 11, 865–868. 10.1023/a:1018985909777
    1. Dubreuil C. I., Marklund N., Deschamps K., Mcintosh T. K., Mckerracher L. (2006). Activation of Rho after traumatic brain injury and seizure in rats. Exp. Neurol. 198, 361–369. 10.1016/j.expneurol.2005.12.002
    1. Dubreuil C. I., Winton M. J., Mckerracher L. (2003). Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system. J. Cell Biol. 162, 233–243. 10.1083/jcb.200301080
    1. Emerich D. F., Tracy M. A., Ward K. L., Figueiredo M., Qian R., Henschel C., et al. . (1999). Biocompatibility of poly (DL-lactide-co-glycolide) microspheres implanted into the brain. Cell Transplant. 8, 47–58. 10.1177/096368979900800114
    1. Erlich S., Alexandrovich A., Shohami E., Pinkas-Kramarski R. (2007). Rapamycin is a neuroprotective treatment for traumatic brain injury. Neurobiol. Dis. 26, 86–93. 10.1016/j.nbd.2006.12.003
    1. Eshhar N., Striem S., Kohen R., Tirosh O., Biegon A. (1995). Neuroprotective and antioxidant activities of HU-211, a novel NMDA receptor antagonist. Eur. J. Pharmacol. 283, 19–29. 10.1016/0014-2999(95)00271-l
    1. Faden A., Demediuk P., Panter S., Vink R. (1989). The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244, 798–800. 10.1126/science.2567056
    1. Fawcett J. W. (2006). Overcoming inhibition in the damaged spinal cord. J. Neurotrauma 23, 371–383. 10.1089/neu.2006.23.371
    1. Fawcett J. W., Asher R. A. (1999). The glial scar and central nervous system repair. Brain Res. Bull. 49, 377–391. 10.1016/s0361-9230(99)00072-6
    1. Fehlings M., Theodore N., Harrop J., Maurais G., Kuntz C., Shaffrey C., et al. . (2011). A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. J. Neurotrauma 28, 787–796. 10.1089/neu.2011.1765
    1. Filipovic R., Zecevic N. (2008). Neuroprotective role of minocycline in co-cultures of human fetal neurons and microglia. Exp. Neurol. 211, 41–51. 10.1016/j.expneurol.2007.12.024
    1. Finkelstein E., Corso P. S., Miller T. R. (2006). The Incidence and Economic Burden of Injuries in the United States. New York, NY: Oxford University Press.
    1. Foged C., Nielsen H. M. (2008). Cell-penetrating peptides for drug delivery across membrane barriers. Expert Opin. Drug Deliv. 5, 105–117. 10.1517/17425247.5.1.105
    1. Folkerts M. M., Parks E. A., Dedman J. R., Kaetzel M. A., Lyeth B. G., Berman R. F. (2007). Phosphorylation of calcium calmodulin-dependent protein kinase II following lateral fluid percussion brain injury in rats. J. Neurotrauma 24, 638–650. 10.1089/neu.2006.0188
    1. Follett P. L., Rosenberg P. A., Volpe J. J., Jensen F. E. (2000). NBQX attenuates excitotoxic injury in developing white matter. J. Neurosci. 20, 9235–9241. 10.1523/jneurosci.20-24-09235.2000
    1. Fournier E., Passirani C., Montero-Menei C. N., Benoit J. P. (2003). Biocompatibility of implantable synthetic polymeric drug carriers: focus on brain biocompatibility. Biomaterials 24, 3311–3331. 10.1016/s0142-9612(03)00161-3
    1. Frugier T., Morganti-Kossmann M. C., O’Reilly D., Mclean C. A. (2009). in situ detection of inflammatory mediators in post mortem human brain tissue after traumatic injury. J. Neurotrauma 27, 497–507. 10.1089/neu.2009.1120
    1. Fujitani Y., Hibi M., Fukada T., Takahashi-Tezuka M., Yoshida H., Yamaguchi T., et al. . (1997). An alternative pathway for STAT activation that is mediated by the direct interaction between JAK and STAT. Oncogene 14, 751–761. 10.1038/sj.onc.1200907
    1. Furlani D., Ugurlucan M., Ong L., Bieback K., Pittermann E., Westien I., et al. . (2009). Is the intravascular administration of mesenchymal stem cells safe? Mesenchymal stem cells and intravital microscopy. Microvasc. Res. 77, 370–376. 10.1016/j.mvr.2009.02.001
    1. Galindo L. T., Filippo T. R. M., Semedo P., Ariza C. B., Moreira C. M., Camara N. O. S., et al. . (2011). Mesenchymal stem cell therapy modulates the inflammatory response in experimental traumatic brain injury. Neurol. Res. Int. 2011:564089. 10.1155/2011/564089
    1. Gao J., Prough D. S., Mcadoo D. J., Grady J. J., Parsley M. O., Ma L., et al. . (2006). Transplantation of primed human fetal neural stem cells improves cognitive function in rats after traumatic brain injury. Exp. Neurol. 201, 281–292. 10.1016/j.expneurol.2006.04.039
    1. Gao Y., Zhuang Z., Gao S., Li X., Zhang Z., Ye Z., et al. . (2017). Tetrahydrocurcumin reduces oxidative stress-induced apoptosis via the mitochondrial apoptotic pathway by modulating autophagy in rats after traumatic brain injury. Am. J. Transl. Res. 9, 887–899.
    1. Garrido-Mesa N., Zarzuelo A., Galvez J. (2013). Minocycline: far beyond an antibiotic. Br. J. Pharmacol. 169, 337–352. 10.1111/bph.12139
    1. Gentleman S. M., Leclercq P. D., Moyes L., Graham D. I., Smith C., Griffin W. S. T., et al. . (2004). Long-term intracerebral inflammatory response after traumatic brain injury. Forensic Sci. Int. 146, 97–104. 10.1016/j.forsciint.2004.06.027
    1. Girouard H., Wang G., Gallo E. F., Anrather J., Zhou P., Pickel V. M., et al. . (2009). NMDA receptor activation increases free radical production through nitric oxide and NOX2. J. Neurosci. 29, 2545–2552. 10.1523/jneurosci.0133-09.2009
    1. Goda M., Isono M., Fujiki M., Kobayashi H. (2002). Both MK801 and NBQX reduce the neuronal damage after impact-acceleration brain injury. J. Neurotrauma 19, 1445–1456. 10.1089/089771502320914679
    1. Goodman J. C., Van M., Gopinath S. P., Robertson C. S. (2009). Pro-inflammatory and pro-apoptotic elements of the neuroinflammatory response are activated in traumatic brain injury. Acta Neurochir. Suppl. 102, 437–439. 10.1007/978-3-211-85578-2_85
    1. Grady M. S., Charleston J. S., Maris D., Witgen B. M., Lifshitz J. (2003). Neuronal and glial cell number in the hippocampus after experimental traumatic brain injury: analysis by stereological estimation. J. Neurotrauma 20, 929–941. 10.1089/089771503770195786
    1. Grapp M., Wrede A., Schweizer M., Huwel S., Galla H. J., Snaidero N., et al. . (2013). Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. Nat. Commun. 4:2123. 10.1038/ncomms3123
    1. Guan J., Zhu Z., Zhao R. C., Xiao Z., Wu C., Han Q., et al. . (2013). Transplantation of human mesenchymal stem cells loaded on collagen scaffolds for the treatment of traumatic brain injury in rats. Biomaterials 34, 5937–5946. 10.1016/j.biomaterials.2013.04.047
    1. Guidotti G., Brambilla L., Rossi D. (2017). Cell-penetrating peptides: from basic research to clinics. Trends Pharmacol. Sci. 38, 406–424. 10.1016/j.tips.2017.01.003
    1. Gupta B., Levchenko T. S., Torchilin V. P. (2005). Intracellular delivery of large molecules and small particles by cell-penetrating proteins and peptides. Adv. Drug Deliv. Rev. 57, 637–651. 10.1016/j.addr.2004.10.007
    1. Habgood M. D., Bye N., Dziegielewska K. M., Ek C. J., Lane M. A., Potter A., et al. . (2007). Changes in blood-brain barrier permeability to large and small molecules following traumatic brain injury in mice. Eur. J. Neurosci. 25, 231–238. 10.1111/j.1460-9568.2006.05275.x
    1. Hall E. D. (1992). The neuroprotective pharmacology of methylprednisolone. J. Neurosurg. 76, 13–22. 10.3171/jns.1992.76.1.0013
    1. Hall E. D., Detloff M. R., Johnson K., Kupina N. C. (2004). Peroxynitrite-mediated protein nitration and lipid peroxidation in a mouse model of traumatic brain injury. J. Neurotrauma 21, 9–20. 10.1089/089771504772695904
    1. Hardingham G. E. (2009). Coupling of the NMDA receptor to neuroprotective and neurodestructive events. Biochem. Soc. Trans. 37, 1147–1160. 10.1042/bst0371147
    1. Hardingham G. E., Fukunaga Y., Bading H. (2002). Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5, 405–414. 10.1038/nn835
    1. Heile A., Brinker T. (2011). Clinical translation of stem cell therapy in traumatic brain injury: the potential of encapsulated mesenchymal cell biodelivery of glucagon-like peptide-1. Dialogues Clin. Neurosci. 13, 279–286.
    1. Hellewell S. C., Yan E. B., Agyapomaa D. A., Bye N., Morganti-Kossmann M. C. (2010). Post-traumatic hypoxia exacerbates brain tissue damage: analysis of axonal injury and glial responses. J. Neurotrauma 27, 1997–2010. 10.1089/neu.2009.1245
    1. Höltje M., Djalali S., Hofmann F., Münster-Wandowski A., Hendrix S., Boato F., et al. . (2009). A 29-amino acid fragment of clostridium botulinum C3 protein enhances neuronal outgrowth, connectivity and reinnervation. FASEB J. 23, 1115–1126. 10.1096/fj.08-116855
    1. Homsi S., Federico F., Croci N., Palmier B., Plotkine M., Marchand-Leroux C., et al. . (2009). Minocycline effects on cerebral edema: relations with inflammatory and oxidative stress markers following traumatic brain injury in mice. Brain Res. 1291, 122–132. 10.1016/j.brainres.2009.07.031
    1. Hong S. J., Dawson T. M., Dawson V. L. (2004). Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharmacol. Sci. 25, 259–264. 10.1016/j.tips.2004.03.005
    1. Houchin M. L., Neuenswander S. A., Topp E. M. (2007). Effect of excipients on PLGA film degradation and the stability of an incorporated peptide. J. Control. Release 117, 413–420. 10.1016/j.jconrel.2006.11.023
    1. Houchin M. L., Topp E. M. (2008). Chemical degradation of peptides and proteins in PLGA: a review of reactions and mechanisms. J. Pharm. Sci. 97, 2395–2404. 10.1002/jps.21176
    1. Huelsenbeck S., Rohrbeck A., Handreck A., Hellmich G., Kiaei E., Roettinger I., et al. . (2012). C3 peptide promotes axonal regeneration and functional motor recovery after peripheral nerve injury. Neurotherapeutics 9, 185–198. 10.1007/s13311-011-0072-y
    1. Imer M., Omay B., Uzunkol A., Erdem T., Sabanci P. A., Karasu A., et al. . (2009). Effect of magnesium, MK-801 and combination of magnesium and MK-801 on blood brain barrier permeability and brain edema after experimental traumatic diffuse brain injury. Neurol. Res. 31, 977–981. 10.1179/174313209X385617
    1. Jain K. K. (2008). Neuroprotection in traumatic brain injury. Drug Discov. Today 13, 1082–1089. 10.1016/j.drudis.2008.09.006
    1. Jain R. A. (2000). The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. Biomaterials 21, 2475–2490. 10.1016/s0142-9612(00)00115-0
    1. Jeong J. O., Han J. W., Kim J. M., Cho H. J., Park C., Lee N., et al. . (2011). Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy. Circ. Res. 108, 1340–1347. 10.1161/CIRCRESAHA.110.239848
    1. Jin K., Mao X. O., Greenberg D. A. (2006). Vascular endothelial growth factor stimulates neurite outgrowth from cerebral cortical neurons via Rho kinase signaling. J. Neurobiol. 66, 236–242. 10.1002/neu.20215
    1. Johnson V. E., Stewart J. E., Begbie F. D., Trojanowski J. Q., Smith D. H., Stewart W. (2013). Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain 136, 28–42. 10.1093/brain/aws322
    1. Kawamura M., Nakajima W., Ishida A., Ohmura A., Miura S., Takada G. (2005). Calpain inhibitor MDL 28170 protects hypoxic-ischemic brain injury in neonatal rats by inhibition of both apoptosis and necrosis. Brain Res. 1037, 59–69. 10.1016/j.brainres.2004.12.050
    1. Kawasaki H., Morooka T., Shimohama S., Kimura J., Hirano T., Gotoh Y., et al. . (1997). Activation and involvement of p38 mitogen-activated protein kinase in glutamate-induced apoptosis in rat cerebellar granule cells. J. Biol. Chem. 272, 18518–18521. 10.1074/jbc.272.30.18518
    1. Kelsen J., Karlsson M., Hansson M. J., Yang Z., Fischer W., Hugerth M., et al. . (2019). Copenhagen head injury ciclosporin (CHIC) study: a phase iia safety, pharmacokinetics and biomarker study of ciclosporin in severe traumatic brain injury patients. J. Neurotrauma [Epub ahead of print]. 10.1089/neu.2018.6369
    1. Khalin I., Alyautdin R., Wong T. W., Gnanou J., Kocherga G., Kreuter J. (2016). Brain-derived neurotrophic factor delivered to the brain using poly (lactide-co-glycolide) nanoparticles improves neurological and cognitive outcome in mice with traumatic brain injury. Drug Deliv. 23, 3520–3528. 10.1080/10717544.2016.1199609
    1. Kim H. J., Lee J. H., Kim S. H. (2009). Therapeutic effects of human mesenchymal stem cells for traumatic brain injury in rats: secretion of neurotrophic factors and inhibition of apoptosis. J. Neurotrauma 27, 131–138. 10.1089/neu.2008-0818
    1. Kim D. K., Nishida H., An S. Y., Shetty A. K., Bartosh T. J., Prockop D. J. (2016). Chromatographically isolated CD63+CD81+ extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI. Proc. Natl. Acad. Sci. U S A 113, 170–175. 10.1073/pnas.1522297113
    1. Kleindienst A., Harvey H. B., Rice A. C., Müller C., Hamm R. J., Gaab M. R., et al. . (2004). Intraventricular infusion of the neurotrophic protein S100B improves cognitive recovery after fluid percussion injury in the rat. J. Neurotrauma 21, 541–547. 10.1089/089771504774129874
    1. Knoblach S. M., Alroy D. A., Nikolaeva M., Cernak I., Stoica B. A., Faden A. I. (2004). Caspase inhibitor z-DEVD-fmk attenuates calpain and necrotic cell death in vitro and after traumatic brain injury. J. Cereb. Blood Flow Metab. 24, 1119–1132. 10.1097/01.WCB.0000138664.17682.32
    1. Koren E., Torchilin V. P. (2012). Cell-penetrating peptides: breaking through to the other side. Trends Mol. Med. 18, 385–393. 10.1016/j.molmed.2012.04.012
    1. Kossmann T., Stahel P. F., Lenzlinger P. M., Redl H., Dubs R. W., Trentz O., et al. . (1997). Interleukin-8 released into the cerebrospinal fluid after brain injury is associated with blood-brain barrier dysfunction and nerve growth factor production. J. Cereb. Blood Flow Metab. 17, 280–289. 10.1097/00004647-199703000-00005
    1. Kovesdi E., Kamnaksh A., Wingo D., Ahmed F., Grunberg N. E., Long J. B., et al. . (2012). Acute minocycline treatment mitigates the symptoms of mild blast-induced traumatic brain injury. Front. Neurol. 3:111. 10.3389/fneur.2012.00111
    1. Kromer L. F. (1987). Nerve growth factor treatment after brain injury prevents neuronal death. Science 235, 214–216. 10.1126/science.3798108
    1. Kucher K., Johns D., Maier D., Abel R., Badke A., Baron H., et al. . (2018). First-in-man intrathecal application of neurite growth-promoting anti-nogo-A antibodies in acute spinal cord injury. Neurorehabil. Neural Repair 32, 578–589. 10.1177/1545968318776371
    1. Kulbe J. R., Singh I. N., Wang J. A., Cebak J. E., Hall E. D. (2018). Continuous infusion of phenelzine, cyclosporine A, or their combination: evaluation of mitochondrial bioenergetics, oxidative damage and cytoskeletal degradation following severe controlled cortical impact traumatic brain injury in rats. J. Neurotrauma 35, 1280–1293. 10.1089/neu.2017.5353
    1. Lampe K. J., Kern D. S., Mahoney M. J., Bjugstad K. B. (2011). The administration of BDNF and GDNF to the brain via PLGA microparticles patterned within a degradable PEG-based hydrogel: protein distribution and the glial response. J. Biomed. Mater. Res. A 96A, 595–607. 10.1002/jbm.a.33011
    1. Laskowski A., Schmidt W., Dinkel K., Martínez-Sánchez M., Reymann K. G. (2005). bFGF and EGF modulate trauma-induced proliferation and neurogenesis in juvenile organotypic hippocampal slice cultures. Brain Res. 1037, 78–89. 10.1016/j.brainres.2004.12.035
    1. Lee L. L., Galo E., Lyeth B. G., Muizelaar J. P., Berman R. F. (2004). Neuroprotection in the rat lateral fluid percussion model of traumatic brain injury by SNX-185, an N-type voltage-gated calcium channel blocker. Exp. Neurol. 190, 70–78. 10.1016/j.expneurol.2004.07.003
    1. Li D., Huang S., Zhu J., Hu T., Han Z., Zhang S., et al. . (2019). Exosomes from MiR-21–5p-increased neurons play a role in neuroprotection by suppressing rab11a-mediated neuronal autophagy in vitro after traumatic brain injury. Med. Sci. Monit. 25, 1871–1885. 10.12659/MSM.915727
    1. Li W. J., Laurencin C. T., Caterson E. J., Tuan R. S., Ko F. K. (2002). Electrospun nanofibrous structure: a novel scaffold for tissue engineering. J. Biomed. Mater. Res. 60, 613–621. 10.1002/jbm.10167
    1. Liao Z. B., Jiang G. Y., Tang Z. H., Zhi X. G., Sun X. C., Tang W. Y., et al. . (2009). Erythropoietin can promote survival of cerebral cells by downregulating Bax gene after traumatic brain injury in rats. Neurol. India 57, 722–728. 10.4103/0028-3886.59466
    1. Liao Z. B., Zhi X. G., Shi Q. H., He Z. H. (2008). Recombinant human erythropoietin administration protects cortical neurons from traumatic brain injury in rats. Eur. J. Neurol. 15, 140–149. 10.1111/j.1468-1331.2007.02013.x
    1. Lifshitz J., Sullivan P. G., Hovda D. A., Wieloch T., McIntosh T. K. (2004). Mitochondrial damage and dysfunction in traumatic brain injury. Mitochondrion 4, 705–713. 10.1016/j.mito.2004.07.021
    1. Ligade P. C., Jadhav K. R., Kadam V. J. (2010). Brain drug delivery system: an overview. Curr. Drug Ther. 5, 105–110. 10.2174/157488510791065085
    1. Lin R., Kwok J. C., Crespo D., Fawcett J. W. (2008). Chondroitinase ABC has a long-lasting effect on chondroitin sulphate glycosaminoglycan content in the injured rat brain. J. Neurochem. 104, 400–408. 10.1111/j.1471-4159.2007.05066.x
    1. Lindgren M., Hällbrink M., Prochiantz A., Langel U. (2000). Cell-penetrating peptides. Trends Pharmacol. Sci. 21, 99–103. 10.1016/s0165-6147(00)01447-4
    1. Ling G. S., Ecklund J. M. (2011). Traumatic brain injury in modern war. Curr. Opin. Anaesthesiol. 24, 124–130. 10.1097/ACO.0b013e32834458da
    1. Liu Y., Wong T. P., Aarts M., Rooyakkers A., Liu L., Lai T. W., et al. . (2007). NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J. Neurosci. 27, 2846–2857. 10.1523/JNEUROSCI.0116-07.2007
    1. Lord-Fontaine S., Yang F., Diep Q., Dergham P., Munzer S., Tremblay P., et al. . (2008). Local inhibition of Rho signaling by cell-permeable recombinant protein BA-210 prevents secondary damage and promotes functional recovery following acute spinal cord injury. J. Neurotrauma 25, 1309–1322. 10.1089/neu.2008.0613
    1. Lotocki G., de Rivero Vaccari J. P., Perez E. R., Sanchez-Molano J., Furones-Alonso O., Bramlett H. M., et al. . (2009). Alterations in blood-brain barrier permeability to large and small molecules and leukocyte accumulation after traumatic brain injury: effects of post-traumatic hypothermia. J. Neurotrauma 26, 1123–1134. 10.1089/neu.2008.0802
    1. Lu K. T., Cheng N. C., Wu C. Y., Yang Y. L. (2008). NKCC1-mediated traumatic brain injury-induced brain edema and neuron death via Raf/MEK/MAPK cascade. Crit. Care Med. 36, 917–922. 10.1097/CCM.0B013E31816590C4
    1. Lu D., Mahmood A., Qu C., Goussev A., Schallert T., Chopp M. (2005). Erythropoietin enhances neurogenesis and restores spatial memory in rats after traumatic brain injury. J. Neurotrauma 22, 1011–1017. 10.1089/neu.2005.22.1011
    1. Lu D., Mahmood A., Wang L., Li Y., Lu M., Chopp M. (2001). Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome. Neuroreport 12, 559–563. 10.1097/00001756-200103050-00025
    1. Lu K. T., Sun C. L., Wo P. Y., Yen H. H., Tang T. H., Ng M. C., et al. . (2011). Hippocampal neurogenesis after traumatic brain injury is mediated by vascular endothelial growth factor receptor-2 and the Raf/MEK/ERK cascade. J. Neurotrauma 28, 441–450. 10.1089/neu.2010.1473
    1. Luo P., Fei F., Zhang L., Qu Y., Fei Z. (2011). The role of glutamate receptors in traumatic brain injury: implications for postsynaptic density in pathophysiology. Brain Res. Bull. 85, 313–320. 10.1016/j.brainresbull.2011.05.004
    1. Maas A. I. R., Menon D. K., Adelson P. D., Andelic N., Bell M. J., Belli A., et al. . (2017). Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 16, 987–1048. 10.1016/S1474-4422(17)30371-X
    1. Maas A. I., Murray G., Henney H., III., Kassem N., Legrand V., Mangelus M., et al. . (2006). Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol. 5, 38–45. 10.1016/s1474-4422(05)70253-2
    1. Maas A., Roozenbeek B., Manley G. (2010). Clinical trials in traumatic brain injury: past experience and current developments. Neurotherapeutics 7, 115–126. 10.1016/j.nurt.2009.10.022
    1. Mahmood A., Lu D., Chopp M. (2004a). Intravenous administration of marrow stromal cells (MSCs) increases the expression of growth factors in rat brain after traumatic brain injury. J. Neurotrauma 21, 33–39. 10.1089/089771504772695922
    1. Mahmood A., Lu D., Chopp M. (2004b). Marrow stromal cell transplantation after traumatic brain injury promotes cellular proliferation within the brain. Neurosurgery 55, 1185–1193. 10.1227/01.neu.0000141042.14476.3c
    1. Maiuri M. C., Zalckvar E., Kimchi A., Kroemer G. (2007). Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 8, 741–752. 10.1038/nrm2239
    1. Mammis A., McIntosh T. K., Maniker A. H. (2009). Erythropoietin as a neuroprotective agent in traumatic brain injury review. Surg. Neurol. 71, 527–531. 10.1016/j.surneu.2008.02.040
    1. Mazzeo A. T., Brophy G. M., Gilman C. B., Alves Ó. L., Robles J. R., Hayes R. L., et al. . (2009). Safety and tolerability of cyclosporin a in severe traumatic brain injury patients: results from a prospective randomized trial. J. Neurotrauma 26, 2195–2206. 10.1089/neu.2009.1012
    1. Mbye L. H., Singh I. N., Carrico K. M., Saatman K. E., Hall E. D. (2008). Comparative neuroprotective effects of cyclosporin A and NIM811, a nonimmunosuppressive cyclosporin A analog, following traumatic brain injury. J. Cereb. Blood Flow Metab. 29, 87–97. 10.1038/jcbfm.2008.93
    1. McKerracher L., Anderson K. D. (2013). Analysis of recruitment and outcomes in the phase I/IIa Cethrin clinical trial for acute spinal cord injury. J. Neurotrauma 30, 1795–1804. 10.1089/neu.2013.2909
    1. McKerracher L., Guertin P. (2013). Rho as a target to promote repair: translation to clinical studies with cethrin. Curr. Pharm. Des. 19, 4400–4410. 10.2174/1381612811319240007
    1. Meldrum B. S. (2000). Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J. Nutr. 130, 1007S–1015S. 10.1093/jn/130.4.1007s
    1. Mi S., Lee X., Shao Z., Thill G., Ji B., Relton J., et al. . (2004). LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat. Neurosci. 7, 221–228. 10.1038/nn1188
    1. Mizushima N. (2007). Autophagy: process and function. Genes Dev. 21, 2861–2873. 10.1101/gad.1599207
    1. Mizushima N., Levine B., Cuervo A. M., Klionsky D. J. (2008). Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075. 10.1038/nature06639
    1. Monnier P. P., Sierra A., Schwab J. M., Henke-Fahle S., Mueller B. K. (2003). The Rho/ROCK pathway mediates neurite growth-inhibitory activity associated with the chondroitin sulfate proteoglycans of the CNS glial scar. Mol. Cell. Neurosci. 22, 319–330. 10.1016/s1044-7431(02)00035-0
    1. Morganti-Kossmann M. C., Rancan M., Stahel P. F., Kossmann T. (2002). Inflammatory response in acute traumatic brain injury: a double-edged sword. Cur. Opin. Crit. Care 8, 101–105. 10.1097/00075198-200204000-00002
    1. Morganti-Kossmann M. C., Satgunaseelan L., Bye N., Kossmann T. (2007). Modulation of immune response by head injury. Injury 38, 1392–1400. 10.1016/j.injury.2007.10.005
    1. Mori T., Wang X., Jung J. C., Sumii T., Singhal A. B., Fini M. E., et al. . (2002). Mitogen-activated protein kinase inhibition in traumatic brain injury: in vitro and in vivo effects. J. Cereb. Blood Flow Metab. 22, 444–452. 10.1097/00004647-200204000-00008
    1. Na D. H., DeLuca P. P. (2005). PEGylation of octreotide: I. Separation of positional isomers and stability against acylation by poly(D,L-lactide-co-glycolide). Pharm. Res. 22, 736–742. 10.1007/s11095-005-2589-4
    1. Nadler V., Biegon A., Beit-Yannai E., Adamchik J., Shohami E. (1995). 45Ca accumulation in rat brain after closed head injury; attenuation by the novel neuroprotective agent HU-211. Brain Res. 685, 1–11. 10.1016/0006-8993(95)00367-y
    1. Nadler V., Mechoulam R., Sokolovsky M. (1993). The non-psychotropic cannabinoid (+)-(3S,4S)-7-hydroxy-Δ6-tetrahydrocannabinol 1,1-dimethylheptyl (HU-211) attenuates N-methyl-d-aspartate receptor-mediated neurotoxicity in primary cultures of rat forebrain. Neurosci. Lett. 162, 43–45. 10.1016/0304-3940(93)90555-y
    1. Naga K. K., Sullivan P. G., Geddes J. W. (2007). High cyclophilin D content of synaptic mitochondria results in increased vulnerability to permeability transition. J. Neurosci. 27, 7469–7475. 10.1523/JNEUROSCI.0646-07.2007
    1. Nagamoto-Combs K., McNeal D. W., Morecraft R. J., Combs C. K. (2007). Prolonged microgliosis in the rhesus monkey central nervous system after traumatic brain injury. J. Neurotrauma 24, 1719–1742. 10.1089/neu.2007.0377
    1. Namiki J., Kojima A., Tator C. H. (2000). Effect of brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 on functional recovery and regeneration after spinal cord injury in adult rats. J. Neurotrauma 17, 1219–1231. 10.1089/neu.2000.17.1219
    1. Nash M., Pribiag H., Fournier A., Jacobson C. (2009). Central nervous system regeneration inhibitors and their intracellular substrates. Mol. Neurobiol. 40, 224–235. 10.1007/s12035-009-8083-y
    1. Newcomb R., Abbruscato T. J., Singh T., Nadasdi L., Davis T. P., Miljanich G. (2000). Bioavailability of Ziconotide in brain: influx from blood, stability and diffusion. Peptides 21, 491–501. 10.1016/s0196-9781(00)00175-3
    1. Ng S. Y., Semple B. D., Morganti-Kossmann M. C., Bye N. (2012). Attenuation of microglial activation with minocycline is not associated with changes in neurogenesis after focal traumatic brain injury in adult mice. J. Neurotrauma 29, 1410–1425. 10.1089/neu.2011.2188
    1. Nichol A., French C., Little L., Haddad S., Presneill J., Arabi Y., et al. . (2015). Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial. Lancet 386, 2499–2506. 10.1016/s0140-6736(15)00386-4
    1. Okiyama K., Rosenkrantz T., Smith D., Gennarelli T., McIntosh T. (1994). (S)-emopamil attenuates acute reduction in regional cerebral blood flow following experimental brain injury. J. Neurotrauma 11, 83–95. 10.1089/neu.1994.11.83
    1. Okiyama K., Smith D. H., Thomas M. J., McIntosh T. K. (1992). Evaluation of a novel calcium channel blocker, (S)-emopamil, on regional cerebral edema and neurobehavioral function after experimental brain injury. J. Neurosurg. 77, 607–615. 10.3171/jns.1992.77.4.0607
    1. Okonkwo D. O., Büki A., Siman R., Povlishock J. T. (1999). Cyclosporin A limits calcium-induced axonal damage following traumatic brain injury. Neuroreport 10, 353–358. 10.1097/00001756-199902050-00026
    1. Okonkwo D. O., Povlishock J. T. (1999). An intrathecal bolus of cyclosporin A before injury preserves mitochondrial integrity and attenuates axonal disruption in traumatic brain injury. J. Cereb. Blood Flow Metab. 19, 443–451. 10.1097/00004647-199904000-00010
    1. Orive G., Anitua E., Pedraz J. L., Emerich D. F. (2009). Biomaterials for promoting brain protection, repair and regeneration. Nat. Rev. Neurosci. 10, 682–692. 10.1038/nrn2685
    1. Parachikova A., Vasilevko V., Cribbs D. H., LaFerla F. M., Green K. N. (2010). Reductions in amyloid-β-derived neuroinflammation, with minocycline, restore cognition but do not significantly affect tau hyperphosphorylation. J. Alzheimers Dis. 21, 527–542. 10.3233/jad-2010-100204
    1. Park T. G. (1995). Degradation of poly(lactic-co-glycolic acid) microspheres: effect of copolymer composition. Biomaterials 16, 1123–1130. 10.1016/0142-9612(95)93575-x
    1. Park J. B., Yiu G., Kaneko S., Wang J., Chang J., He Z. (2005). A TNF receptor family member, TROY, is a coreceptor with Nogo receptor in mediating the inhibitory activity of myelin inhibitors. Neuron 45, 345–351. 10.1016/j.neuron.2004.12.040
    1. Pasterkamp R. J., Anderson P. N., Verhaagen J. (2001). Peripheral nerve injury fails to induce growth of lesioned ascending dorsal column axons into spinal cord scar tissue expressing the axon repellent Semaphorin3A. Eur. J. Neurosci. 13, 457–471. 10.1046/j.0953-816x.2000.01398.x
    1. Pasterkamp R. J., Kolodkin A. L. (2003). Semaphorin junction: making tracks toward neural connectivity. Curr. Opin. Neurobiol. 13, 79–89. 10.1016/s0959-4388(03)00003-5
    1. Pierce J., Trojanowski J., Graham D., Smith D., McIntosh T. (1996). Immunohistochemical characterization of alterations in the distribution of amyloid precursor proteins and β-amyloid peptide after experimental brain injury in the rat. J. Neurosci. 16, 1083–1090. 10.1523/JNEUROSCI.16-03-01083.1996
    1. Popovic N., Brundin P. (2006). Therapeutic potential of controlled drug delivery systems in neurodegenerative diseases. Int. J. Pharm. 314, 120–126. 10.1016/j.ijpharm.2005.09.040
    1. Povlishock J. (1992). Traumatically induced axonal injury: pathogenesis and pathobiological implications. Brain Pathol. 2, 1–12.
    1. Praticò D., Reiss P., Tang L. X., Sung S., Rokach J., McIntosh T. K. (2002). Local and systemic increase in lipid peroxidation after moderate experimental traumatic brain injury. J. Neurochem. 80, 894–898. 10.1046/j.0022-3042.2002.00777.x
    1. Raghupathi R. (2004). Cell death mechanisms following traumatic brain injury. Brain Pathol. 14, 215–222. 10.1111/j.1750-3639.2004.tb00056.x
    1. Raghupathi R., Strauss K., Zhang C., Krajewski S., Reed J., McIntosh T. (2003). Temporal alterations in cellular Bax:Bcl-2 ratio following traumatic brain injury in the rat. J. Neurotrauma 20, 421–435. 10.1089/089771503765355504
    1. Rancan M., Otto V. I., Hans V. H., Gerlach I., Jork R., Trentz O., et al. . (2001). Upregulation of ICAM-1 and MCP-1 but not of MIP-2 and sensorimotor deficit in response to traumatic axonal injury in rats. J. Neurosci. Res. 63, 438–446. 10.1002/1097-4547(20010301)63:5<438::aid-jnr1039>;2-g
    1. Rao V. L., Başkaya M. K., Doğan A., Rothstein J. D., Dempsey R. J. (1998). Traumatic brain injury down-regulates glial glutamate transporter (GLT-1 and GLAST) proteins in rat brain. J. Neurochem. 70, 2020–2027. 10.1046/j.1471-4159.1998.70052020.x
    1. Ray S. K., Dixon C. E., Banik N. L. (2002). Molecular mechanisms in the pathogenesis of traumatic brain injury. Histol. Histopathol. 17, 1137–1152. 10.14670/HH-17.1137
    1. Reynolds I. J., Hastings T. G. (1995). Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. J. Neurosci. 15, 3318–3327. 10.1523/JNEUROSCI.15-05-03318.1995
    1. Riess P., Zhang C., Saatman K. E., Laurer H. L., Longhi L. G., Raghupathi R., et al. . (2002). Transplanted neural stem cells survive, differentiate, and improve neurological motor function after experimental traumatic brain injury. Neurosurgery 51, 1043–1054. 10.1097/00006123-200210000-00035
    1. Risdall J. E., Menon D. K. (2011). Traumatic brain injury. Philos. Trans. R. Soc. Lond. B Biol. Sci. 366, 241–250. 10.1098/rstb.2010.0230
    1. Saatman K. E., Abai B., Grosvenor A., Vorwerk C. K., Smith D. H., Meaney D. F. (2003). Traumatic axonal injury results in biphasic calpain activation and retrograde transport impairment in mice. J. Cereb. Blood Flow Metab. 23, 34–42. 10.1097/01.WCB.0000035040.10031.B0
    1. Saatman K. E., Duhaime A. C., Bullock R., Maas A. I., Valadka A., Manley G. T. (2008). Classification of traumatic brain injury for targeted therapies. J. Neurotrauma 25, 719–738. 10.1089/neu.2008.0586
    1. Sakai K., Fukuda T., Iwadate K. (2014). Immunohistochemical analysis of the ubiquitin proteasome system and autophagy lysosome system induced after traumatic intracranial injury: association with time between the injury and death. Am. J. Forensic Med. Pathol. 35, 38–44. 10.1097/paf.0000000000000067
    1. Samii A., Badie H., Fu K., Luther R. R., Hovda D. A. (1999). Effects of an N-type calcium channel antagonist (SNX 111; Ziconotide) on calcium-45 accumulation following fluid-percussion injury. J. Neurotrauma 16, 879–892. 10.1089/neu.1999.16.879
    1. Sanchez Mejia R. O., Ona V. O., Li M., Friedlander R. M. (2001). Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage and neurological dysfunction. Neurosurgery 48, 1393–1401. 10.1097/00006123-200106000-00051
    1. Sanchez-Ramos J., Song S., Cardozo-Pelaez F., Hazzi C., Stedeford T., Willing A., et al. . (2000). Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp. Neurol. 164, 247–256. 10.1006/exnr.2000.7389
    1. Saraiva C., Praca C., Ferreira R., Santos T., Ferreira L., Bernardino L. (2016). Nanoparticle-mediated brain drug delivery: overcoming blood-brain barrier to treat neurodegenerative diseases. J. Control. Release 235, 34–47. 10.1016/j.jconrel.2016.05.044
    1. Sarkar C., Zhao Z., Aungst S., Sabirzhanov B., Faden A. I., Lipinski M. M. (2014). Impaired autophagy flux is associated with neuronal cell death after traumatic brain injury. Autophagy 10, 2208–2222. 10.4161/15548627.2014.981787
    1. Sattler R., Xiong Z., Lu W.-Y., Hafner M., Macdonald J. F., Tymianski M. (1999). Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science 284, 1845–1848. 10.1126/science.284.5421.1845
    1. Schäbitz W.-R., Schwab S., Spranger M., Hacke W. (1997). Intraventricular brain-derived neurotrophic factor reduces infarct size after focal cerebral ischemia in rats. J. Cereb. Blood Flow Metab. 17, 500–506. 10.1097/00004647-199705000-00003
    1. Scheff S. W., Sullivan P. G. (1999). Cyclosporin A significantly ameliorates cortical damage following experimental traumatic brain injury in rodents. J. Neurotrauma 16, 783–792. 10.1089/neu.1999.16.783
    1. Schenk U., Menna E., Kim T., Passafaro M., Chang S., De Camilli P., et al. . (2005). A novel pathway for presynaptic mitogen-activated kinase activation via AMPA receptors. J. Neurosci. 25, 1654–1663. 10.1523/jneurosci.3074-04.2005
    1. Schmidt O. I., Infanger M., Heyde C. E., Ertel W., Stahel P. F. (2004). The role of neuroinflammation in traumatic brain injury. Eur. J. Trauma 30, 135–149. 10.1007/s00068-004-1394-9
    1. Schneider A., Simons M. (2013). Exosomes: vesicular carriers for intercellular communication in neurodegenerative disorders. Cell Tissue Res. 352, 33–47. 10.1007/s00441-012-1428-2
    1. Sebbage V. (2009). Cell-penetrating peptides and their therapeutic applications. Biosci. Horiz. 2, 64–72. 10.1093/biohorizons/hzp001
    1. Semple B. D., Bye N., Rancan M., Ziebell J. M., Morganti-Kossmann M. C. (2010). Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2−/− mice. J. Cereb. Blood Flow Metab. 30, 769–782. 10.1038/jcbfm.2009.262
    1. Shahlaie K., Lyeth B. G., Gurkoff G. G., Muizelaar J. P., Berman R. F. (2009). Neuroprotective effects of selective N-type VGCC blockade on stretch-injury-induced calcium dynamics in cortical neurons. J. Neurotrauma 27, 175–187. 10.1089/neu.2009.1003
    1. Shohami E., Gallily R., Mechoulam R., Bass R., Ben-Hur T. (1997). Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNF-α inhibitor and an effective neuroprotectant. J. Neuroimmunol. 72, 169–177. 10.1016/s0165-5728(96)00181-6
    1. Shohami E., Kohen R. (2011). “The role of reactive oxygen species in the pathogenesis of traumatic brain injury,” in Oxidative Stress and Free Radical Damage in Neurology, eds Gadoth N., Göbel H. H. (Humana Press; ), 99–118.
    1. Shohami E., Novikov M., Bass R. (1995). Long-term effect of HU-211, a novel non-competitive NMDA antagonist, on motor and memory functions after closed head injury in the rat. Brain Res. 674, 55–62. 10.1016/0006-8993(94)01433-i
    1. Simeoli R., Montague K., Jones H. R., Castaldi L., Chambers D., Kelleher J. H., et al. . (2017). Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma. Nat. Commun. 8:1778. 10.1038/s41467-017-01841-5
    1. Singh I. N., Sullivan P. G., Deng Y., Mbye L. H., Hall E. D. (2006). Time course of post-traumatic mitochondrial oxidative damage and dysfunction in a mouse model of focal traumatic brain injury: implications for neuroprotective therapy. J. Cereb. Blood Flow Metab. 26, 1407–1418. 10.1038/sj.jcbfm.9600297
    1. Sinson G., Perri B. R., Trojanowski J. Q., Flamm E. S., Mcintosh T. K. (1997). Improvement of cognitive deficits and decreased cholinergic neuronal cell loss and apoptotic cell death following neurotrophin infusion after experimental traumatic brain injury. J. Neurosurg. 86, 511–518. 10.3171/jns.1997.86.3.0511
    1. Siopi E., Cho A., Homsi S., Croci N., Plotkine M., Marchand-Leroux C., et al. . (2011). Minocycline restores sAPPα levels and reduces the late histopathological consequences of traumatic brain injury in mice. J. Neurotrauma 28, 2135–2143. 10.1089/neu.2010.1738
    1. Skandsen T., Kvistad K. A., Solheim O., Strand I. H., Folvik M., Vik A. (2010). Prevalence and impact of diffuse axonal injury in patients with moderate and severe head injury: a cohort study of early magnetic resonance imaging findings and 1-year outcome. J. Neurosurg. 113, 556–563. 10.3171/2009.9.JNS09626
    1. Skardelly M., Gaber K., Burdack S., Scheidt F., Hilbig H., Boltze J., et al. . (2011). Long-term benefit of human fetal neuronal progenitor cell transplantation in a clinically adapted model after traumatic brain injury. J. Neurotrauma 28, 401–414. 10.1089/neu.2010.1526
    1. Smith D. H., Chen X. H., Pierce J. E., Wolf J. A., Trojanowski J. Q., Graham D. I., et al. . (1997). Progressive atrophy and neuron death for one year following brain trauma in the rat. J. Neurotrauma 14, 715–727. 10.1089/neu.1997.14.715
    1. Smith D. H., Meaney D. F., Shull W. H. (2003). Diffuse axonal injury in head trauma. J. Head Trauma Rehabil. 18, 307–316. 10.1097/00001199-200307000-00003
    1. Soppimath K. S., Aminabhavi T. M., Kulkarni A. R., Rudzinski W. E. (2001). Biodegradable polymeric nanoparticles as drug delivery devices. J. Control. Release 70, 1–20. 10.1016/s0168-3659(00)00339-4
    1. Stoica B., Faden A. (2010). Cell death mechanisms and modulation in traumatic brain injury. Neurotherapeutics 7, 3–12. 10.1016/j.nurt.2009.10.023
    1. Sullivan P. G., Keller J. N., Bussen W. L., Scheff S. W. (2002). Cytochrome c release and caspase activation after traumatic brain injury. Brain Res. 949, 88–96. 10.1016/s0006-8993(02)02968-2
    1. Sullivan P. G., Rabchevsky A. G., Waldmeier P. C., Springer J. E. (2005). Mitochondrial permeability transition in CNS trauma: cause or effect of neuronal cell death? J. Neurosci. Res. 79, 231–239. 10.1002/jnr.20292
    1. Sullivan P. G., Sebastian A. H., Hall E. D. (2010). Therapeutic window analysis of the neuroprotective effects of cyclosporine A after traumatic brain injury. J. Neurotrauma 28, 311–318. 10.1089/neu.2010.1646
    1. Sullivan P. G., Thompson M. B., Scheff S. W. (1999). Cyclosporin A attenuates acute mitochondrial dysfunction following traumatic brain injury. Exp. Neurol. 160, 226–234. 10.1006/exnr.1999.7197
    1. Sullivan P. G., Thompson M., Scheff S. W. (2000). Continuous infusion of cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury. Exp. Neurol. 161, 631–637. 10.1006/exnr.1999.7282
    1. Sun D., Bullock M. R., Mcginn M. J., Zhou Z., Altememi N., Hagood S., et al. . (2009). Basic fibroblast growth factor-enhanced neurogenesis contributes to cognitive recovery in rats following traumatic brain injury. Exp. Neurol. 216, 56–65. 10.1016/j.expneurol.2008.11.011
    1. Sun D. A., Deshpande L. S., Sombati S., Baranova A., Wilson M. S., Hamm R. J., et al. . (2008). Traumatic brain injury causes a long-lasting calcium (Ca2+)-plateau of elevated intracellular Ca levels and altered Ca2+ homeostatic mechanisms in hippocampal neurons surviving brain injury. Eur. J. Neurosci. 27, 1659–1672. 10.1111/j.1460-9568.2008.06156.x
    1. Susin S. A., Zamzami N., Kroemer G. (1998). Mitochondria as regulators of apoptosis: doubt no more. Biochim. Biophys. Acta 1366, 151–165. 10.1016/s0005-2728(98)00110-8
    1. Tan E. Y., Law J. W., Wang C. H., Lee A. Y. (2007). Development of a cell transducible RhoA inhibitor TAT-C3 transferase and its encapsulation in biocompatible microspheres to promote survival and enhance regeneration of severed neurons. Pharm. Res. 24, 2297–2308. 10.1007/s11095-007-9454-6
    1. Tang-Schomer M. D., Patel A. R., Baas P. W., Smith D. H. (2010). Mechanical breaking of microtubules in axons during dynamic stretch injury underlies delayed elasticity, microtubule disassembly and axon degeneration. FASEB J. 24, 1401–1410. 10.1096/fj.09-142844
    1. Taylor D. D., Gercel-Taylor C. (2013). The origin, function and diagnostic potential of RNA within extracellular vesicles present in human biological fluids. Front. Genet. 4:142. 10.3389/fgene.2013.00142
    1. Taylor D. D., Gercel-Taylor C. (2014). Exosome platform for diagnosis and monitoring of traumatic brain injury. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369:20130503. 10.1098/rstb.2013.0503
    1. Temsamani J., Scherrmann J. M., Rees A. R., Kaczorek M. (2000). Brain drug delivery technologies: novel approaches for transporting therapeutics. Pharm. Sci. Technol. Today 3, 155–162. 10.1016/s1461-5347(00)00258-3
    1. Thau-Zuchman O., Shohami E., Alexandrovich A. G., Leker R. R. (2010). Vascular endothelial growth factor increases neurogenesis after traumatic brain injury. J. Cereb. Blood Flow Metab. 30, 1008–1016. 10.1038/jcbfm.2009.271
    1. Thompson H. J., Bakshi A. (2005). Methylprednisolone was associated with an increase in death after head injury. Evid. Based Nurs. 8:51. 10.1136/ebn.8.2.51
    1. Thompson S. N., Carrico K. M., Mustafa A. G., Bains M., Hall E. D. (2010). A pharmacological analysis of the neuroprotective efficacy of the brain- and cell-permeable calpain inhibitor MDL-28170 in the mouse controlled cortical impact traumatic brain injury model. J. Neurotrauma 27, 2233–2243. 10.1089/neu.2010.1474
    1. Tian C., Wang X., Wang X., Wang L., Wang X., Wu S., et al. . (2013). Autologous bone marrow mesenchymal stem cell therapy in the subacute stage of traumatic brain injury by lumbar puncture. Exp. Clin. Transplant. 11, 176–181. 10.6002/ect.2012.0053
    1. Tikka T. M., Koistinaho J. E. (2001). Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J. Immunol. 166, 7527–7533. 10.4049/jimmunol.166.12.7527
    1. Trams E. G., Lauter C. J., Salem N., Jr., Heine U. (1981). Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochim. Biophys. Acta 645, 63–70. 10.1016/0005-2736(81)90512-5
    1. Tsujimoto Y., Shimizu S. (2007). Role of the mitochondrial membrane permeability transition in cell death. Apoptosis 12, 835–840. 10.1007/s10495-006-0525-7
    1. Turkoglu O. F., Eroglu H., Gurcan O., Bodur E., Sargon M. F., Öner L., et al. . (2010). Local administration of chitosan microspheres after traumatic brain injury in rats: a new challenge for cyclosporine - a delivery. Br. J. Neurosurg. 24, 578–583. 10.3109/02688697.2010.487126
    1. van Landeghem F. K., Weiss T., Oehmichen M., Von Deimling A. (2006). Decreased expression of glutamate transporters in astrocytes after human traumatic brain injury. J. Neurotrauma 23, 1518–1528. 10.1089/neu.2006.23.1518
    1. Veng L. M., Mesches M. H., Browning M. D. (2003). Age-related working memory impairment is correlated with increases in the L-type calcium channel protein α1D (Cav1.3) in area CA1 of the hippocampus and both are ameliorated by chronic nimodipine treatment. Brain Res. Mol. Brain Res. 110, 193–202. 10.1016/s0169-328x(02)00643-5
    1. Verweij B. H., Muizelaar J. P., Vinas F. C., Peterson P. L., Xiong Y., Lee C. P. (2000). Improvement in mitochondrial dysfunction as a new surrogate efficiency measure for preclinical trials: dose—response and time-window profiles for administration of the calcium channel blocker Ziconotide in experimental brain injury. J. Neurosurg. 93, 829–834. 10.3171/jns.2000.93.5.0829
    1. Wang K. C., Kim J. A., Sivasankaran R., Segal R., He Z. (2002). p75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420, 74–78. 10.1038/nature01176
    1. Warden D. (2006). Military TBI during the Iraq and Afghanistan wars. J. Head Trauma Rehabil. 21, 398–402. 10.1097/00001199-200609000-00004
    1. Weber J. T. (2012). Altered calcium signaling following traumatic brain injury. Front. Pharmacol. 3:60. 10.3389/fphar.2012.00060
    1. Wennersten A., Holmin S., Mathiesen T. (2003). Characterization of Bax and Bcl-2 in apoptosis after experimental traumatic brain injury in the rat. Acta Neuropathol. 105, 281–288. 10.1007/s00401-002-0649-y
    1. Winton M. J., Dubreuil C. I., Lasko D., Leclerc N., Mckerracher L. (2002). Characterization of new cell permeable C3-like proteins that inactivate Rho and stimulate neurite outgrowth on inhibitory substrates. J. Biol. Chem. 277, 32820–32829. 10.1074/jbc.m201195200
    1. Wu H., Lu D., Jiang H., Xiong Y., Qu C., Li B., et al. . (2008). Simvastatin-mediated upregulation of VEGF and BDNF, activation of the PI3K/Akt pathway and increase of neurogenesis are associated with therapeutic improvement after traumatic brain injury. J. Neurotrauma 25, 130–139. 10.1089/neu.2007.0369
    1. Xin H., Katakowski M., Wang F., Qian J. Y., Liu X. S., Ali M. M., et al. . (2017). MicroRNA cluster miR-17–92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke 48, 747–753. 10.1161/STROKEAHA.116.015204
    1. Xiong Y., Gu Q., Peterson P. L., Muizelaar J. P., Lee C. P. (1997). Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. J. Neurotrauma 14, 23–34. 10.1089/neu.1997.14.23
    1. Xiong Y., Mahmood A., Chopp M. (2017). Emerging potential of exosomes for treatment of traumatic brain injury. Neural Regen. Res. 12, 19–22. 10.4103/1673-5374.198966
    1. Xiong Y., Mahmood A., Qu C., Kazmi H., Zhang Z. G., Noguchi C. T., et al. . (2010). Erythropoietin improves histological and functional outcomes after traumatic brain injury in mice in the absence of the neural erythropoietin receptor. J. Neurotrauma 27, 205–215. 10.1089/neu.2009.1001
    1. Xu J., Wang H., Lu X., Ding K., Zhang L., He J., et al. . (2014). Posttraumatic administration of luteolin protects mice from traumatic brain injury: implication of autophagy and inflammation. Brain Res. 1582, 237–246. 10.1016/j.brainres.2014.07.042
    1. Xu B., Zhang Y., Du X. F., Li J., Zi H. X., Bu J. W., et al. . (2017). Neurons secrete miR-132-containing exosomes to regulate brain vascular integrity. Cell Res. 27, 882–897. 10.1038/cr.2017.62
    1. Yagita Y., Kitagawa K., Sasaki T., Terasaki Y., Todo K., Omura-Matsuoka E., et al. . (2007). Rho-kinase activation in endothelial cells contributes to expansion of infarction after focal cerebral ischemia. J. Neurosci. Res. 85, 2460–2469. 10.1002/jnr.21375
    1. Yatsiv I., Grigoriadis N., Simeonidou C., Stahel P. F., Schmidt O. I., Alexandrovitch A. G., et al. . (2005). Erythropoietin is neuroprotective, improves functional recovery and reduces neuronal apoptosis and inflammation in a rodent model of experimental closed head injury. FASEB J. 19, 1701–1703. 10.1096/fj.05-3907fje
    1. Yick L. W., Cheung P. T., So K. F., Wu W. (2003). Axonal regeneration of Clarke’s neurons beyond the spinal cord injury scar after treatment with chondroitinase ABC. Exp. Neurol. 182, 160–168. 10.1016/s0014-4886(02)00052-3
    1. Yu P., Huang L., Zou J., Yu Z., Wang Y., Wang X., et al. . (2008). Immunization with recombinant Nogo-66 receptor (NgR) promotes axonal regeneration and recovery of function after spinal cord injury in rats. Neurobiol. Dis. 32, 535–542. 10.1016/j.nbd.2008.09.012
    1. Yu P., Huang L., Zou J., Zhu H., Wang X., Yu Z., et al. . (2007). DNA vaccine against NgR promotes functional recovery after spinal cord injury in adult rats. Brain Res. 1147, 66–76. 10.1016/j.brainres.2007.02.013
    1. Yuan D., Zhao Y., Banks W. A., Bullock K. M., Haney M., Batrakova E., et al. . (2017). Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain. Biomaterials 142, 1–12. 10.1016/j.biomaterials.2017.07.011
    1. Zaloshnja E., Miller T., Langlois J. A., Selassie A. W. (2008). Prevalence of long-term disability from traumatic brain injury in the civilian population of the United States, 2005. J. Head Trauma Rehabil. 23, 394–400. 10.1097/
    1. Zhang Y., Ang B. T., Xiao Z. C., Ng I., Steiger H. J. (2009). DNA vaccination against neurite growth inhibitors to enhance functional recovery following traumatic brain injury. Acta Neurochir. Suppl. 102, 347–351. 10.1007/978-3-211-85578-2_66
    1. Zhang B., Chen X., Lin Y., Tan T., Yang Z., Dayao C., et al. . (2011). Impairment of synaptic plasticity in hippocampus is exacerbated by methylprednisolone in a rat model of traumatic brain injury. Brain Res. 1382, 165–172. 10.1016/j.brainres.2011.01.065
    1. Zhang Y., Chopp M., Meng Y., Katakowski M., Xin H., Mahmood A., et al. . (2015). Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J. Neurosurg. 122, 856–867. 10.3171/2014.11.jns14770
    1. Zhang Z., Fauser U., Schluesener H. (2008). Dexamethasone suppresses infiltration of RhoA+ cells into early lesions of rat traumatic brain injury. Acta Neuropathol. 115, 335–343. 10.1007/s00401-007-0301-y
    1. Zhang X., Graham S. H., Kochanek P. M., Marion D. W., Nathaniel P. D., Watkins S. C., et al. . (2003). Caspase-8 expression and proteolysis in human brain after severe head injury. FASEB J. 17, 1367–1369. 10.1096/fj.02-1067fje
    1. Zhang Y. B., Li S. X., Chen X. P., Yang L., Zhang Y. G., Liu R., et al. . (2008). Autophagy is activated and might protect neurons from degeneration after traumatic brain injury. Neurosci. Bull. 24, 143–149. 10.1007/s12264-008-1108-0
    1. Zhang L., Wang H., Fan Y., Gao Y., Li X., Hu Z., et al. . (2017). Fucoxanthin provides neuroprotection in models of traumatic brain injury via the Nrf2-ARE and Nrf2-autophagy pathways. Sci. Rep. 7:46763. 10.1038/srep46763
    1. Zhang Y., Winterbottom J. K., Schachner M., Lieberman A. R., Anderson P. N. (1997). Tenascin-C expression and axonal sprouting following injury to the spinal dorsal columns in the adult rat. J. Neurosci. Res. 49, 433–450. 10.1002/(sici)1097-4547(19970815)49:4<433::aid-jnr5>;2-9
    1. Zhao J. B., Zhang Y., Li G. Z., Su X. F., Hang C. H. (2011). Activation of JAK2/STAT pathway in cerebral cortex after experimental traumatic brain injury of rats. Neurosci. Lett. 498, 147–152. 10.1016/j.neulet.2011.05.001
    1. Zhu X., Lee J., Wong J., Tan W. L., Feng Z., Wang T., et al. (2007). Pre-stroke DNA immunization against neurite growth inhibitors is beneficial to the recovery from focal cerebral ischemia in rats. Neural Regen. Res. 2, 513–518. 10.1016/s1673-5374(07)60102-9

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