Pharmacologic neuroprotection for functional outcomes after traumatic brain injury: a systematic review of the clinical literature
Open accessAbstract
Introduction Traumatic brain injury (TBI) is a major cause of death and disability worldwide. The deleterious effects of secondary brain injury may be attenuated by early pharmacological therapy in the emergency room and intensive care unit (ICU). Current medical management of acute TBI is primarily supportive, aimed at reducing intracranial pressure (ICP) and optimizing cerebral perfusion. There are no pharmacological therapies to date that have been unequivocally demonstrated to improve neurological outcomes after TBI. Objectives The purpose of this systematic review was to evaluate the recent clinical studies from January 2013 through November 2015 that investigated neuroprotective functional outcomes of pharmacological agents after TBI. Methods The following databases were searched for relevant studies: MEDLINE (OvidSP January Week 1, 2013-November Week 2 2015), Embase (OvidSP 2013 January 1-2015 November 24), and the unindexed material in PubMed (National Library of Medicine/National Institutes of Health [NLM/NIH]). This systematic review included only full-length clinical studies and case series that included at least five patients and were published in the English language. Only studies that examined functional clinical outcomes were included. Results Twenty-five of 527 studies met our inclusion criteria, which investigated 15 independent pharmacological therapies. Eight of these therapies demonstrated possible neuroprotective properties and improved functional outcomes, of which five were investigated with randomized clinical trials: statins, N-acetyl cysteine (NAC), Enzogenol, Cerebrolysin, and nitric oxide synthase inhibitor (VAS203). Three pharmacological agents did not demonstrate neuroprotective effects, and four agents had mixed results. Conclusions While there is currently no single pharmacological therapy that will unequivocally improve clinical outcomes after TBI, several agents have demonstrated promising clinical benefits for specific TBI patients and should be investigated further.
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No effective interventions are available to improve recovery following TBI.
“To date, no effective interventions are available to improve recovery following TBI (42–44).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [44]
The Conclusions state that no single pharmacological therapy has been shown to unequivocally improve clinical outcomes after TBI. The claim extends that narrower, qualified finding to all interventions; the Results also report functional-outcome benefits for eight therapies in the studies reviewed. Page numbers were not supplied for these passages. (LLM, conf=0.88)
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BackgroundMethodInfluentialHead injuries in four British neurosurgical centres
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BARBITURATE INFUSION FOR INTRACTABLE INTRACRANIAL HYPERTENSION AND ITS EFFECT ON BRAIN OXYGENATION
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Acute Alcohol Intoxication and Long-Term Outcome in Patients with Traumatic Brain Injury
Raj, R., Skrifvars, M. B., Kivisaari, R. P., Hernesniemi, J. A., Lappalainen, J., & Siironen, J. O. (2014) · Journal of Neurotrauma · doi:10.1089/neu.2014.3488 · Cited by 56 · cited 3× · see citing works
“…GOS at 6 months, mortality rate, Disability Rating Scale score Progesterone did not improve the outcome of patients with acute moderate-to-severe TBI Raj et al. 2015 [65] Retrospective chart review 405 Ethanol 6-month mortality and unfavorable neurological outcome (GOS 1–3) Low admission BAC…”
BackgroundMethodInfluentialShakeri, M., Boustani, M. R., Pak, N., Panahi, F., Salehpour, F., Lotfinia, I., Meshkini, A., Daghighi, S., Vahedi, P., Khani, M., et al. (2013) · Clinical Neurology and Neurosurgery · doi:10.1016/j.clineuro.2013.06.013 · Cited by 56 · cited 3× · see citing works
“2013 [61] Randomized controlled trial 76 Progesterone Mortality rate, GCS on discharge, and GOS 3 months after discharge Progesterone improves neurological outcome in patients with severe TBI”
BackgroundMethodInfluentialTerpolilli, N. A., Zweckberger, K., Trabold, R., Schilling, L., Schinzel, R., Tegtmeier, F., & Plesnila, N. (2009) · Journal of Neurotrauma · doi:10.1089/neu.2008.0853 · Cited by 55 · see citing works
Stover, J. F., Belli, A., Boret, H., Bulters, D., Sahuquillo, J., Schmutzhard, E., Zavala, E., Ungerstedt, U., Schinzel, R., Tegtmeier, F., et al. (2014) · Journal of Neurotrauma · doi:10.1089/neu.2014.3344 · Cited by 53 · cited 12× · see citing works
“The remaining pharmacological therapies were each tested in one study, including glibenclamide, N-acetyl-L-cysteine (NAC), marijuana, Enzogenol, b-blockers, cerebrolysin, ciclosporin, anticonvulsants, and nitric oxide (NO) synthase inhibitor Antipterin (VAS203).”
BackgroundMethodInfluentialLONG-TERM BENEFITS AFTER TREATMENT OF TRAUMATIC BRAIN INJURY WITH SIMVASTATIN IN RATS
Mahmood, A., Goussev, A. V., Kazmi, H., Qu, C., Lu, D., & Chopp, M. (2009) · Neurosurgery · doi:10.1227/01.neu.0000343540.24780.d6 · Cited by 50 · see citing works
Taylor, S., Heinrichs, R. J., Janzen, J. M., & Ehtisham, A. (2010) · Neurocritical Care · doi:10.1007/s12028-010-9341-6 · Cited by 49 · cited 1× · see citing works
“This finding, combined with similar findings in earlier preclinical and clinical studies [52, 53], have led some experts to suggest that levetiracetam has neuroprotective properties [54].”
ResultSeizure Prophylaxis in Neurocritical Care: A Review of Evidence‐Based Support
Rowe, A. S., Goodwin, H. E., Brophy, G. M., Bushwitz, J., Castle, A., Deen, D., Johnson, D., Lesch, C. A., Liang, N., Potter, E. M., et al. (2013) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.1374 · Cited by 49 · cited 1× · see citing works
“has emerged as an attractive alternative because of its simpler dosing regimen and more favorable side effect profile [50].”
BackgroundMellion, S. A., Bennett, K. S., Ellsworth, G. L., Moore, K. R., Riva-Cambrin, J. K., Metzger, R. R., & Bratton, S. L. (2013) · Pediatric Critical Care Medicine · doi:10.1097/pcc.0b013e318271c3b2 · Cited by 48 · cited 3× · see citing works
“2013 [73] Retrospective chart review 36 Barbiturates Control of refractory intracranial hypertension, pediatric cerebral performance category scores at hospital discharge and at 3 months The addition of high-dose barbiturates achieved control of refractory intracranial hypertension in almost 30 % of treated children,…”
BackgroundInfluentialMajdán, M., Mauritz, W., Wilbacher, I., Bražinová, A., Rusňák, M., & Leitgeb, J. (2012) · Journal of Neurotrauma · doi:10.1089/neu.2012.2554 · Cited by 48 · cited 3× · see citing works
“In the first study, the charts of 1172 patients with severe TBI were retrospectively reviewed in 13 centers across five European countries, and investigated the effects of barbiturates on ICP, use of vasopressors, and short- and long-term outcomes [72].”
BackgroundEffect of alcohol in traumatic brain injury: is it really protective?
Pandit, V., Patel, N. J., Rhee, P., Kulvatunyou, N., Aziz, H., Green, D. J., O’Keeffe, T., Zangbar, B., Tang, A. L., Gries, L. M., et al. (2014) · Journal of Surgical Research · doi:10.1016/j.jss.2014.04.039 · Cited by 48 · cited 3× · see citing works
“A second recent study [66] retrospectively reviewed the charts of 23,983 patients with severe TBI, and examined the effects of ethanol intoxication on in-hospital complications and mortality.”
BackgroundInfluentialGabriel, W. M., & Rowe, A. S. (2014) · Annals of Pharmacotherapy · doi:10.1177/1060028014549013 · Cited by 48 · cited 7× · see citing works
“Levels of tumor necrosis factor (TNF)-a, interleukin (IL)-1b, IL-6, and IL-10 were Table 1 continued Study, year Study design N Intervention Primary endpoints Conclusions Aloizos et al. 2015 [76] Randomized controlled trial 42 Erythropoietin Unfavorable neurological outcomes at 6 months (GOS-E 2–4, or death), probabil…”
BackgroundMethodInfluentialTreatment of Increased Intracranial Pressure
Levin, A. B., Duff, T. A., & Javid, M. J. (1979) · Neurosurgery · doi:10.1227/00006123-197911000-00005 · Cited by 46 · see citing works
Neuroprotective effects of erythropoietin in patients with severe closed brain injury
Aloizos, S., Evodia, E., Gourgiotis, S., Isaia, E.-C., Seretis, C., & Baltopoulos, G. J. (2015) · Turkish Neurosurgery · doi:10.5137/1019-5149.jtn.9685-14.4 · Cited by 43 · cited 3× · see citing works
“2015 [76] Randomized controlled trial 42 Erythropoietin Unfavorable neurological outcomes at 6 months (GOS-E 2–4, or death), probability of an equal, greater, or lesser GOS-E at 6 months, proportion of surviving patients with unfavorable neurological outcome (GOS-E 2–4) at 6 months, 6-month mortality Erythropoietin ma…”
BackgroundInfluentialBrewster, M. E., Pop, E., Foltz, R. L., Reuschel, S., Griffith, W., Amselem, S., & Biegon, A. R. (1997) · PubMed · Cited by 41 · see citing works
The efficacy of cyclosporine-A on diffuse axonal injury after traumatic brain injury
Fard, S., Aminmansour, B., Habibabadi, M. R., Moein, P., Norouzi, R., & Naderan, M. (2014) · Advanced Biomedical Research · doi:10.4103/2277-9175.125031 · Cited by 36 · cited 4× · see citing works
“We identified a recent randomized, double-blind, placebo-controlled study [47] that randomly assigned patients to receive either ciclosporin 5 mg/kg/24 h via 250 mL DW 5 % (n = 50) during the first 8 h after TBI, or only 250 mL DW 5 % without ciclosporin (n = 50).”
BackgroundMethodInfluentialPreinjury β-blockade is protective in isolated severe traumatic brain injury
Mohseni, S., Talving, P., Wallin, G., Ljungqvist, O. H., & Riddez, L. (2014) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/ta.0000000000000139 · Cited by 36 · cited 1× · see citing works
“…et al. 2014 [28] Retrospective chart review 446 Marijuana Mortality A positive THC screen is associated with a decreased mortality after TBI Mohseni et al. 2014 [31] Retrospective chart review 662 b-Blockers In-hospital mortality Pre-injury b-blockade improves survival following isolated…”
BackgroundEffect of elevated serum alcohol level on the outcome of severely injured patients
Scheyerer, M. J., Dütschler, J., Billeter, A. T., Zimmermann, S. M., Sprengel, K., Werner, C. M. L., Simmen, H., & Wanner, G. A. (2013) · Emergency Medicine Journal · doi:10.1136/emermed-2013-202804 · Cited by 32 · cited 3× · see citing works
“A third study [67] retrospectively reviewed 383 charts and grouped patients according to BAC ([0.”
BackgroundInfluentialShand, B. I., Strey, C. H., Scott, R. S., Morrison, Z., & Gieseg, S. P. (2003) · Phytotherapy Research · doi:10.1002/ptr.1181 · Cited by 27 · cited 1× · see citing works
“Enzogenol is a pine bark extract from New Zealand that has been shown to have antioxidant and anti-inflammatory properties [35].”
BackgroundOrlando, A. (2013) · Journal of Clinical Medicine Research · doi:10.4021/jocmr1333w · Cited by 23 · cited 3× · see citing works
“2013 [22] Retrospective chart review 93 Statins In-hospital mortality, having at least one complication, and length of hospital stay[1 week Abrupt, unintended discontinuation of statin therapy is associated with an increased risk of mortality in the elderly TBI population”
BackgroundInfluentialUpdate on epidemiology, etiology, and diagnosis of adult growth hormone deficiency.
Prodam, F., Pagano, L., Corneli, G., Golisano, G., Belcastro, S., Busti, A., Gasco, V., Beccuti, G., Grottoli, S., Somma, C. D., et al. (2008) · PubMed · Cited by 18 · see citing works
Influence of glibenclamide on outcome in patients with type 2 diabetes and traumatic brain injury
Ding, J., Yuan, F., Guo, J.-Y., Chen, H., & Tian, H. (2013) · Clinical Neurology and Neurosurgery · doi:10.1016/j.clineuro.2013.08.010 · Cited by 9 · cited 3× · see citing works
“2013 [46] Retrospective chart review 70 Glibenclamide GCS on discharge, GOS on discharge, hospital and ICU length of stay Pretreatment and treatment with glibenclamide does not improve outcome in TBI patients with type II DM.”
BackgroundInfluentialAdvances in diagnosis, treatments, and molecular mechanistic studies of traumatic brain injury
Lu, C., Xia, J., Bin, W., Wu, Y., Liu, X., & Zhang, Y. (2015) · BioScience Trends · doi:10.5582/bst.2015.01066 · Cited by 8 · cited 1× · see citing works
“Despite recent advances in the management of trauma patients with multiple injuries [1], traumatic brain injury (TBI) remains a leading cause of morbidity and mortality in young people [2].”
BackgroundShakeri, M., Boustani, M. R., & Mahdkhah, A. (2014) · Neurosurgery Quarterly · doi:10.1097/wnq.0b013e3182a2fcc0 · Cited by 4 · see citing works
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Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift
Jassam, Y. N., Izzy, S., Whalen, M., McGavern, D. B., & El Khoury, J. (2017) · Neuron · doi:10.1016/j.neuron.2017.07.010 · Cited by 799 · see citing works
Microglial Activation in Traumatic Brain Injury
Donat, C. K., Scott, G., Gentleman, S., & Sastre, M. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00208 · Cited by 489 · see citing works
“This is further aggravated by the constant failure of clinical trials (reviewed in Loane and Faden, 2010; Gruenbaum et al., 2016), leaving patients without any treatment.”
BackgroundCannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease
Kendall, D. A., & Yudowski, G. A. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00294 · Cited by 363 · see citing works
“There is an ‘‘on-demand’’ signal to generate eCB following TBI that can decrease brain edema and inflammation (Shohami et al., 2011; Gruenbaum et al., 2016).”
BackgroundInfluentialOpportunities for the repurposing of PARP inhibitors for the therapy of non‐oncological diseases
Berger, N. A., Besson, V. C., Boulares, A. H., Bürkle, A., Chiarugi, A., Clark, R. S. B., Curtin, N. J., Cuzzocrea, S., Dawson, T. M., Dawson, V. L., et al. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13748 · Cited by 212 · see citing works
“…viewed as ‘pharmaceutical graveyard’ indications where some very spectacular therapeutic failures (e.g. Opal and Cross, 1999; Moretti et al., 2015; Gruenbaum et al., 2016; Standiford and Ward, 2016) have been encountered over recent decades, but there are also important lessons learned from…”
Russo, M. V., Latour, L. L., & McGavern, D. B. (2018) · Nature Immunology · doi:10.1038/s41590-018-0086-2 · Cited by 149 · see citing works
The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease
Kokiko-Cochran, O. N., & Godbout, J. P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00672 · Cited by 128 · see citing works
Truettner, J. S., Bramlett, H., & Dietrich, W. (2017) · Journal of Cerebral Blood Flow and Metabolism · doi:10.1177/0271678x16680003 · Cited by 75 · see citing works
“For example, matrix metalloproteinases (MMPs) are known to contribute to acute edema and increased vascular permeability after several types of brain injury.31 Interestingly, increased levels of MMP-9 seen after TBI are reduced with PTH.35 In our study, PTH also reduced the expression of the chemokine CC ligand-2 (Ccl…”
BackgroundInfluentialImpact of Traumatic Brain Injury on Dopaminergic Transmission
Chen, Y.-H., Huang, E. Y., Kuo, T., Miller, J., Chiang, Y. H., & Hoffer, B. J. (2017) · Cell Transplantation · doi:10.1177/0963689717714105 · Cited by 74 · see citing works
“NAC effects on TBI are controversial, with some studies showing extended behavioral recovery after injury.(104,105) Enzogenol is well tolerated and may reduce self-perceived cognitive failures in patients 3 to 12 mo postmTBI(106) and can improve clinical outcomes after TBI.”
BackgroundZhao, C., Deng, Y., He, Y., Huang, X., Wang, C., & Li, W. (2021) · Neurotherapeutics · doi:10.1007/s13311-020-00999-z · Cited by 61 · see citing works
Si, G., & Álvarez, A. (2020) · Medicinal Research Reviews · doi:10.1002/med.21722 · Cited by 61 · see citing works
Traumatic Brain Injury Advances
Stein, D. M., Feather, C. B., & Napolitano, L. M. (2016) · Critical Care Clinics · doi:10.1016/j.ccc.2016.08.008 · Cited by 59 · see citing works
Sigma-1 receptor: a potential therapeutic target for traumatic brain injury
Shi, M., Chen, F., Chen, Z., Yang, W., Yue, S., Zhang, J., & Chen, X. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.685201 · Cited by 58 · see citing works
Astrocytes, reactive astrogliosis, and glial scar formation in traumatic brain injury
Cieri, M. B., & Ramos, A. J. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-02091 · Cited by 58 · see citing works
“…been shown that therapies based on the administration of drugs that attenuate neuroinflammation, reduce reactive gliosis, and are beneficial in post-TBI functional recovery, among which we can highlight statins, cannabinoids, progesterone, beta blockers, and cerebrolysin (Gruenbaum et al., 2016).”
BackgroundMuresanu, D. F., Florian, I. Ş., Hömberg, V., Matula, C., von Steinbüchel, N., Vos, P. E., Wild, K. V., Bîrle, C., Mureșanu, I. A., Slăvoacă, D., et al. (2020) · Neurological Sciences · doi:10.1007/s10072-019-04181-y · Cited by 56 · see citing works
Current and Potential Pharmacologic Therapies for Traumatic Brain Injury
Tani, J., Wen, Y.-T., Hu, C., & Sung, J. (2022) · Pharmaceuticals · doi:10.3390/ph15070838 · Cited by 56 · see citing works
Intravenous Immunomodulatory Nanoparticle Treatment for Traumatic Brain Injury
Sharma, S., Ifergan, I., Kurz, J., Linsenmeier, R., Xu, D.-L., Cooper, J. G., Miller, S. D., & Kessler, J. (2020) · Annals of Neurology · doi:10.1002/ana.25675 · Cited by 47 · see citing works
“clinical and clinical trials designed to limit such secondary damage, no successful therapies have emerged.(5,6) Here, we”
BackgroundTarudji, A. W., Gee, C. C., Romereim, S. M., Convertine, A. J., & Kievit, F. (2021) · Biomaterials · doi:10.1016/j.biomaterials.2021.120766 · Cited by 40 · see citing works
Krämer, T. J., Grob, T., Menzel, L., Hirnet, T., Griemert, E., Radyushkin, K., Thal, S. C., Methner, A., & Schaefer, M. K. E. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14220 · Cited by 45 · see citing works
Soriano, S., Curry, K. D., Wang, Q., Chow, E., Treangen, T. J., & Villapol, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094476 · Cited by 44 · see citing works
Cheng, S., Zhang, Y., Chen, S., & Zhou, Y.-L. (2020) · Journal of Molecular Neuroscience · doi:10.1007/s12031-020-01623-7 · Cited by 43 · see citing works
Enhancement of the liver’s neuroprotective role ameliorates traumatic brain injury pathology
Dai, Y., Dong, J.-H., Wu, Y. H., Zhu, M., Xiong, W., Li, H., Zhao, Y., Hammock, B. D., & Zhu, X. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2301360120 · Cited by 41 · see citing works
“TBI is a devastating injury that often results in long-term neurological deficits, including locomotor function and memory impairments (25, 26).”
Drugs with anti-inflammatory effects to improve outcome of traumatic brain injury: a meta-analysis
Begemann, M., Leon, M., van der Horn, H. J., van der Naalt, J., & Sommer, I. (2020) · Scientific Reports · doi:10.1038/s41598-020-73227-5 · Cited by 34 · see citing works
Hummel, R., Ulbrich, S., Appel, D., Li, S., Hirnet, T., Zander, S., Bobkiewicz, W., Gölz, C., & Schäfer, M. K. E. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15259 · Cited by 38 · see citing works
Ignowski, E., Winter, A. N., Duval, N., Fleming, H., Wallace, T., Manning, E., Koza, L. A., Huber, K. M., Serkova, N. J., & Linseman, D. A. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.06.026 · Cited by 36 · see citing works
“Given the multi-factorial nature of secondary injury, many different therapeutic approaches have been investigated in an attempt to mitigate the post-acute neuronal damage caused by TBI including antioxidants, neurorestorative therapies, neuroprotective pharmacological agents, and drugs that modulate neuroinflammation…”
Kawoos, U., McCarron, R. M., & Chavko, M. (2017) · Frontiers in Neurology · doi:10.3389/fneur.2017.00219 · Cited by 28 · see citing works
“All these trials failed in Phase II or Phase III evaluation (28).”
BackgroundBozdemir, E., Vigil, F. A., Chun, S. H., Espinoza, L., Bugay, V., Khoury, S. M., Holstein, D. M., Stoja, A. P., Lozano, D., Tunca, C., et al. (2021) · Neurotherapeutics · doi:10.1007/s13311-021-01113-7 · Cited by 26 · see citing works
Why Does Brain Trauma Research Fail?
Alves, J. L., Rato, J. R., & da Silva, V. M. M. (2019) · World Neurosurgery · doi:10.1016/j.wneu.2019.06.212 · Cited by 26 · see citing works
The protection effect and mechanism of hyperbaric oxygen therapy in rat brain with traumatic injury
Xing, P., Ma, K., Li, L., Wang, D., Hu, G., & Long, W. (2018) · Acta Cirúrgica Brasileira · doi:10.1590/s0102-865020180040000006 · Cited by 25 · see citing works
Mason, H. D., Johnson, A. M., Mihelson, N., Mastorakos, P., & McGavern, D. B. (2021) · JCI Insight · doi:10.1172/jci.insight.149229 · Cited by 23 · see citing works
“Currently, no therapeutic has succeeded in improving outcomes after TBI (8).”
BackgroundVester, J., Buzoianu, A. D., Florian, I. Ş., Hömberg, V., Kim, S.-H., Lee, T. M. C., Matula, C., Poon, W. S., Săndesc, D., von Steinbüchel, N., et al. (2021) · Neurological Sciences · doi:10.1007/s10072-020-04974-6 · Cited by 22 · see citing works
Novel Synthetic and Natural Therapies for Traumatic Brain Injury
Battaglini, D., Siwicka-Gieroba, D., Rocco, P. R. M., Cruz, F. F., Silva, P. L., Dąbrowski, W., Brunetti, I., Patroniti, N. A., Pelosi, P. P., & Robba, C. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666210225145957 · Cited by 22 · see citing works
“Novel therapeutic pharmacological strategies have been investigated in the latest years [3].”
BackgroundInfluentialDenniss, R. J., & Barker, L. A. (2023) · Behavioral Sciences · doi:10.3390/bs13050388 · Cited by 22 · see citing works
“There has been a focus on pharmacological treatments for traumatic brain injury (see [5] for meta-analysis), but the potential of a holistic, cost-effective, person-centered approach to recovery from TBI has been somewhat overlooked.”
BackgroundLi, H., Zhang, C.-G., Yang, C.-Z., Blevins, M. A., Norris, D., Zhao, R., & Huang, M. (2019) · bioRxiv · doi:10.7150/ijbs.42109 · Cited by 18 · see citing works
“There is a compelling need for effective neuroprotective interventions that improve functional outcomes in TBI patients [22, 23].”
BackgroundEnhanced Spontaneous Motor Recovery After Stroke in Mice Treated With Cerebrolysin
DeBoer, S. R., Hubbard, R., Mersha, M. D., Pinilla-Monsalve, G. D., Winter, S., & Zeiler, S. R. (2021) · Neurorehabilitation and neural repair · doi:10.1177/15459683211000734 · Cited by 18 · see citing works
Priester, A. M., Waters, R., Abbott, A., Hilmas, K., Woelk, K., Miller, H. A., Tarudji, A. W., Gee, C. C., McDonald, B. Z., Kievit, F. M., et al. (2022) · Biomacromolecules · doi:10.1021/acs.biomac.1c01635 · Cited by 16 · see citing works
Abecasis, F., Dias, C., Zakrzewska, A., Oliveira, V., & Czosnyka, M. (2021) · Child s Nervous System · doi:10.1007/s00381-021-05263-z · Cited by 15 · see citing works
Gerbatin, R. R., Dobrachinski, F., Cassol, G., Soares, F. A. A., & Royes, L. F. F. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.04.014 · Cited by 13 · see citing works
Neuroprotective Agents in the Intensive Care Unit
Panahi, Y., Mojtahedzadeh, M., Najafi, A., Rajaee, S. M., Torkaman, M., & Sahebkar, A. (2018) · Journal of pharmacopuncture · doi:10.3831/kpi.2018.21.026 · Cited by 12 · see citing works
Statins’ Effect on Cognitive Outcome After Traumatic Brain Injury
Sultan, W., Sapkota, A., Khurshid, H., Qureshi, I. A., Jahan, N., Went, T. R., Dominic, J. L., Win, M. T. T., Kannan, A., Tara, A., et al. (2021) · Cureus · doi:10.7759/cureus.16953 · Cited by 11 · see citing works
“conducted a systematic review to evaluate the recent clinical studies from 2013 through 2015 that investigated the neuroprotective roles and functional outcomes of different pharmacological agents, including statins after TBI [29]; 25 studies were included in the analysis with two studies focused on the role of statin…”
BackgroundNorins, L. (2019) · Medical Hypotheses · doi:10.1016/j.mehy.2019.04.019 · Cited by 7 · see citing works
Andreasen, T. H., Madsen, F. A., Barbateskovic, M., Lindschou, J., Gluud, C. N., & Møller, K. (2024) · Neurocritical Care · doi:10.1007/s12028-024-02075-2 · Cited by 11 · see citing works
Tsaousi, G. G., Marocchi, L., Sergi, P. G., Pourzitaki, C., Santoro, A., & Bilotta, F. (2020) · Journal of Neurosurgical Sciences · doi:10.23736/s0390-5616.18.04527-7 · Cited by 9 · see citing works
Self-citationSigaut, S., Tardivon, C., Jacquens, A., Bottlaender, M., Gervais, P., Habert, M., Monsel, A., Roquilly, A., Boutonnet, M., Damien Galanaud, E., et al. (2024) · BMJ Open · doi:10.1136/bmjopen-2024-091441 · Cited by 8 · see citing works
“1 In TBI, the primary damage occurs at the time of impact, then secondary brain insults arise through systemic or intracranial mechanisms that reduce cerebral blood flow.”
Tarudji, A. W., Gee, C. C., Miller, H. A., Steffen, R., Curtis, E. T., Priester, A. M., Convertine, A. J., & Kievit, F. M. (2023) · Advanced Therapeutics · doi:10.1002/adtp.202300147 · Cited by 8 · see citing works
Bîrle, C., Slăvoacă, D., Mureșanu, I. A., Chira, D., Văcăraș, V., Stan, A. D., Dina, C., & Strilciuc, Ș. (2020) · Journal of Medicine and Life · doi:10.25122/jml-2020-0146 · Cited by 8 · see citing works
HMG-CoA Reductase Inhibitors for Traumatic Brain Injury
Katlowitz, K. A., Gopinath, S. P., Navarro, J. C., & Robertson, C. S. (2023) · Neurotherapeutics · doi:10.1007/s13311-023-01399-9 · Cited by 8 · see citing works
“Clinical trials have investigated a wide variety of known medications [15], such as magnesium [16] and cyclosporine-A [17].”
BackgroundAdvances in diagnosis, treatments, and molecular mechanistic studies of traumatic brain injury
Lu, C., Xia, J., Bin, W., Wu, Y., Liu, X., & Zhang, Y. (2015) · BioScience Trends · doi:10.5582/bst.2015.01066 · Cited by 8 · see citing works
Veillette, C., Umaña, M., Gagnon, M., Costerousse, O., Zarychanski, R., McAuley, D. F., Lawler, P. R., Lauzier, F., English, S. W., Moore, L., et al. (2025) · BMJ Open · doi:10.1136/bmjopen-2024-091971 · Cited by 7 · see citing works
Madsen, F. A., Andreasen, T. H., Lindschou, J., Gluud, C. N., & Møller, K. (2021) · PLoS ONE · doi:10.1371/journal.pone.0259899 · Cited by 7 · see citing works
“These outcomes depend on both the primary brain injury, which is immediate and irreversible, and the ensuing secondary brain injury, which is potentially reversible [18, 25–27] and induced by triggers such as hypoxia, hypotension, and inflammation [12, 13, 18, 28, 29].”
BackgroundHuang, G., Chen, K., Sun, Y., Zhu, L., Sun, Z.-L., & Feng, D. (2018) · Journal of Neurotrauma · doi:10.1089/neu.2018.6048 · Cited by 7 · see citing works
Andreasen, T. H., Olsen, M. H., Gluud, C. N., Lindschou, J., Fabricius, M. E., Hauerberg, J., & Møller, K. (2025) · BMJ Open · doi:10.1136/bmjopen-2025-101426 · Cited by 6 · see citing works
Overlapping pathways of migraine and the endocannabinoid system: Potential therapeutic targets
Pietra, A. D., & Russo, A. F. (2026) · Neurotherapeutics · doi:10.1016/j.neurot.2026.e00833 · Cited by 6 · see citing works
“Additionally, enhancing 2-AG signaling following TBI has demonstrated the ability to reduce neuroinflammation and brain edema [174,175], which could facilitate glymphatic restoration and support their use in headache disorders with disrupted waste clearance.”
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Intravenous Immunomodulatory Nanoparticles Prevent Secondary Damage after Traumatic Brain Injury
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Sortilin is dispensable for secondary injury processes following traumatic brain injury in mice
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“However no pharmacological therapies for moderate or severe TBI have been successful translated into clinical trials (7–9).”
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“For the acute phase of moderate to severe TBI, surgical intervention and optimization of cerebral perfusion pressure are the primary therapeutic approaches (Bullock et al., 2006; Timofeev et al., 2008; Gruenbaum et al., 2016).”
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“The secondary portion of TBI will cause damage at the cellular stage with severe consequences including the following; (1) inflammation, (2) excitotoxicity, (3) failure of nerve energy generation, (4) glial injury and dysfunction, (5) microvascular destruction and stenosis, and (6) aberrant ionic homeostasis in neuron…”
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- Authors
- Gruenbaum, S. E., Zlotnik, A., Gruenbaum, B. F., Hersey, D., & Bilotta, F.
- Affiliations
- Yale University (US)
- Ben-Gurion University of the Negev (IL)
- Sapienza University of Rome (IT)
- Corresponding author
- Bilotta, Federico
- Venue
- CNS Drugs
- Published
- 2016-06-23
- Volume
- 30
- Issue
- 9
- Pages
- 791-806
- ISSN
- 1172-7047 (ISSN-L)
- 1179-1934
- PMC
- PMC5116376
- OpenAlex
- W2464572702
- Cited by
- 86
- References
- 80
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 10 · 2023: 4 · 2022: 7 · 2021: 13 · 2020: 12 · 2019: 5 · 2018: 7 · 2017: 11 · 2016: 2 · 2015: 1 · 2013: 1
- FWCI
- 1.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- CNS Drugs (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000142)
- National Institute of General Medical Sciences (T32GM086287)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- traumatic brain injury, neuroprotection, pharmacotherapy, functional outcome, secondary brain injury, statins, N-acetylcysteine, Cerebrolysin, nitric oxide synthase inhibitors, intracranial pressure, cerebral perfusion
- MeSH terms
- Brain Injuries, Traumatic, Emergency Service, Hospital, Humans, Intensive Care Units, Intracranial Pressure, Time Factors, Randomized Controlled Trials as Topic, Treatment Outcome, Neuroprotective Agents
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