A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury

McConeghy, Kevin W.; Hatton, Jimmi; Hughes, Lindsey; Cook, Aaron M.

doi:10.2165/11634020-000000000-00000

Cited by 158Traumatic Brain Injury and Neurovascular DisturbancesTraumatic Brain Injury ResearchNeurological Disorders and Treatments

A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury

McConeghy, Kevin W., Hatton, Jimmi, Hughes, Lindsey, Cook, Aaron M.·2012·CNS Drugs

DOI 10.2165/11634020-000000000-00000

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Abstract

Traumatic brain injury (TBI) affects 1.6 million Americans annually. The injury severity impacts the overall outcome and likelihood for survival. Current treatment of acute TBI includes surgical intervention and supportive care therapies. Treatment of elevated intracranial pressure and optimizing cerebral perfusion are cornerstones of current therapy. These approaches do not directly address the secondary neurological sequelae that lead to continued brain injury after TBI. Depending on injury severity, a complex cascade of processes are activated and generate continued endogenous changes affecting cellular systems and overall outcome from the initial insult to the brain. Homeostatic cellular processes governing calcium influx, mitochondrial function, membrane stability, redox balance, blood flow and cytoskeletal structure often become dysfunctional after TBI. Interruption of this cascade has been the target of numerous pharmacotherapeutic agents investigated over the last two decades. Many agents such as selfotel, pegorgotein (PEG-SOD), magnesium, deltibant and dexanabinol were ineffective in clinical trials. While progesterone and ciclosporin have shown promise in phase II studies, success in larger phase III, randomized, multicentre, clinical trials is pending. Consequently, no neuroprotective treatment options currently exist that improve neurological outcome after TBI. Investigations to date have extended understanding of the injury mechanisms and sites for intervention.…

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From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [42]

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Fine Tuning of Traumatic Brain Injury Management in Neurointensive Care—Indicative Observations and Future Perspectives
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Effects of early rolipram treatment on histopathological outcome after controlled cortical impact injury in mice
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Can Microbiota Research Change Our Understanding of Neurodegenerative diseases?
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The cysteine-rich whey protein supplement, Immunocal®, preserves brain glutathione and improves cognitive, motor, and histopathological indices of traumatic brain injury in a mouse model of controlled cortical impact
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Effect of Telenursing on Levels of Depression and Anxiety in Caregivers of Patients with Stroke: A Randomized Clinical Trial
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Background
ROS-Induced Aggregation of Nanozyme for Neuron Injury.
He, H., Shi, X., Wang, J., Wang, X., Wang, Q., Yu, D.-Y., Ge, B.-S., Zhang, X.-D., & Huang, F. (2019) · ACS Applied Materials and Interfaces · doi:10.1021/acsami.9b17509 · Cited by 32 · see citing works
Xuefu zhuyu decoction improves cognitive impairment in experimental traumatic brain injury via synaptic regulation
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Curcumin alleviates brain edema by lowering AQP4 expression levels in a rat model of hypoxia-hypercapnia-induced brain damage
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“These drugs, which typically have a single therapeutic target and defined underlying pharmacological mechanisms, have demonstrated effectiveness in various experimental studies; however, they have shown mixed effectiveness and, in some cases serious side-effects, in human clinical trials (6-8).”
Downregulation of Homer1b/c improves neuronal survival after traumatic neuronal injury.
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“However, none of them has shown favorable efficacy on severe brain injuries in the recent clinical trials (Loane and Faden, 2010; McConeghy et al., 2012).”
Fluid biomarkers of chronic traumatic brain injury
Friberg, S., Lindblad, C., Zeiler, F. A., Zetterberg, H., Granberg, T., Svenningsson, P., Piehl, F., & Thelin, E. P. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-01024-z · Cited by 31 · see citing works
Downregulation of miR-491-5p promotes neovascularization after traumatic brain injury
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“Secondary ischemic injury exacerbates secondary brain injury, resulting in excessive inflammation and oxidative stress, which eventually aggravates neuronal apoptosis (McConeghy et al., 2012; Gyoneva and Ransohoff, 2015).”
Background
The potential for immune checkpoint modulators in cerebrovascular injury and inflammation
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Background
Guanosine Attenuates Behavioral Deficits After Traumatic Brain Injury by Modulation of Adenosinergic Receptors
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Protective Effects of Hinokitiol on Neuronal Ferroptosis by Activating the Keap1/Nrf2/HO-1 Pathway in Traumatic Brain Injury
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“26,27 Unfortunately, none of the compounds have been moved into clinical trials.”
Evaluating differential nanoparticle accumulation and retention kinetics in a mouse model of traumatic brain injury via Ktrans mapping with MRI
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Adjudin Attenuates Cerebral Edema and Improves Neurological Function in Mice with Experimental Traumatic Brain Injury
Liu, Y.-L., Yuan, F., Yang, D.-X., Xu, Z., Jing, Y., Yang, G.-Y., Geng, Z., Xia, W., & Tian, H.-L. (2018) · Journal of Neurotrauma · doi:10.1089/neu.2017.5397 · Cited by 26 · see citing works
“3 Cerebral edema, which is a fatal pathological phenomenon following TBI, elevates intracranial pressure (ICP) due to an increase in brain volume within the enclosed skull.”
Maturation-dependent response of neurogenesis after traumatic brain injury in children.
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Bexarotene promotes microglia/macrophages - Specific brain - Derived Neurotrophic factor expression and axon sprouting after traumatic brain injury
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Effects of estrogen receptor GPR30 agonist G1 on neuronal apoptosis and microglia polarization in traumatic brain injury rats
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“Neurological motor symptoms of TBI were attenuated by limiting excess glutamate with dextorphan [28], n-methyl-D-aspartate (NMDA) antagonists [29], stimulation of Na+ -dependent excitatory amino acid transporters [30], or antibiotics and other drugs that block calcium channels or glutamate release [31].”
Background
The migration and differentiation of hUC-MSCsCXCR4/GFP encapsulated in BDNF/chitosan scaffolds for brain tissue engineering
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Background
Hypocalcaemia as a prognostic factor of early mortality in moderate and severe traumatic brain injury
Viñas-Ríos, J. M., Sánchez-Aguilar, M., Sánchez-Rodríguez, J., González-Aguirre, D., Heinen, C., Meyer, F., & Kretschmer, T. (2014) · Neurological Research · doi:10.1179/1743132813y.0000000272 · Cited by 23
Early increase of cannabinoid receptor density after experimental traumatic brain injury in the newborn piglet
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“However, while some trials are still ongoing, many failed (Tolias and Bullock 2004, McConeghy et al. 2012).”
Background
Comparison of the Effect of Minocycline and Simvastatin on Functional Recovery and Gene Expression in a Rat Traumatic Brain Injury Model
Haar, C. V., Anderson, G., Elmore, B. E., Moore, L. H., Wright, A. M., Kantor, E., Farin, F., Bammler, T., MacDonald, J. W., & Hoane, M. (2014) · Journal of Neurotrauma · doi:10.1089/neu.2013.3119 · Cited by 22 · see citing works
Pharmacological inhibition of STING reduces neuroinflammation‐mediated damage post‐traumatic brain injury
Fryer, A. L., Abdullah, A., Mobilio, F., Jobling, A., Moore, Z., de Veer, M., Zheng, G., Wong, B., Taylor, J. M., & Crack, P. (2024) · British Journal of Pharmacology · doi:10.1111/bph.16347 · Cited by 21 · see citing works
“Secondary injury in TBI is a complex array of interrelated molecular processes, such as excitotoxicity, necrosis and neuroinflammation, which all contribute to chronic neurodegeneration (Dixon, 2017; McConeghy et al., 2012).”
Argon gas: a potential neuroprotectant and promising medical therapy
Nowrangi, D., Tang, J.-P., & Zhang, J. H. (2014) · Medical Gas Research · doi:10.1186/2045-9912-4-3 · Cited by 20 · see citing works
“physical trauma [33,34].”
The Role of Magnesium in Depression, Migraine, Alzheimer’s Disease, and Cognitive Health: A Comprehensive Review
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“Patients with acute neurological conditions (e.g., stroke, traumatic brain injury) may not benefit substantially from magnesium therapy due to its slow cellular uptake and the narrow therapeutic window in such emergencies [176,177].”
Proteomics: in pursuit of effective traumatic brain injury therapeutics
Lizhnyak, P. N., & Ottens, A. K. (2015) · Espert Review of Proteomics · doi:10.1586/14789450.2015.1000869 · Cited by 19 · see citing works
“On reflection, we have been ineffective matching drug pharmacology within the heterogeneous human TBI population [13].”
Method
Neuroprotection strategies in traumatic brain injury: Studying the effectiveness of different clinical approaches
Buccilli, B., Alan, A., Baha’, A., Shahzad, A., Almealawy, Y. F., Chisvo, N., Ennabe, M., & Weinand, M. E. (2024) · Surgical neurology international · doi:10.25259/sni_773_2023 · Cited by 18 · see citing works
“[49,53] Immune system modulation e immunosuppressant Cyclosporine-A reduces T-cell-mediated immunity and is used in organ transplant recipients.”
Background
The lncRNA-AK046375 Upregulates Metallothionein-2 by Sequestering miR-491-5p to Relieve the Brain Oxidative Stress Burden after Traumatic Brain Injury
Tang, W., Chai, W., Du, D., Xia, Y.-Z., Wu, Y.-F., Jiang, L., Cheng, C.-J., Guo, Z.-D., Sun, X.-C., Huang, Z., et al. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/8188404 · Cited by 18
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Design and Synthesis of Brain Penetrant Glycopeptide Analogues of PACAP With Neuroprotective Potential for Traumatic Brain Injury and Parkinsonism
Apostol, C. R., Bernard, K., Tanguturi, P., Molnar, G., Bartlett, M. J., Szabó, L., Liu, C., Ortiz, J. B., Saber, M., Giordano, K. R., et al. (2022) · Frontiers in Drug Discovery · doi:10.3389/fddsv.2021.818003 · Cited by 20 · see citing works
“None of the available treatments have been clinically successful for TBI to date (Hall et al., 2010; Xiong et al., 2010; McConeghy et al., 2012; Tsang and Whitfield, 2012; Algattas and Huang, 2013).”
Background
C-terminal binding proteins 1 and 2 in traumatic brain injury-induced inflammation and their inhibition as an approach for anti-inflammatory treatment
Li, 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].”
Background
Post‐injury administration of a combination of memantine and 17&bgr;‐estradiol is protective in a rat model of traumatic brain injury
Day, N. L., Carle, M. S., & Floyd, C. L. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.04.018 · Cited by 18 · see citing works
“L. Day), Msc4705@uab.edu du (C.L. Floyd). pharmacotherapeutics available that effectively attenuate the secondary biochemical damage (Loane and Faden, 2010; McConeghy et al., 2012).”
Protection against Blast-Induced Traumatic Brain Injury by Increase in Brain Volume
Gu, M., Kawoos, U., Mccarron, R., & Chavko, M. (2017) · BioMed Research International · doi:10.1155/2017/2075463 · Cited by 18
“Several attempts to minimize secondary brain injury after TBI by pharmacological intervention or hypothermia were ineffective in clinical trials [14].”
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
Diltiazem Promotes Regenerative Axon Growth
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A Pulsed Electromagnetic Field Protects against Glutamate-Induced Excitotoxicity by Modulating the Endocannabinoid System in HT22 Cells
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“However, clinical trials have reported unsatisfactory results for drugs designed to treat excitotoxicity (McConeghy et al., 2012).”
Background
The neuroprotective potential of arginine-rich peptides for the acute treatment of traumatic brain injury
Chiu, L.-S., Anderton, R., Knuckey, N., & Meloni, B. (2016) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2016.1150180 · Cited by 17
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Background
Therapeutic Development of Apolipoprotein E Mimetics for Acute Brain Injury: Augmenting Endogenous Responses to Reduce Secondary Injury
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Blood Glutamate Scavenging With Pyruvate as a Novel Preventative and Therapeutic Approach for Depressive-Like Behavior Following Traumatic Brain Injury in a Rat Model
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Effects of nicotinamide on spatial memory and inflammation after juvenile traumatic brain injury
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“Preclinical trials of neuroprotective compounds have been numerous over the years, but many of these treatments have failed to show consistent neuroprotection in Phase II/III trials [13].”
Endogenous Neuroprotective Molecules and Their Mechanisms in the Central Nervous System.
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“Some studies have found favorable effects of cyclosporin A on mitochondrial dysfunction, 10,12,14 which is linked to LPR1.”

Authors: McConeghy, K. W., Hatton, J., Hughes, L., & Cook, A. M.
Affiliations: University of Kentucky HealthCare (US)
University of Kentucky (US)
Corresponding author: Cook, Aaron M.
ORCID: McConeghy, Kevin W.
Hatton, Jimmi
Cook, Aaron M.
Venue: CNS Drugs
Publisher: Springer Science and Business Media LLC
Published: 2012-07
Volume: 26
Issue: 7
Pages: 613-636
ISSN: 1172-7047 (ISSN-L)
DOI: 10.2165/11634020-000000000-00000
OpenAlex: W2006925820
Cited by: 158
References: 0
Citations by year: 2025: 4 · 2024: 8 · 2023: 3 · 2022: 10 · 2021: 8 · 2020: 10 · 2019: 11 · 2018: 16 · 2017: 20 · 2016: 17 · 2015: 18 · 2014: 17 · 2013: 13 · 2012: 3
FWCI: 2.29
Type: journal article
Language: en
Open access: closed
Locations: CNS Drugs (publishedVersion)
PubMed (publishedVersion)
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, secondary brain injury, intracranial pressure, cerebral perfusion, calcium influx, mitochondrial dysfunction, redox homeostasis, blood flow, cytoskeleton, magnesium, progesterone, cyclosporine, biomarkers, clinical trial design
MeSH terms: Animals, Brain Injuries, Clinical Trials as Topic, Humans, Prognosis, Multicenter Studies as Topic, Randomized Controlled Trials as Topic, Neuroprotective Agents

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A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury

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