Pharmacologic Neuroprotection for Functional Outcomes After Traumatic Brain Injury: A Systematic Review of the Clinical Literature

Abstract

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.

Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease

“…Furthermore, CB 1 receptor and CB 2 receptor antagonists prevent drug-induced neuroprotection in a mouse mode of TBl (Lopez-Rodriguez et al, 2015). However, as indicated previously for other disorders, limited clinical data is available to support efficacy and safety of CBs during TBI (Gruenbaum et al, 2016). …”

“…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). These events may be neuroprotective and prevent excitotoxicity, inhibit inflammatory cytokine production and augment stem cell migration and differentiation.…”

Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift

“…Because of all these contributing factors, no effective interventions were shown to improve functional outcome in survivors despite extensive effort to develop neuroprotective therapies for TBI patients (Gruenbaum et al, 2016; Janowitz and Menon, 2010; McConeghy et al, 2012). To better understand TBI pathogenesis and develop treatments, experimental animal models are routinely used (Marklund and Hillered, 2011; Xiong et al, 2013).…”

Impact of traumatic brain injury on dopaminergic transmission

“…103 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. 105 Cerebrolysin is a parenterally administered neuropeptide preparation that can penetrate the BBB and can act in a manner similar to endogenous neurotrophic factors.…”

“…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. 105 Cerebrolysin is a parenterally administered neuropeptide preparation that can penetrate the BBB and can act in a manner similar to endogenous neurotrophic factors. Cerebrolysin could decrease brain APP accumulation and astrogliosis as well as increase neuroblasts and neurogenesis to improve long-term cognitive function.…”