The neuroprotective potential of arginine-rich peptides for the acute treatment of traumatic brain injury

Traumatic brain injury (TBI) encompasses any insult to the brain resulting from external mechanical forces. The subsequent brain damage is complex, spanning a spectrum of symptoms and disabilities. TBI is a significant, but underappreciated public health and economic concern burdening developed countries. With only preventative and rehabilitative measures currently in place, there is a dire need to develop a therapeutic that preserves brain tissue in the acute stages following TBI. Recent research has highlighted the neuroprotective properties of arginine-rich peptides in vitro following neuronal excitotoxicity and in vivo following stroke. Therefore, based on the in vitro and in vivo neuroprotective actions of arginine-rich peptides these molecules are promising therapeutics to reduce acute TBI. Brain trauma is a major cause of morbidity and mortality in populations worldwide, usually as a consequence of road traffic accidents, falls, street violence and contact sports. Although this affliction perpetuates developed society, the occurrence of TBIrelated hospitalizations is greatest in young adult males [1]. Children, adolescents and adults aged 75 or over are also more susceptible to head trauma because of physical activity, and a risk of falls [1]. More recently, TBI has become a concern for active military personnel, who may be exposed to blast waves and other combat-related traumatic events [2]. Survivors of TBI often suffer from lifelong cognitive, physical, behavioral and communicative deficits that negatively affect families, communities and the economy. Furthermore, TBI sufferers are at a higher risk of developing anxiety and depressive disorders [3], and neurodegenerative diseases such as chronic traumatic encephalopathy, Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis [4]. Current strategies to minimize the impact of TBI focus on preventative measures, acute neuro-critical care and neurorestorative practices. However, targeting the secondary neuro-damaging processes that follow the primary insult provides an additional and potentially more effective, treatment to complement existing interventions. Therefore, any acute neuroprotective treatment strategy that maximizes preservation of brain tissue provides the best opportunity to improve outcomes following TBI. Of the multitude of experimental drugs studied for treating TBI, a number have shown preclinical neuroprotective efficacy and advanced to clinical trials. From there, the drug trials have returned neutral, negative or contradictory outcomes. While there may be several reasons why a pharmacological neuroprotective agent has failed clinically, one possibility is that the therapy specifically targets one of the many pathophysiology events activated in the brain following TBI. Many approaches aimed at mitigating secondary injury after TBI have been directed at attenuating excitotoxicity, a neuro-damaging process caused by the uncontrolled release of the neurotransmitter glutamate into the extracellular space. Clinical studies of glutamate receptor antagonists that target excitotoxicity such as dexanabinol, selfotel and magnesium, reported no statistically significant effects on Glasgow Outcome Score or mortality [5]. Another neuroprotective strategy is to block ion channels, thereby reducing the toxic intracellular influx of calcium and other ions into neurons, and the subsequent production of reactive oxygen species, and activation of calpains and endonucleases [6]. Unfortunately, clinical trials of calcium-channel blockers such as nimodipine and nicardipine have only shown an ability to decrease mortality or severe disability by reducing the onset of vasospasm in a small subset of TBI patients suffering a subarachnoid hemorrhage [5], making this type of medication unsuitable for the general TBI populace. The hormones erythropoietin (Clinicaltrials.gov Identifier: NCT00987454) and progesterone (Clinicaltrials.gov Identifier: NCT00822900), and the immunosuppressive peptide cyclosporine A (CsA) (Clinicaltrials.gov Identifier: NCT02496975) are other therapeutics that have undergone recent clinical trials after demonstrating preclinical efficacy. However, it appears that these agents may be of limited benefit following TBI [5,7]. The jaded nuance felt from the failure of the large number of TBI neuroprotection clinical trials beckons a shift in perspective. Although there have been recent calls for combined therapies of existing drugs, this direction may be ill-advised, as the additive effects could complicate pharmacokinetic interactions to the detriment of the patient [8]. Given the lack of success with previous neuroprotective agents for TBI, and the challenges combined therapy presents, an alternative therapeutic approach involves the use of cationic arginine-rich cell-penetrating peptides (CPP). Cationic CPPs fused to different ‘neuroprotective peptides’ have demonstrated efficacy in numerous acute brain injury models including stroke, perinatal hypoxiaischemia, epilepsy and TBI. The most commonly used cationic CPP is the HIV-derived TAT peptide (GRKKRRQRRR), which allows delivery of fused cargos (e.g. peptides, proteins, drugs) into the brain and neurons without any apparent toxicity in preclinical studies. TAT-mediated uptake into the brain is attributable to its composition of the basic amino acids lysine (K) and especially arginine (R), which confer a positive charge to the peptide [9]. Interactions between the cationic TAT peptide and anionic cell surface structures induces endocytosis and/or membrane transduction resulting in the transport of TAT and its cargo across the blood–brain barrier and cell membranes. EXPERT REVIEW OF NEUROTHERAPEUTICS, 2016 VOL. 16, NO. 4, 361–363 http://dx.doi. org/10.1586/14737175.2016. 1150180