The role of the microbiota-gut-brain axis in long-term neurodegenerative processes following traumatic brain injury.

Traumatic brain injury (TBI) can be a devastating and debilitating disease to endure. Due to improvements in clinical practice, declining mortality rates have led to research into the long-term consequences of TBI. For example, the incidence and severity of TBI have been associated with an increased susceptibility of developing neurodegenerative disorders, such as Parkinson's or Alzheimer's disease. However, the mechanisms linking this alarming association are yet to be fully understood. Recently, there has been a groundswell of evidence implicating the microbiota-gut-brain axis in the pathogenesis of these diseases. Interestingly, survivors of TBI often report gastrointestinal complaints and animal studies have demonstrated gastrointestinal dysfunction and dysbiosis following injury. Autonomic dysregulation and chronic inflammation appear to be the main driver of these pathologies. Consequently, this review will explore the potential role of the microbiota-gut-brain axis in the development of neurodegenerative diseases following TBI.

Effect of Polyarginine Peptide R18D Following a Traumatic Brain Injury in Sprague-Dawley Rats.

BACKGROUND: Despite extensive studies, there are still no clinically available neuroprotective treatments for traumatic brain injury. OBJECTIVES: In previous studies we demonstrated beneficial treatment effects of polyarginine peptides R18 (18-mer of arginine; 300 nmol/kg) and R18D (18-mer of D-arginine; 1000 nmol/kg) in a rat model of impact-acceleration closed-head injury. METHODS: We examined the efficacy of R18D when intravenously administered at a low (100 nmol/kg) and high (1000 nmol/kg) dose, 30 minutes after a closed-head injury in male Sprague-Dawley rats. RESULTS: At postinjury day 3, treatment with R18D at the high dose significantly reduced axonal injury (P = 0.044), whereas the low-dose treatment of R18D showed a trend for reduced axonal injury. Following assessment in the Barnes maze, both doses of R18D treatment appeared to improve learning and memory recovery compared with vehicle treatment at postinjury days 1 and 3, albeit not to a statistically significant level. Rotarod assessment of vestibulomotor recovery did not differ between R18D and the vehicle treatment groups. CONCLUSIONS: R18D modestly decreased axonal injury only at the highest dose used but had no significant effect on functional recovery. These findings warrant further studies with additional doses to better understand peptide pharmacodynamics and provide information to guide optimal dosing.

Peptide Pharmacological Approaches to Treating Traumatic Brain Injury: a Case for Arginine-Rich Peptides.

Traumatic brain injury (TBI) has a devastating effect on victims and their families, and has profound negative societal and economic impacts, a situation that is further compounded by the lack of effective treatments to minimise injury after TBI. The current strategy for managing TBI is partly through preventative measures and partly through surgical and rehabilitative interventions. Secondary brain damage remains the principal focus for the development of a neuroprotective therapeutic. However, the complexity of TBI pathophysiology has meant that single-action pharmacological agents have been largely unsuccessful in combatting the associated brain injury cascades, while combination therapies to date have proved equally ineffective. Peptides have recently emerged as promising lead agents for the treatment of TBI, especially those rich in the cationic amino acid, arginine. Having been shown to lessen the impact of ischaemic stroke in animal models, there are reasonable grounds to believe that arginine-rich peptides may have neuroprotective therapeutic potential in TBI. Here, we review a range of peptides previously examined as therapeutic agents for TBI. In particular, we focus on cationic arginine-rich peptides -- a new class of agents that growing evidence suggests acts through multiple neuroprotective mechanisms.

Assessment of R18, COG1410, and APP96-110 in Excitotoxicity and Traumatic Brain Injury.

Cationic arginine-rich and poly-arginine peptides (referred to as CARPs) have potent neuroprotective properties in in vitro excitotoxicity and in vivo models of stroke. Traumatic brain injury (TBI) shares many pathophysiological processes as stroke, including excitotoxicity. Therefore, we evaluated our lead peptide, poly-arginine R18, with the COG1410 and APP96-110 peptides, which have neuroprotective actions following TBI. In an in vitro cortical neuronal glutamic acid excitotoxicity injury model, R18 was highly neuroprotective and reduced neuronal calcium influx, while COG1410 and APP96-110 displayed modest neuroprotection and were less effective at reducing calcium influx. In an impact-acceleration closed-head injury model (Marmarou model), R18, COG1410, and APP96-110 were administered intravenously (300 nmol/kg) at 30 minutes after injury in male Sprague-Dawley rats. When compared to vehicle, no peptide significantly improved functional outcomes, however the R18 and COG1410 treatment groups displayed positive trends in the adhesive tape test and rotarod assessments. Similarly, no peptide had a significant effect on hippocampal neuronal loss, however a significant reduction in axonal injury was observed for R18 and COG1410. In conclusion, this study has demonstrated that R18 is significantly more effective than COG1410 and APP96-110 at reducing neuronal injury and calcium influx following excitotoxicity, and that both R18 and COG1410 reduce axonal injury following TBI. Additional dose response and treatment time course studies are required to further assess the efficacy of R18 in TBI.