Incretin mimetics as pharmacologic tools to elucidate and as a new drug strategy to treat traumatic brain injury

Abstract

Traumatic brain injury (TBI), either as an isolated injury or in conjunction with other injuries, is an increasingly common event. An estimated 1.7 million injuries occur within the USA each year and 10 million people are affected annually worldwide. Indeed, nearly one third (30.5%) of all injury-related deaths in the USA are associated with TBI, which will soon outpace many common diseases as the major cause of death and disability. Associated with a high morbidity and mortality and no specific therapeutic treatment, TBI has become a pressing public health and medical problem. The highest incidence of TBI occurs in young adults (15-24 years age) and in the elderly (≥75 years of age). Older individuals are particularly vulnerable to these types of injury, often associated with falls, and have shown increased mortality and worse functional outcome after lower initial injury severity. In addition, a new and growing form of TBI, blast injury, associated with the detonation of improvised explosive devices in the war theaters of Iraq and Afghanistan, are inflicting a wave of unique casualties of immediate impact to both military personnel and civilians, for which long-term consequences remain unknown and may potentially be catastrophic. The neuropathology underpinning head injury is becoming increasingly better understood. Depending on severity, TBI induces immediate neuropathologic effects that, for the mildest form, may be transient; however, with increasing severity, these injuries cause cumulative neural damage and degeneration. Even with mild TBI, which represents the majority of cases, a broad spectrum of neurologic deficits, including cognitive impairments, can manifest that may significantly influence quality of life. Further, TBI can act as a conduit to longer term neurodegenerative disorders. Prior studies of glucagon-like peptide-1 (GLP-1) and long-acting GLP-1 receptor agonists have demonstrated neurotrophic/neuroprotective activities across a broad spectrum of cellular and animal models of chronic neurodegenerative (Alzheimer's and Parkinson's diseases) and acute cerebrovascular (stroke) disorders. In view of the mechanisms underpinning these disorders as well as TBI, we review the literature and recent studies assessing GLP-1 receptor agonists as a potential treatment strategy for mild to moderate TBI.

Published by Elsevier Inc.

Figures

Figure 1

Amino acid sequence of GLP-1 and that of the long-acting GLP-1 analogs, exendin-4 (Ex-4), lixisenatide and liraglutide. Ex-4 is known clinically as Byetta and Bydureon for subcutaneous (s.c.) twice a day and extended release (once weekly) dosing, respectively. Lixisenatide, known clinically by its trade name Lyxumia, and liraglutide (Victoza) are administered s.c. once daily. Amino acid homology (blue circles) and differences (fuscia circles), in comparison to GLP-1, are highlighted. The peptidase cleavage of GLP-1 by DPP-IV is noted. Of relevance Ex-4 and lixisenatide are close analogues that differ in their tail region. GLP-1 and liraglutide are likewise close analogues, with the latter possessing a C-16 fatty acid (palmitic acid) with a glutamic acid spacer attached to the lysine residue at position 26, permitting its binding to albumin to augment its half-life. By contrast, exendin (9-39) is a widely used pharmacological tool that is an antagonist at the GLP-1R.

Figure 2

Direct (upper) and indirect (lower) pharmacological actions of GLP-1R agonists. (Upper) GLP-1 agonists act directly by stimulating the GLP-1R to induce multiple coordinated actions at the level of pancreatic islet cells, within the heart, gastrointestinal tract, on subsets of immune cells and within the brain. (Lower) Within the brain, that GLP-1R agonists appear to freely enter, activation of select GLP-1R signaling pathways instigates biological actions within the gastrointestinal tract, liver and adipose tissue. Importantly, the activation of GLP-1R signaling cascades within the central and peripheral nervous systems appear to underpin the benefits of GLP-1R agonists described in preclinical animal models of AD, PD, stroke, ALS, Huntington's disease and, more recently TBI (adapted from Campbell and Drucker [82] and Salcedo et al., [75]).

Figure 3

Ex-4 Post-treatment protects against concussive mild TBI (mTBI)-induced cognitive loss, as assessed by novel object recognition at 7 day and 30 day testing post mTBI in two separate groups of mice (a similar protection was provided in a blast-TBI model that closely mimics military personnel trauma). Concussive (30 g weight drop) mTBI induces an impairment in visual memory (red column), as assessed by the novel object recognition paradigm, that was fully ameliorated when Ex-4 was administered (green column) pre-trauma (A (7 days), B (30 days)) and post-trauma (C (7 days), C (30 days)). Mice undergoing cognitive testing initiated on day 7 were euthanized on day 14, and their hippocampus was subjected to gene expression analyses. The mouse Ex-4 dose was 3.5 pM/kg/min (subcutaneously administered as a steady-state dose), which is 21 ug/kg/day and equivalent to a dose of 1.7 ug/kg/day in a human following normalization of body surface area between mouse and human. This dose compares favorably to once weekly exenatide LAR: 2 mg/week that provides a 60 kg human subject 4.8 ug/kg/day. Significantly impaired behavior compared to sham (uninjured) controls: Fisher's LSD post hoc, *p

Figure 4

Gene array analyses of the impact of concussive (30 g weight drop) mTBI (versus uninjured controls) on the hippocampus of animals derived from Figure 3, and the ameliorative effects of Ex-4 administration. (A) Pathway analysis: the effects of mild TBI (mTBI) vs. sham on the 10 most down-regulated (green) and up-regulated (red) pathway gene sets in mouse hippocampus are shown (pathway Z-scores are presented). The effects of treatment of mTBI with Ex-4 are shown in the black bars. In these black bars Ex-4 treatment of mTBI induced a change in gene sets relative to the mTBI group. Where no black bar is present, Ex-4 had no effect on gene sets relative to mTBI. In large part, treatment with Ex-4 prevented the down-regulation of the 10 most affected pathways associated with mTBI, while Ex-4 treatment had beneficial effects upon three of 10 up-regulated pathways. (B) Selecting the ‘Alzheimers disease dn’ pathway as a representative of those whose changes induced by mTBI were ameliorated by Ex-4, the pathway is opened to reveal the individual genes that comprise it (whose gene identities are shown as their gene symbol), presented as a classic heat map: up-regulation (red) and down-regulation (green). Remarkably, across the majority of individual genes mTBI-induced up-regulation is countered by Ex-4 mitigation. APP up-regulation by mTBI is noted, in line with TBI providing a conduit towards AD, which is mitigated by Ex-4. The scale for expression level is shown on the upper right, and the group comparisons are shown at the bottom of each section on the heat map. Adapted from Tweedie et al., [162].