Incretin Mimetics as Rational Candidates for the Treatment of Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is becoming an increasing public health issue. With an annually estimated 1.7 million TBIs in the United States (U.S.) and nearly 70 million worldwide, the injury, isolated or compounded with others, is a major cause of short-and longterm disability and mortality. This, along with no specific treatment, has made exploration of TBI therapies a priority of the health system. Age and sex differences create a spectrum of vulnerability to TBI, with the highest prevalence among younger and older populations. Increased public interest in the long term effects and prevention of TBI have recently reached peaks, with media attention bringing heightened awareness to sport and war related head injuries. Along with short-term issues, TBI can increase the likelihood for development of long-term neurodegenerative disorders. A growing body of literature supports the use of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon (Gcg) receptor (R) agonists, along with unimolecular combinations of these therapies, for their potent neurotrophic/neuroprotective activities across a variety of cellular and animal models of chronic neurodegenerative diseases (Alzheimer's and Parkinson's diseases) and acute cerebrovascular disorders (stroke). Mild or moderate TBI shares many of the hallmarks of these conditions; recent work provides evidence that use of these compounds is an effective strategy for its treatment. Safety and efficacy of many incretinbased therapies (GLP-1 and GIP) have been demonstrated in humans for the treatment of type 2 diabetes mellitus (T2DM), making these compounds ideal for rapid evaluation in clinical trials of mild and moderate TBI.

Neuroprotective Effects and Treatment Potential of Incretin Mimetics in a Murine Model of Mild Traumatic Brain Injury

“…We avoided anxiety symptoms following the injury by using short-term anesthesia at the time of the TBI impact induction, to ensure that animals were unaware of the procedure. Hence, untoward actions on either anxiety or motor activity cannot be considered confounds when evaluating liraglutide and twincretin mitigation of mTBI-induced cognitive impairments, and these positive actions are in line with prior reports regarding the cognitive alleviation provided by incretin analogs following an mTBI challenge (Rachmany et al, 2013;Li et al, 2015;Tamargo et al, 2017;Bader et al, 2019;Glotfelty et al, 2019), as well as in Alzheimer's disease models (Faivre and Holscher, 2013;Shi et al, 2017;Batista et al, 2018;Glotfelty et al, 2019). FIGURE 7 | mTBI results in a decline in p-PKA levels in ipsilateral cortex.…”

“…Our previous studies focused on the effects of several clinically relevant incretin analogs on mTBI-induced impairments in cellular and rodent mTBI models following administration of clinically translatable doses (Glotfelty et al, 2019). Specifically, FIGURE 5 | Liraglutide and twincretin treatments do not affect the mTBI-induced elevation in reactive astrocyte expression, 72 h post trauma.…”

“…Liraglutide treatment following mTBI did not prevent the elevation in GFAP expression as compared to sham mice in the CA3 region ( * p < 0.05); GFAP expression in the twincretin treatment group was significantly higher than control in all three regions ( we demonstrated the efficacy of exendin-4 (a GLP-1 analog), liraglutide (a long acting GLP-1 analog), twincretin (a dual GLP-1/GIP analog), and PT302 (a sustained release formulation of the GLP-1 analog Exanatide) to mitigate cellular damage associated with mTBI pathologies such as oxidative stress, glutamate induced toxicity, and apoptotic cell death. Moreover, these agents were successful in ameliorating the cognitive deficits evident following exposure to mTBI in mice (Rachmany et al, 2013;Li et al, 2015;Tamargo et al, 2017;Bader et al, 2019;Glotfelty et al, 2019) and other mTBI-induced brain pathologies such as neurodegeneration and neuroinflammation (Bader et al, 2019).…”

“…A caveat of our study is that we were unable to evaluate twincretin in comparison to a clinically translatable dose of a single GIPR agonist. Whereas single GIPR agonists are available as pharmacological tools and several are long-acting (Glotfelty et al, 2019), none have translated into humans and hence no information is available as to a clinically translatable dose to support a comparative evaluation. Our prior studies evaluating a constant infusion of GIP in moderate TBI to overcome its rapid disappearance, demonstrated its ability to mitigate impairments when plasma GIP levels were raised by 2.2-fold (Yu et al, 2016).…”

“…Finally, to understand how our mTBI model and incretin analogs regulate neuroprotective protein expression, we examined the levels of PKA and PI3K phosphorylation in the cortex and hippocampus by Western blot. Contrary to the cellular pathways that incretins activate in the pancreas, those activated in brain remain to be fully characterized (Glotfelty et al, 2019). Multiple studies have proposed signaling pathways downstream to GLP-1R or GIPR activation in neurons (Perry and Greig, 2003;Li et al, 2010b;Holscher, 2014;McGrath et al, 2015;Kim et al, 2017;Athauda and Foltynie, 2018;Verma et al, 2018).…”