Glucose-Dependent Insulinotropic Polypeptide Ameliorates Mild Traumatic Brain Injury-Induced Cognitive and Sensorimotor Deficits and Neuroinflammation in Rats

Abstract

Mild traumatic brain injury (mTBI) is a major public health issue, representing 75–90% of all cases of TBI. In clinical settings, mTBI, which is defined as a Glascow Coma Scale (GCS) score of 13–15, can lead to various physical, cognitive, emotional, and psychological-related symptoms. To date, there are no pharmaceutical-based therapies to manage the development of the pathological deficits associated with mTBI. In this study, the neurotrophic and neuroprotective properties of glucose-dependent insulinotropic polypeptide (GIP), an incretin similar to glucagon-like peptide-1 (GLP-1), was investigated after its steady-state subcutaneous administration, focusing on behavior after mTBI in an in vivo animal model. The mTBI rat model was generated by a mild controlled cortical impact (mCCI) and used to evaluate the therapeutic potential of GIP. We used the Morris water maze and novel object recognition tests, which are tasks for spatial and recognition memory, respectively, to identify the putative therapeutic effects of GIP on cognitive function. Further, beam walking and the adhesive removal tests were used to evaluate locomotor activity and somatosensory functions in rats with and without GIP administration after mCCI lesion. Lastly, we used immunohistochemical (IHC) staining and Western blot analyses to evaluate the inflammatory markers, glial fibrillary acidic protein (GFAP), amyloid-β precursor protein (APP), and bone marrow tyrosine kinase gene in chromosome X (BMX) in animals with mTBI. GIP was well tolerated and ameliorated mTBI-induced memory impairments, poor balance, and sensorimotor deficits after initiation in the post-injury period. In addition, GIP mitigated mTBI-induced neuroinflammatory changes on GFAP, APP, and BMX protein levels. These findings suggest GIP has significant benefits in managing mTBI-related symptoms and represents a novel strategy for mTBI treatment.

Novel GLP-1R/GIPR co-agonist “twincretin” is neuroprotective in cell and rodent models of mild traumatic brain injury

“…To this end, incretins and incretin mimetics have been investigated in regard to their anti-apoptotic, neuroprotective and neurotrophic effects in neurons expressing incretin receptors: namely the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) and the glucose-dependent insulinotropic peptide (GIP) receptor (GIPR) (Rachmany et al, 2013b; Tweedie et al, 2013a; Li et al, 2015; Tweedie et al, 2016; Yu et al, 2016). …”

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

“…The pathophysiology of mTBI is complex and characterized especially by neuronal cell death and axonal damage induced primarily by the direct physical impact itself and secondarily by oxidative stress, neuroinflammation, mitochondrial dysfunction, DNA damage, and other pathological processes (Maas et al, 2008;Choe, 2016;McInnes et al, 2017). Since incretins have the capability to intervene in more than one of these pathological events (Perry et al, 2002;Nyberg et al, 2005;Iwai et al, 2006;Li et al, 2010b;Paratore et al, 2011;Yu et al, 2016;Verma et al, 2017), incretin mimetics have the potential to serve as neuroprotective agents following mTBI.…”

“…In animal models, incretin analogs have been efficacious in preclinical models of: (i) Alzheimer's disease (Li et al, 2010a;McClean et al, 2011;Faivre and Holscher, 2013), (ii) Parkinson's disease (Bertilsson et al, 2008;Li et al, 2009Li et al, , 2016, (iii) stroke and ischemia (Li et al, 2009;Hyun Lee et al, 2011), (iv) peripheral neuropathy (Perry et al, 2007), (v) amyotrophic lateral sclerosis (Li et al, 2012), (vi) Huntington's disease (Martin et al, 2009), and (vii) TBI (Rachmany et al, 2013;Li et al, 2015;Yu et al, 2016;Tamargo et al, 2017;Bader et al, 2019). Moreover, as marketed GLP-1 analogs to treat T2DM are well-tolerated and rarely cause hypoglycemia, clinical trials have been undertaken to investigate the therapeutic effects of exendin-4 or liraglutide on Alzheimer's disease (Egefjord et al, 2012;Gejl et al, 2016), and Parkinson's disease patients (Aviles-Olmos et al, 2013;Athauda et al, 2017), and continue to be evaluated.…”

Neurotrophic and neuroprotective effects of oxyntomodulin in neuronal cells and a rat model of stroke

“…These group B receptors additionally include GPCRs that selectively bind glucose-dependent insulinotropic peptide (GIP), vasoactive intestinal peptide (VIP), pituitary adenylyl cyclase-activating peptide (PACAP) and other peptides (Harmar 2001; Nadkarni et al, 2014), several of which have demonstrated neuroprotective actions (Dejda et al, 2005; Brenneman 2007; Li et al, 2016; Yu et al, 2016). Heterotrimeric stimulatory (Gs) GTP-binding proteins are activated in response to GLP-1R and GCGR agonist binding, and they couple agonist occupancy to the stimulation of transmembrane adenylyl cyclases that in neurons, like pancreatic β-cells, catalyze conversion of ATP to cytosolic cAMP, a second messenger that then activates key downstream proteins (Campbell and Drucker, 2013; Nadkarni et al, 2014).…”