Traumatic brain injury (TBI) is a commonly occurring injury in sports, victims of motor vehicle accidents, and falls. TBI has become a pressing public health concern with no specific therapeutic treatment. Mild TBI (mTBI), which accounts for approximately 90% of all TBI cases, may frequently lead to long-lasting cognitive, behavioral, and emotional impairments. The
incretins glucagon-like peptide-1 (GLP-1) and
glucose-dependent insulinotropic
polypeptide (GIP) are
gastrointestinal hormones that induce
glucose-dependent insulin secretion, promote β-cell proliferation, and enhance resistance to apoptosis.
GLP-1 mimetics are marketed as treatments for
type 2 diabetes mellitus (T2DM) and are well tolerated. Both
GLP-1 and GIP mimetics have shown neuroprotective properties in animal models of Parkinson's and
Alzheimer's disease. The aim of this study is to evaluate the potential
neuroprotective effects of
liraglutide, a
GLP-1 analog, and twincretin, a dual GLP-1R/GIPR agonist, in a murine mTBI model. First, we subjected mice to mTBI using a weight-drop device and, thereafter, administered
liraglutide or twincretin as a 7-day regimen of subcutaneous (s.c.)
injections. We then investigated the effects of these drugs on mTBI-induced
cognitive impairments, neurodegeneration, and
neuroinflammation. Finally, we assessed their effects on neuroprotective
proteins expression that are downstream to GLP-1R/GIPR activation; specifically, PI3K and PKA phosphorylation. Both drugs ameliorated mTBI-induced
cognitive impairments evaluated by the novel object recognition (NOR) and the Y-maze paradigms in which neither anxiety nor locomotor activity were confounds, as the latter were unaffected by either mTBI or drugs. Additionally, both drugs significantly mitigated mTBI-induced neurodegeneration and
neuroinflammation, as quantified by immunohistochemical staining with
Fluoro-Jade/anti-NeuN and anti-Iba-1
antibodies, respectively. mTBI challenge significantly decreased PKA phosphorylation levels in ipsilateral cortex, which was mitigated by both drugs. However, PI3K phosphorylation was not affected by mTBI. These findings offer a new potential therapeutic approach to treat mTBI, and support further investigation of the
neuroprotective effects and mechanism of action of
incretin-based
therapies for
neurological disorders.