http://www.springerlink.com/content/g91720178324113h/
Abstract
Mild
traumatic brain injury (mTBI) represents a major and increasing public
health concern and is both the most frequent cause
of mortality and disability in young adults and a chief
cause of morbidity in the elderly. Albeit mTBI patients do not show
clear structural brain defects and, generally, do not
require hospitalization, they frequently suffer from long-lasting
cognitive,
behavioral, and emotional problems. No effective
pharmaceutical therapy is available, and existing treatment chiefly
involves
intensive care management after injury. The diffuse neural
cell death evident after mTBI is considered mediated by oxidative
stress and glutamate-induced excitotoxicity. Prior studies
of the long-acting GLP-1 receptor agonist, exendin-4 (Ex-4), an
incretin mimetic approved for type 2 diabetes mellitus
treatment, demonstrated its neurotrophic/protective activity in cellular
and animal models of stroke, Alzheimer’s and Parkinson’s
diseases, and, consequent to commonalities in mechanisms underpinning
these disorders, Ex-4 was assessed in a mouse mTBI model. In
neuronal cultures in this study, Ex-4 ameliorated H2O2-induced
oxidative stress and glutamate toxicity. To evaluate in vivo
translation, we administered steady-state Ex-4 (3.5 pM/kg/min)
or saline to control and mTBI mice over 7 days starting 48 h
prior to or 1 h post-sham or mTBI (30 g weight drop under anesthesia).
Ex-4 proved well-tolerated and fully ameliorated
mTBI-induced deficits in novel object recognition 7 and 30 days
post-trauma.
Less mTBI-induced impairment was evident in Y-maze, elevated
plus maze, and passive avoidance paradigms, but when impairment
was apparent Ex-4 induced amelioration. Together, these
results suggest that Ex-4 may act as a neurotrophic/neuroprotective
drug to minimize mTBI impairment.
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