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Exendin-4 induced glucagon-like peptide-1 receptor activation reverses behavioral impairments of mild traumatic brain injury in mice

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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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Acknowledgments

This research was supported in part by the Intramural Research Program of both the National Institute on Aging, National Institutes of Health, and the Sackler School of Medicine, Tel-Aviv University.

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Authors and Affiliations

  1. Department of Anatomy and Anthropology, Sackler School of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

    Lital Rachmany, Vardit Rubovitch & Chaim G. Pick

  2. Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA

    David Tweedie, Yazhou Li, Harold W. Holloway & Nigel H. Greig

  3. Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Jonathan Miller & Barry J. Hoffer

  4. Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, BRC Room 05 C220, 251 Bayview Blvd, Baltimore, MD, 21224, USA

    Nigel H. Greig

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  1. Lital Rachmany
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Correspondence to Nigel H. Greig.

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Nigel H. Greig, Chaim G. Pick, and Barry J. Hoffer contributed equally to this work as senior authors.

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Rachmany, L., Tweedie, D., Li, Y. et al. Exendin-4 induced glucagon-like peptide-1 receptor activation reverses behavioral impairments of mild traumatic brain injury in mice. AGE 35, 1621–1636 (2013). https://doi.org/10.1007/s11357-012-9464-0

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