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Neurobiol Dis. 2019 Apr;124:439-453. doi: 10.1016/j.nbd.2018.11.023. Epub 2018 Nov 22.

Pharmacokinetics and efficacy of PT302, a sustained-release Exenatide formulation, in a murine model of mild traumatic brain injury.

Author information

1
Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.
2
Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institutes of Health, National Institute on Aging, Baltimore, MD, USA.
3
Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institutes of Health, National Institute on Aging, Baltimore, MD, USA; Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
4
Peptron Inc., Yuseong-gu, Daejeon, Republic of Korea.
5
Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
6
Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel; Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 69978, Israel; Center for the Biology of Addictive Diseases, Tel-Aviv University, Tel-Aviv 69978, Israel.
7
Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institutes of Health, National Institute on Aging, Baltimore, MD, USA. Electronic address: Greign@mail.nih.gov.

Abstract

Traumatic brain injury (TBI) is a neurodegenerative disorder for which no effective pharmacological treatment is available. Glucagon-like peptide 1 (GLP-1) analogues such as Exenatide have previously demonstrated neurotrophic and neuroprotective effects in cellular and animal models of TBI. However, chronic or repeated administration was needed for efficacy. In this study, the pharmacokinetics and efficacy of PT302, a clinically available sustained-release Exenatide formulation (SR-Exenatide) were evaluated in a concussive mild (m)TBI mouse model. A single subcutaneous (s.c.) injection of PT302 (0.6, 0.12, and 0.024 mg/kg) was administered and plasma Exenatide concentrations were time-dependently measured over 3 weeks. An initial rapid regulated release of Exenatide in plasma was followed by a secondary phase of sustained-release in a dose-dependent manner. Short- and longer-term (7 and 30 day) cognitive impairments (visual and spatial deficits) induced by weight drop mTBI were mitigated by a single post-injury treatment with Exenatide delivered by s.c. injection of PT302 in clinically translatable doses. Immunohistochemical evaluation of neuronal cell death and inflammatory markers, likewise, cross-validated the neurotrophic and neuroprotective effects of SR-Exenatide in this mouse mTBI model. Exenatide central nervous system concentrations were 1.5% to 2.0% of concomitant plasma levels under steady-state conditions. These data demonstrate a positive beneficial action of PT302 in mTBI. This convenient single, sustained-release dosing regimen also has application for other neurological disorders, such as Alzheimer's disease, Parkinson's disease, multiple system atrophy and multiple sclerosis where prior preclinical studies, likewise, have demonstrated positive Exenatide actions.

KEYWORDS:

Exenatide; Exendin-4; Glucagon-like peptide-1; Incretin mimetic; Mild traumatic brain injury; Neurodegeneration; Neuroinflammation; PT302

PMID:
30471415
DOI:
10.1016/j.nbd.2018.11.023

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