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

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 neuro-trophic 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 0.024mg/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.

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

“…These results are in accord with elevations in neurodegenerative processes that occur following blast-mTBI and their amelioration by a clinically translatable dose of the GLP-1R agonist exendin-4 (Tweedie et al, 2016b). Moreover, a sustained-release formulation of exenatide (PT302) similarly prevented the elevation in neurodegenerative processes and prolonged neuronal loss following injury exposure in the same mTBI-model as in the present study (Bader et al, 2019).…”

“…We avoided anxiety symptoms following the injury by using short-term anesthesia at the time of the TBI impact induction, to ensure that animals were unaware of the procedure. Hence, untoward actions on either anxiety or motor activity cannot be considered confounds when evaluating liraglutide and twincretin mitigation of mTBI-induced cognitive impairments, and these positive actions are in line with prior reports regarding the cognitive alleviation provided by incretin analogs following an mTBI challenge (Rachmany et al, 2013;Li et al, 2015;Tamargo et al, 2017;Bader et al, 2019;Glotfelty et al, 2019), as well as in Alzheimer's disease models (Faivre and Holscher, 2013;Shi et al, 2017;Batista et al, 2018;Glotfelty et al, 2019). FIGURE 7 | mTBI results in a decline in p-PKA levels in ipsilateral cortex.…”

“…Our prior studies evaluating a constant infusion of GIP in moderate TBI to overcome its rapid disappearance, demonstrated its ability to mitigate impairments when plasma GIP levels were raised by 2.2-fold (Yu et al, 2016). This prior study suggests that a relatively modest elevation in the level of an incretin can provide a biologically relevant effect, which is important in the light of the relatively small but quantifiable amount that enters the brain following systemic administration of incretin mimetic: with CSF levels achieving some 2% of plasma levels (Bader et al, 2019). Graph showing the p-PKA expression levels in ipsilateral/right cortex 48 h following mTBI.…”

“…Liraglutide treatment following mTBI did not prevent the elevation in GFAP expression as compared to sham mice in the CA3 region ( * p < 0.05); GFAP expression in the twincretin treatment group was significantly higher than control in all three regions ( we demonstrated the efficacy of exendin-4 (a GLP-1 analog), liraglutide (a long acting GLP-1 analog), twincretin (a dual GLP-1/GIP analog), and PT302 (a sustained release formulation of the GLP-1 analog Exanatide) to mitigate cellular damage associated with mTBI pathologies such as oxidative stress, glutamate induced toxicity, and apoptotic cell death. Moreover, these agents were successful in ameliorating the cognitive deficits evident following exposure to mTBI in mice (Rachmany et al, 2013;Li et al, 2015;Tamargo et al, 2017;Bader et al, 2019;Glotfelty et al, 2019) and other mTBI-induced brain pathologies such as neurodegeneration and neuroinflammation (Bader et al, 2019).…”

“…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.…”