Abstract
We previously demonstrated that pretreatment with Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) –mediated dopaminergic neurodegeneration. The use of GLP-1 or Exendin-4 for Parkinson’s disease (PD) patients is limited by their short half-lives. The purpose of this study was to evaluate a new extended release Exendin-4 formulation, PT302, in a rat model of PD. Subcutaneous administration of PT302 resulted in sustained elevations of Exendin-4 in plasma for >20 days in adult rats. To define an efficacious dose within this range, rats were administered PT302 once every 2 weeks either before or following the unilaterally 6-hydroxydopamine lesioning. Pre- and post-treatment with PT302 significantly reduced methamphetamine–induced rotation after lesioning. For animals given PT302 post lesion, blood and brain samples were collected on day 47 for measurements of plasma Exendin-4 levels and brain tyrosine hydroxylase immunoreactivity (TH-IR). PT302 significantly increased TH-IR in the lesioned substantia nigra and striatum. There was a significant correlation between plasma Exendin-4 levels and TH-IR in the substantia nigra and striatum on the lesioned side. Our data suggest that post-treatment with PT302 provides long-lasting Exendin-4 release and reduces neurodegeneration of nigrostriatal dopaminergic neurons in a 6-hydroxydopamine rat model of PD at a clinically relevant dose.
Highlights
We previously demonstrated that pretreatment with Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) –mediated dopaminergic neurodegeneration
Neuropathological studies of Parkinson’s disease (PD) patients indicate a dense localization of insulin receptors in dopaminergic neurons within the substantia nigra pars compacta[17], and their decline, as evaluated by messenger RNA or immunoreactivity (IR), is associated with a loss of tyrosine hydroxylase (TH) messenger RNA, the rate-limiting enzyme involved in dopamine synthesis[18]
We previously demonstrated that pretreatment with Exendin-4 protected primary ventromesenchephalic neurons from 6-hydroxydopamine (6-OHDA) lesioning
Summary
We previously demonstrated that pretreatment with Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) –mediated dopaminergic neurodegeneration. Neuropathological studies of PD patients indicate a dense localization of insulin receptors in dopaminergic neurons within the substantia nigra pars compacta[17], and their decline, as evaluated by messenger RNA or immunoreactivity (IR), is associated with a loss of tyrosine hydroxylase (TH) messenger RNA, the rate-limiting enzyme involved in dopamine synthesis[18] In parallel with this is evidence from animal models, in which the development of insulin resistance coincides with a decline in surface dopamine transporter levels in striatum[19], reduced insulin-evoked striatal dopamine release[20] and a decreased dopamine turnover[15,20,21]. The activation of GLP-1R on neurons induces potent neurotrophic and neuroprotective actions in cellular and animal models of neural injury and neurodegeneration[26], including models of PD27,28
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