dose. or following the unilaterally 6-hydroxydopamine lesioning. Pre- and post-treatment with PT302 significantly reduced methamphetamineCinduced rotation after lesioning. For animals given PT302 post lesion, blood and brain samples were collected on day 47 for measurements of plasma Ribavirin 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. Introduction Parkinsons disease (PD) is the second most common neurodegenerative disorder after Alzheimers Ribavirin disease, and afflicts approximately 1% of the population worldwide over the age of 60 years1. The number of PD patients is expected to more than double by 20402,3, and, although there are many symptomatic treatments for PD, none appear to have a significant effect on disease progression. The primary mechanism underpinning most approved PD drugs is to augment the dopaminergic transmission. Levodopa is the most commonly prescribed drug for PD, but its use and that of other dopaminergic agonists are limited by side effects and complications4. Thus, there is a need to develop non-dopaminergic pharmacological treatments for PD and, in particular, neuroprotective or disease modifying therapies that can slow or halt disease progression. Metabolic syndrome is increasingly recognized as a key factor in PD5C7, together with growing evidence that impaired insulin signaling plays Ribavirin a role in PD pathogenesis8C10. Supporting this, numerous, albeit not all, epidemiological studies suggest that diabetes is associated with increased risk for PD11C13. Furthermore, dysfunctional neuronal insulin signaling has been demonstrated in toxin-induced as well as high fat diet-induced animal models of PD and appears to exacerbate PD-associated impairments14C16. There is also evidence of dysregulated neuronal insulin signaling in human PD and Ribavirin PD dementia8. Given that efficient insulin signaling is critical for neuronal survival, the loss of this important pathway may thereby result in neurodegeneration. Neuropathological studies of PD patients indicate a dense localization of insulin receptors in dopaminergic neurons within the substantia nigra pars compacta17, 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 synthesis18. 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 striatum19, reduced insulin-evoked striatal dopamine release20 and a decreased dopamine turnover15,20,21. Overcoming aberrant insulin signaling can potentially be clinically achieved, and hence could represent a new treatment approach for neurodegenerative disorders. Incretins, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are gastrointestinal peptides that, following their release from the L and K cells of the Ribavirin gastrointestinal tract in response to food ingestion, regulate pancreatic -cell insulin release. Their receptors, GLP-1R and GIP-R, respectively, are expressed within the brain, in addition to pancreatic -cells22C24. The presence of the GLP-1R, in particular, has been demonstrated in the midbrain and striatum25. The Rabbit polyclonal to SIRT6.NAD-dependent protein deacetylase. Has deacetylase activity towards ‘Lys-9’ and ‘Lys-56’ ofhistone H3. Modulates acetylation of histone H3 in telomeric chromatin during the S-phase of thecell cycle. Deacetylates ‘Lys-9’ of histone H3 at NF-kappa-B target promoters and maydown-regulate the expression of a subset of NF-kappa-B target genes. Deacetylation ofnucleosomes interferes with RELA binding to target DNA. May be required for the association ofWRN with telomeres during S-phase and for normal telomere maintenance. Required for genomicstability. Required for normal IGF1 serum levels and normal glucose homeostasis. Modulatescellular senescence and apoptosis. Regulates the production of TNF protein activation of GLP-1R on neurons induces potent neurotrophic and neuroprotective actions in cellular and animal models of neural injury and neurodegeneration26, including models of PD27,28. The use of GLP-1 and GIP as potential treatments for diabetes mellitus type 2 (T2DM) or PD is greatly limited by their short half-lives, of less than 5?min29. However, long-acting analogues that include Exendin-4 (Exenatide), a GLP-1R.