Within this program several studies are on-going Old monkeys were treated with Rituximab to deplete the B cell population. Once B cells were replenished, Rituximab-treated monkeys, and young and old controls were vaccinated against the influenza virus. Plasma samples were collected to assess the antigen response to the vaccination. Analysis is on-going. Inhibition of PI3K signaling has been shown to increase energy expenditure, protect from obesity and metabolic syndrome, and increase longevity in rodent models. In our study, obese monkeys were treated daily for 3 months with an oral dose of a PI3K inhibitor resulting in decreased adiposity, and lowered serum glucose and triglyceride levels, without any detectable side effects. Dipeptidyl protease-4 (DPP-4) inhibitors also known as gliptins - are widely used in the effective treatment of type 2 diabetes to safely regulate blood glucose levels. DPP-4 is the key enzyme responsible for the metabolism of the endogenous incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) whose elevated levels in brain, were hypothesized to provide neurotrophic/neuroprotective actions in cellular and rodent models of Parkinsons disease (PD). On evaluating several DPP-4 inhibitors, brain and plasma incretin levels were, indeed, substantially elevated in rodents, and this resulted in amelioration of Parkinsonism and elevations in brain dopamine levels in a well-characterized rodent PD model. In the current study, we evaluated sitagliptin in nonhuman primates to assess whether translational doses elevate systemic (plasma) and central (CSF) incretin levels, as achieved in rats, to (i) cross-validate our studies across species and (ii) de-risk clinical translation of this drug as a new treatment for PD. Twenty adult rhesus monkeys (Macaca mulatta) were given 1 of 4 drug conditions (Control, 5, 20, or 100 mg/kg) daily for 6 days. On day 6, an oral glucose load was given to stimulate incretin release. Blood and cerebral spinal fluid samples were collected at specified time points during the subsequent 24 hours. Active incretin levels were observed in both plasma and CSF with all 3 doses. The intermediate dose (20 mg/kg) induced the greatest response. DPP4 inhibition in the plasma was dose-dependent. An inverted U dose-response relationship on incretin levels in both plasma and CSF was evident with the high dose providing less activitylikely due to compensatory mechanisms at the level of incretin synthesis/secretion. The current results validate those from rat studies and lay the groundwork for dose selection for repositioning sitagliptin in a potential clinical trial in PD. To better understand muscle dysfunction and factors contributing to sarcopenia, we are assessing muscle and mitochondria function of young and old monkeys in comparison to young and old humans. Several samples have been collected and the analysis is on-going.
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