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. In a follow up study with Dr. Biragyns lab, we will deplete 4BL cells in old monkeys using daily antibiotic treatment. Fecal samples will be collected throughout the study to determine if age-related changes in the microbiota are associated with changes in 4BL cells. 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). 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. Neuropathic pain affects the quality of life of individuals with age-associated diseases like cancer and diabetes. Currently, clinical management of chronic neuropathic pain is limited by marginal effectiveness and problematic side effects available with pharmaceutical drugs. New classes of drugs are needed. Recently it has been demonstrated that selective adenosine kinase inhibition increases endogenous adenosine and produces analgesic effects in rodent models of neuropathic pain. The A3 subtype of the adenosine receptor is expressed in many tissues including neurons and glial cells, and highly selective A3 receptor agonists have been synthesized and characterized in the laboratory of Kenneth Jacobson, NIDDK. Early clinical trials of this class of compounds suggest pain relief without the cardiovascular side effects that are common with the other adenosine receptor subtypes. However, in a preliminary trial, the compound MRS5980 was not well tolerated after an oral dose. The reason for the poor reaction is not mechanism related, as other A3 agonists have been successfully administered to other species. Preliminary testing in NHPs was planned to confirm gastrointestinal tolerance and provide bioavailability data in NHPs, a species more closely related to humans. Disulfiram is best known for its role to curb alcoholism by inhibiting alcohol dehydrogenase to raise acetaldehyde following alcohol consumption. The reaction is unpleasant and is thus considered a deterrent to alcohol consumption. Disulfiram also serves as an antioxidant and thus has therapeutic potential for conditions such as type II diabetes, in which the pancreatic islet cells deteriorate, likely due to reactive oxygen species damage. In a type II diabetic rat model, Nagai et al. report attenuation of the age-associated increase in plasma glucose and triglycerides, as well as increased insulin. Current findings from mice in Dr. de Cabos lab, suggest that disulfiram may reduce body weight and improve associated metabolic complications in a diet induced model of rodent obesity. Ultimately, we would like to translate the rodent effects to a monkey model. 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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