As key members of the Johns Hopkins NIMH Center for Novel Therapeutics for HIV-Associated Neurocognitive Disorders (HAND), JHDD scientists are contributing to the discovery of potential new treatments for HAND. HAND encompasses a hierarchy of progressive neurocognitive impairments up to and including cognitive, motor and behavioral abnormalities, 1-3 and remains a central health issue in patients with chronic HIV infection on combination antiretroviral therapy (cART). 4, 5 In a recent study examining HIV-infected adults recruited from six university clinics across the United States, nearly half of HIV-infected individuals without confounding conditions had some form of HAND. 6
Multiple, novel drug targets with therapeutic promise for HAND are under investigation in JHDD and collaborating labs. Administration of intranasal insulin represents one of these approaches, based on several preclinical and clinical reports indicating a role for this hormone in cognitive function 7-14 and HAND pathology15-18. A recent study found intranasal insulin to improve cognition in a feline model of HAND.15 Because peripheral administration of insulin can cause hyperinsulinemia and hypoglycemia, insulin therapy utilization for cognition enhancement has focused on intranasal administration. Intranasal administration can provide rapid delivery of insulin selectively to the brain via bulk flow along olfactory and trigeminal perivascular channels, and via olfactory bulb axonal transport while maintaining peripheral euglycemia [64-66]. This advantage of intranasal dosing has been replicated in preclinical testing of compounds developed by JHDD which show improved brain exposure when administered via the intranasal route in rodents and non-human primates.20
Studies are now ongoing to test the effect of intranasal insulin on cognition in a rodent model of HAND, and to fully characterize the pharmacokinetics of insulin administered via this route. Efforts to delineate the mechanism of insulin efficacy in HAND are also underway with particular attention being paid to the effect of insulin on energy metabolism in key brain regions, as well as a potential effect on viral load. These experiments will inform study design and dose selection for a clinical trial of intranasal insulin administration in HAND patients currently being enrolled by Johns Hopkins collaborators.
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- Mamik, M. K.; Asahchop, E. L.; Chan, W. F.; Zhu, Y.; Branton, W. G.; McKenzie, B. A.; Cohen, E. A.; Power, C. Insulin Treatment Prevents Neuroinflammation and Neuronal Injury with Restored Neurobehavioral Function in Models of HIV/AIDS Neurodegeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience 2016, 36, 10683-10695.
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