Intranasal insulin therapy reverses hippocampal dendritic injury and cognitive impairment in a model of HAND in EcoHIV-infected mice

OBJECTIVE:Almost half of HIV-positive people on antiretroviral therapy (ART) have demonstrable mild neurocognitive impairment (HIV-NCI), even when virologically suppressed. Intranasal (IN) insulin therapy improves cognition in Alzheimerʼs disease and diabetes. Here we tested IN insulin therapy in a model of HIV-NCI in EcoHIV-infected conventional mice. DESIGN AND METHODS:Insulin pharmacokinetics following IN administration to mice was determined by ELISA. Mice were inoculated with EcoHIV to cause NCI; 23 days or 3 months after infection they were treated daily for 9 days with IN insulin (2.4 IU/mouse) and examined for NCI in behavioral tests and HIV burdens by QPCR. Some animals were tested for hippocampal neuronal integrity by immunostaining and expression of neural function related genes by RT-QPCR. The effect of insulin treatment discontinuation on cognition and neuropathology was also examined. RESULTS:IN insulin administration to mice resulted in μIU/ml levels of insulin in CSF with a half-life of about 2 h, resembling pharmacokinetic parameters of patients receiving 40 IU. IN insulin treatment starting 23 days or 3 months after infection completely reversed NCI in mice. Murine NCI correlated with reductions in hippocampal dendritic arbors and downregulation of neuronal function genes; IN insulin reversed these changes coincident with restoration of cognitive acuity, but they returned within 24 h of treatment cessation. IN insulin treatment reduced brain HIV DNA when started 23 but not 90 days after infection. CONCLUSIONS:Our preclinical studies support the use of IN insulin administration for treatment of HIV-NCI and suggest that some dendritic injury in this condition is reversible.Thisis an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0