期刊
AIDS
卷 33, 期 6, 页码 973-984出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAD.0000000000002150
关键词
EcoHIV; fear conditioning; HIV-associated neurocognitive impairment; insulin; intranasal insulin therapy; mouse models; quantitative PCR; radial arm water maze; synaptodendritic injury; working memory
资金
- JHU Center for AIDS Research [P01MH105280, R01DA037611, R01MH104145, P30MH075673, R01NS094146, P30AI094189-06]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [P30AI094189] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [P30MH075673, R01MH104145, R01MH110246, P01MH105280] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS094146] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA037611] Funding Source: NIH RePORTER
Objective: Almost half of HIV-positive people on antiretroviral therapy have demonstrable mild neurocognitive impairment (HIV-NCI), even when virologically suppressed. Intranasal insulin therapy improves cognition in Alzheimer's disease and diabetes. Here we tested intranasal insulin therapy in a model of HIV-NCI in Eco-HIV-infected conventional mice. Design and methods: Insulin pharmacokinetics following intranasal 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 intranasal insulin (2.4 IU/mouse) and examined for NCI in behavioral tests and HIV burdens by quantitative PCR. Some animals were tested for hippocampal neuronal integrity by immunostaining and expression of neuronal function-related genes by real time-quantitative PCR. The effect of insulin treatment discontinuation on cognition and neuropathology was also examined. Results: Intranasal insulin administration to mice resulted in mIU/ml levels of insulin in cerebrospinal fluid with a half-life of about 2 h, resembling pharmacokinetic parameters of patients receiving 40 IU. Intranasal 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; intranasal insulin reversed these changes coincident with restoration of cognitive acuity, but they returned within 24 h of treatment cessation. Intranasal insulin treatment reduced brain HIV DNA when started 23 but not 90 days after infection. Conclusion: Our preclinical studies support the use of intranasal insulin administration for treatment of HIV-NCI and suggest that some dendritic injury in this condition is reversible. Copyright (C) 2019 The Author(s). Published by Wolters Kluwer Health, Inc.
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