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  • PMID: 30649046 was deleted because it is a duplicate of PMID: 30946151
AIDS. 2019 May 1;33(6):973-984. doi: 10.1097/QAD.0000000000002150.

Intranasal insulin therapy reverses hippocampal dendritic injury and cognitive impairment in a model of HIV-associated neurocognitive disorders in EcoHIV-infected mice.

Author information

1
Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
2
Johns Hopkins Drug Discovery Program.
3
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

Abstract

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 EcoHIV-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 μIU/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.

PMID:
30946151
PMCID:
PMC6457131
[Available on 2020-05-01]
DOI:
10.1097/QAD.0000000000002150

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