期刊
ACS CHEMICAL NEUROSCIENCE
卷 9, 期 4, 页码 809-816出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.7b00434
关键词
Insulin; intranasal; pharmacokinetics; neurocognitive impairment; glucose; energy metabolism
资金
- NIMH [P30 MH075673]
- NIH/NIMH [PO1MH105280]
- Johns Hopkins PREP [R25GM109441]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R25GM109441] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [P30MH075673, R01MH104145, P01MH105280] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS044807] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA037611] Funding Source: NIH RePORTER
Insulin delivery to the brain has emerged as an important therapeutic target for cognitive disorders associated with abnormal brain energy metabolism. Although insulin is transported across the blood-brain barrier, peripheral routes of administration are problematic due to systemic effects of insulin on blood glucose. Intranasal (IN) administration is being investigated as an alternative route. We conducted a head-to-head comparison of subcutaneous (SC) and IN insulin, assessing plasma and brain pharmacokinetics and blood glucose levels in the mouse. SC insulin (2.4 IU) achieved therapeutically relevant concentrations in the brain (AUC(brain) = 2537 h center dot mu IU/mL) but dramatically increased plasma insulin (AUC(plasma) = 520 351 h center dot*mu IU/mL), resulting in severe hypoglycemia and in some cases death. IN administration of the same dose resulted in similar insulin levels in the brain (AUC(brain) = 3442 h center dot mu IU/mL) but substantially lower plasma concentrations (AUC(plasma) = 354 h center dot mu IU/mL,), amounting to a similar to 2000-fold increase in the AUC(brain:plasma) ratio relative to SC. IN dosing also had no significant effect on blood glucose. When administered daily for 9 days, IN insulin increased brain glucose and energy metabolite concentrations (e.g., adenosine triphosphate and phosphocreatine) without causing overt toxicity, suggesting that IN insulin may be a safe therapeutic option for cognitively impaired patients.
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