title: Impact of Single or Repeated Dose Intranasal Zinc-free Insulin in Young and Aged F344 Rats on Cognition, Signaling, and Brain Metabolism.
abstract: Novel therapies have turned to delivering compounds to the brain using nasal sprays, bypassing the blood brain barrier, and enriching treatment options for brain aging and/or Alzheimer's disease. We conducted a series of in vivo experiments to test the impact of intranasal Apidra, a zinc-free insulin formulation, on the brain of young and aged F344 rats. Both single acute and repeated daily doses were compared to test the hypothesis that insulin could improve memory recall in aged memory-deficient animals. We quantified insulin signaling in different brain regions and at different times following delivery. We measured cerebral blood flow (CBF) using MRI and also characterized several brain metabolite levels using MR spectroscopy. We show that neither acute nor chronic Apidra improved memory or recall in young or aged animals. Within 2 hours of a single dose, increased insulin signaling was seen in ventral areas of the aged brains only. Although chronic Apidra was able to offset reduced CBF with aging, it also caused significant reductions in markers of neuronal integrity. Our data suggest that this zinc-free insulin formulation may actually hasten cognitive decline with age when used chronically.
authors.affiliation: Department of Pharmacology and Nutritional Sciences.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Anderson
authors.affiliation: Department of Pharmacology and Nutritional Sciences.
authors.forename: Hilaree N
authors.initials: HN
authors.lastname: Frazier
authors.affiliation: Department of Pharmacology and Nutritional Sciences.
authors.forename: Shaniya
authors.initials: S
authors.lastname: Maimaiti
authors.affiliation: The Sanders-Brown Center on Aging, and.
authors.forename: Vikas V
authors.initials: VV
authors.lastname: Bakshi
authors.affiliation: The School of Biology, University of Kentucky, Lexington.
authors.forename: Zana R
authors.initials: ZR
authors.lastname: Majeed
authors.affiliation: Department of Pharmacology and Nutritional Sciences.
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Brewer
authors.affiliation: Department of Pharmacology and Nutritional Sciences.
authors.forename: Nada M
authors.initials: NM
authors.lastname: Porter
authors.affiliation: The Sanders-Brown Center on Aging, and.
authors.forename: Ai-Ling
authors.initials: AL
authors.lastname: Lin
authors.affiliation: Department of Pharmacology and Nutritional Sciences, othibau@uky.edu.
authors.forename: Olivier
authors.initials: O
authors.lastname: Thibault
mesh_terms: D000281:Administration, Intranasal; D000367:Age Factors; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002560:Cerebrovascular Circulation; D003071:Cognition / Q000187:drug effects*; D007328:Insulin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects*; D015032:Zinc
chemical_list: D007328:Insulin; C479079:insulin glulisine; D015032:Zinc
keywords: Cognition; Diabetes; Metabolism; Vascular