Brain Advance Access published online on November 16, 2008
Brain, doi:10.1093/brain/awn288
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Intranasal insulin prevents cognitive decline, cerebral atrophy and white matter changes in murine type I diabetic encephalopathy
1Department of Clinical Neurosciences and the Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada, 2Alzheimer's Research Center at Regions Hospital, HealthPartners Research Foundation, St. Paul, MN, USA and 3Department of Pharmacology and Therapeutics, Division of Neurodegenerative Disorders, University of Manitoba, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada
Correspondence to:
Dr C. Toth, University of Calgary, Department of Clinical Neurosciences, Room 155, 3330 Hospital Drive, N.W., Calgary, Alberta, Canada T2N 4N1 E-mail: corytoth{at}shaw.ca
Insulin deficiency in type I diabetes may lead to cognitive impairment, cerebral atrophy and white matter abnormalities. We studied the impact of a novel delivery system using intranasal insulin (I-I) in a mouse model of type I diabetes (streptozotocin-induced) for direct targeting of pathological and cognitive deficits while avoiding potential adverse systemic effects. Daily I-I, subcutaneous insulin (S-I) or placebo in separate cohorts of diabetic and non-diabetic CD1 mice were delivered over 8 months of life. Radio-labelled insulin delivery revealed that I-I delivered more rapid and substantial insulin levels within the cerebrum with less systemic insulin detection when compared with S-I. I-I delivery slowed development of cognitive decline within weekly cognitive/behavioural testing, ameliorated monthly magnetic resonance imaging abnormalities, prevented quantitative morphological abnormalities in cerebrum, improved mouse mortality and reversed diabetes-mediated declines in mRNA and protein for phosphoinositide 3-kinase (PI3K)/Akt and for protein levels of the transcription factors cyclic AMP response element binding protein (CREB) and glycogen synthase kinase 3β (GSK-3β) within different cerebral regions. Although the murine diabetic brain was not subject to cellular loss, a diabetes-mediated loss of protein and mRNA for the synaptic elements synaptophysin and choline acetyltransferase was prevented with I-I delivery. As a mechanism of delivery, I-I accesses the brain readily and slows the development of diabetes-induced brain changes as compared to S-I delivery. This therapy and delivery mode, available in humans, may be of clinical utility for the prevention of pathological changes in the diabetic human brain.
Key Words: diabetes; insulin; leukoencephalopathy; white matter abnormalities; brain atrophy; cognitive decline
Abbreviations: APP, amyloid precursor protein; CSF, cerebrospinal fluid; DW, diffusion-weighted; EMSA, electrophoretic mobility shift assay; IGF-1, insulin-like growth factor; IR, insulin receptor; NGF, nerve growth factor; SNMTS, spatial non-matching-to-sample; WMAs, white matter abnormalities
Received May 27, 2008. Revised October 3, 2008. Accepted October 8, 2008.
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