Intranasal insulin improves memory in humans

Benedict, Christian; Hallschmid, Manfred; Hatke, Astrid; Schultes, Bernd; Fehm, Horst L.; Born, Jan; Kern, Werner

doi:10.1016/j.psyneuen.2004.04.003

Cited by 621 publications

(498 citation statements)

References 32 publications

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“…Moreover, the loss of Irs2 in the mouse brain is associated with reduced neuronal proliferation during development, as well as accumulation of neurofibrillary tangles containing phosphorylated tau in the hippocampus, favouring intact Irs2 signalling in the hypothalamus as neuroprotective [30]. This is in agreement with a study in humans showing that intranasal administration of insulin leads to an improvement of cognitive function and memory, opening a whole new aspect in insulin therapy [25].…”

Section: Discussionsupporting

confidence: 86%

“…In these healthy subjects the administration of nasal insulin led to a loss of body weight and body fat over an 8-week treatment accompanied by a drop in plasma leptin levels. These data provide a profound basis for a negative feedback signal of insulin in the regulation of body weight and adiposity [25]. Moreover, a recent study in humans compared the effect of human insulin and insulin detemir on hepatic glucose production [26].…”

Section: Discussionmentioning

confidence: 90%

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Tissue selectivity of insulin detemir action in vivo

et al. 2006

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Aims/hypothesis: Recombinant DNA technology is a useful tool that can be used to create insulin analogues with modified absorption kinetics to improve glycaemic control in patients with type 1 and type 2 diabetes. Among conventional insulin analogues, which are usually created by amino acid exchange, insulin detemir is the first analogue to be acylated with a fatty acid to enable reversible albumin binding. In this study we determined activation of the insulin receptor (IR)-signalling cascade by insulin detemir at the level of IR and IR substrate (Irs) phosphorylation, as well as downstream signalling elements such as phosphatidylinositol 3-kinase and Akt, and performed epidural EEG in vivo. Methods: C57Bl/6 mice were injected i.v. with either insulin detemir or human insulin and Western blot analysis was performed on liver, muscle, hypothalamic and cerebrocortical tissues. Moreover, cerebrocortical activity was detected by EEG in awake mice and cerebral insulin concentrations were measured following human insulin and insulin detemir injection. Results: The time course and extent of IR phosphorylation in peripheral tissues were similar following insulin detemir treatment compared with human insulin, but insulin signalling in hypothalamic and cerebrocortical tissue determined by tyrosine-phosphorylation of the IR and Irs2 proteins occurred faster and was enhanced due to a higher insulin detemir concentration in the brain. Moreover, epidural EEG in mice displayed increased cortical activity using insulin detemir. Conclusions/interpretation: Taken together, these data suggest that insulin detemir has a tissue-selective action, with a relative preference for brain compared with peripheral tissues.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 90%

Tissue selectivity of insulin detemir action in vivo

et al. 2006

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“…As reported previously (Benedict et al, 2004), 8 weeks of RH-I administration significantly improved declarative memory performance as assessed by a delayed recall of words learned 1 week earlier.…”

Section: Discussionsupporting

confidence: 85%

“…The data of the RH-I and placebo conditions were partly derived from a male subsample of eight subjects per group from a previously published study (Benedict et al, 2004). Both groups (n ¼ 12) were each supplemented by four subjects to match all groups according to age and BMI.…”

Section: Methodsmentioning

confidence: 99%

“…Intranasal administration of bioactive compounds has been demonstrated to effectively deliver drugs to the brain without inducing systemic side effects (Born et al, 2002;Ross et al, 2004;Thorne et al, 2004; for review see Illum, 2000). Recent studies have revealed beneficial effects of acute and long-term (8 weeks) intranasal administration of regular human insulin (RH-I) on declarative memory in humans (Benedict et al, 2004;Reger et al, 2006). As RH-I molecules tend to self-associate into dimeric, tetrameric, and hexameric units, their absorption after subcutaneous administration is delayed (Kang et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

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Intranasal Insulin Improves Memory in Humans: Superiority of Insulin Aspart

Benedict

Hallschmid

Schmitz

et al. 2006

Neuropsychopharmacol

264

157

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There is compelling evidence that intranasal administration of regular human insulin (RH-I) improves memory in humans. Owing to the reduced tendency of its molecules to form hexamers, the rapid-acting insulin analog insulin aspart (ASP-I) is more rapidly absorbed than RH-I after subcutaneous administration. Since after intranasal insulin administration, ASP-I may also be expected to access the brain, we examined whether intranasal ASP-I has stronger beneficial effects on declarative memory than RH-I in humans. Acute (40 IU) and longterm (4 Â 40 IU/day over 8 weeks) effects of intranasally administered ASP-I, RH-I, and placebo on declarative memory (word lists) were assessed in 36 healthy men in a between-subject design. Plasma insulin and glucose levels were not affected. After 8 weeks of treatment, however, word list recall was improved compared to placebo in both the ASP-I (po0.01) and the RH-I groups (po0.05). ASP-I-treated subjects performed even better than those of the RH-I-treated group (po0.05). Our results indicate that insulin-induced memory improvement can be enhanced by using ASP-I. This finding may be especially relevant for a potential clinical administration of intranasal insulin in the treatment of memory disorders like Alzheimer's disease.

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The Blood–Brain Barrier and CNS Drug Delivery

Banks

2021

Burger's Medicinal Chemistry and Drug Discovery

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One of the biggest obstacles to drug development for the central nervous system (CNS) is the blood–brain barriers (BBBs). These consist of the vascular BBB, the choroid plexus (blood‐cerebrospinal fluid barrier), the tanycytic barrier at the circumventricular organs, and some specialized barriers, such as the blood–retinal barrier. Of these barriers, the vascular BBB is the most studied and most targeted for CNS drug delivery. An understanding of the composition and nature of the barriers is useful in drug development and explains both the success and difficulties of using transcellular diffusion, the mechanism used by nearly all the currently CNS active drugs, for small molecules. An understanding of the vascular BBB also explains why the intuitively appealing approaches of BBB disruption and Trojan horse have been so disappointing. Alternative approaches, including discovery, use, or modulation of transporters, adaption of adsorptive transcytosis, and targeting the BBB itself are intriguing but largely unexploited. Strategies for using these underexploited approaches are examined and specific examples are given.

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Intranasal insulin improves memory in humans

Cited by 621 publications

References 32 publications

Tissue selectivity of insulin detemir action in vivo

Tissue selectivity of insulin detemir action in vivo

Intranasal Insulin Improves Memory in Humans: Superiority of Insulin Aspart

The Blood–Brain Barrier and CNS Drug Delivery

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