Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition

Salameh, Therese S.; Bullock, Kristin M.; Hujoel, Isabel A.; Niehoff, Michael L.; Wolden‐Hanson, Tami; Kim, Jung-Hyun; Morley, John E.; Farr, Susan A.; Banks, William A.

doi:10.3233/jad-150307

Cited by 108 publications

(95 citation statements)

References 44 publications

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“…The level of radioactivity in each of the regions and the serum was measured in a Wizard2 Automatic Gamma Counter (PerkinElmer, Waltham, MA, USA). The percentage of injected dose present in a milliliter of serum (%Inj/mL) and the percentage of the injected dose taken up per gram of tissue (%Inj/g) was calculated as previously described [55,56]. …”

Section: Methodsmentioning

confidence: 99%

Passage through the Ocular Barriers and Beneficial Effects in Retinal Ischemia of Topical Application of PACAP1-38 in Rodents

Werling

Banks

Salameh

et al. 2017

IJMS

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The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has two active forms, PACAP1-27 and PACAP1-38. Among the well-established actions are PACAP’s neurotrophic and neuroprotective effects, which have also been proven in models of different retinopathies. The route of delivery is usually intravitreal in studies proving PACAP’s retinoprotective effects. Recently, we have shown that PACAP1-27 delivered as eye drops in benzalkonium-chloride was able to cross the ocular barriers and exert retinoprotection in ischemia. Since PACAP1-38 is the dominant form of the naturally occurring PACAP, our aim was to investigate whether the longer form is also able to cross the barriers and exert protective effects in permanent bilateral common carotid artery occlusion (BCCAO), a model of retinal hypoperfusion. Our results show that radioactive PACAP1-38 eye drops could effectively pass through the ocular barriers to reach the retina. Routine histological analysis and immunohistochemical evaluation of the Müller glial cells revealed that PACAP1-38 exerted retinoprotective effects. PACAP1-38 attenuated the damage caused by hypoperfusion, apparent in almost all retinal layers, and it decreased the glial cell overactivation. Overall, our results confirm that PACAP1-38 given in the form of eye drops is a novel protective therapeutic approach to treat retinal diseases.

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Section: Methodsmentioning

confidence: 99%

Passage through the Ocular Barriers and Beneficial Effects in Retinal Ischemia of Topical Application of PACAP1-38 in Rodents

Werling

Banks

Salameh

et al. 2017

IJMS

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“…Intranasal insulin therapy has been shown to improve memory function in AD patients and in healthy individuals (Benedict et al , 2004; Reger et al , 2006; Hanson & Frey, 2008; Reger et al , 2008; Craft et al , 2012; Schioth et al , 2012b; Freiherr et al , 2013; Craft et al , 2017). Further, animal models of aging and AD also show the positive impact of intranasal insulin in combating cognitive decline (Francis et al , 2008; Marks et al , 2009; Apostolatos et al , 2012; de la Monte, 2013; Adzovic et al , 2015; Salameh et al , 2015; Anderson et al , 2016; Maimaiti et al , 2016). Despite these promising outcomes, the mechanisms of action in the brain, and specifically on neurons of the hippocampus where insulin plays a recognizable role in learning and memory (Zhao et al , 1999; Zhao et al , 2004), remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Novel calcium-related targets of insulin in hippocampal neurons

et al. 2017

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Both insulin signaling disruption and Ca2+ dysregulation are closely related to memory loss during aging and increase the vulnerability to Alzheimer's disease (AD). In hippocampal neurons, aging-related changes in calcium regulatory pathways have been shown to lead to higher intracellular calcium levels and an increase in the Ca2+-dependent afterhyperpolarization (AHP), which is associated with cognitive decline. Recent studies suggest that insulin reduces the Ca2+-dependent AHP. Given the sensitivity of neurons to insulin and evidence that brain insulin signaling is reduced with age, insulin-mediated alterations in calcium homeostasis may underlie the beneficial actions of insulin in the brain. Indeed, increasing insulin signaling in the brain via intranasal delivery has yielded promising results such as improving memory in both clinical and animal studies. However, while several mechanisms have been proposed, few have focused on regulation on intracellular Ca2+. In the present study, we further examined the effects of acute insulin on calcium pathways in primary hippocampal neurons in culture. Using the whole-cell patch-clamp technique, we found that acute insulin delivery reduced voltage-gated calcium currents. Fura-2 imaging was used to also address acute insulin effects on spontaneous and depolarization-mediated Ca2+ transients. Results indicate that insulin reduced Ca2+ transients, which appears to have involved a reduction in ryanodine receptor function. Together, these results suggest insulin regulates pathways that control intracellular Ca2+ which may reduce the AHP and improve memory. This may be one mechanism contributing to improved memory recall in response to intranasal insulin therapy in the clinic.

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“…Several small‐scale clinical trials have shown that intranasal insulin improves memory and attention in healthy participants, as well as in patients with mild cognitive impairment and AD (Craft et al ., 2012). Preclinical studies have also been conducted to confirm the cognitive improvement by intranasal insulin and the way how it reaches the brain (Marks et al ., 2009; Salameh et al ., 2015). However, the mechanisms underlying improved memory with insulin treatment remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

et al. 2016

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SummaryBrain insulin signaling deficits contribute to multiple pathological features of Alzheimer's disease (AD). Although intranasal insulin has shown efficacy in patients with AD, the underlying mechanisms remain largely unillustrated. Here, we demonstrate that intranasal insulin improves cognitive deficits, ameliorates defective brain insulin signaling, and strongly reduces β‐amyloid (Aβ) production and plaque formation after 6 weeks of treatment in 4.5‐month‐old APPswe/PS1dE9 (APP/PS1) mice. Furthermore, c‐Jun N‐terminal kinase activation, which plays a pivotal role in insulin resistance and AD pathologies, is significantly inhibited. The alleviation of amyloid pathology by intranasal insulin results mainly from enhanced nonamyloidogenic processing and compromised amyloidogenic processing of amyloid precursor protein (APP), and from a reduction in apolipoprotein E protein which is involved in Aβ metabolism. In addition, intranasal insulin effectively promotes hippocampal neurogenesis in APP/PS1 mice. This study, exploring the mechanisms underlying the beneficial effects of intranasal insulin on Aβ pathologies in vivo for the first time, highlights important preclinical evidence that intranasal insulin is potentially an effective therapeutic method for the prevention and treatment of AD.

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Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition

Cited by 108 publications

References 44 publications

Passage through the Ocular Barriers and Beneficial Effects in Retinal Ischemia of Topical Application of PACAP1-38 in Rodents

Passage through the Ocular Barriers and Beneficial Effects in Retinal Ischemia of Topical Application of PACAP1-38 in Rodents

Novel calcium-related targets of insulin in hippocampal neurons

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

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