Intranasal Insulin Ameliorates Cerebral Hypometabolism, Neuronal Loss, and Astrogliosis in Streptozotocin-Induced Alzheimer’s Rat Model

Abstract

Intracerebroventricular injection of streptozotocin (ICV-STZ) in rodents leads to cognitive impairments and several pathological changes like Alzheimer's disease (AD). However, there is hardly any research about the effect of ICV-STZ on regional cerebral glucose metabolism in rodents. Previous studies have demonstrated that intranasal insulin improves cognition in AD patients. However, the underlying mechanism remains elusive. Here, we treated the ICV-STZ rats with daily intranasal delivery of insulin (2 U/day) for 6 consecutive weeks, then monitored F-fluorodeoxyglucose (F-FDG) uptake using a high-resolution small-animal positron emission tomography (microPET) and studied the expression of neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) using immunohistochemical staining. We observed that F-FDG uptake decreased significantly at the prefrontal cortex, cingulate cortex, striatum, hippocampus, and entorhinal cortex in ICV-STZ rats as compared with the control rats. Intranasal insulin restores the cerebral glucose metabolism in prefrontal and cingulate cortex and attenuates astroglia activation and neuronal loss in the hippocampus of ICV-STZ rats. These findings provide the mechanistic basis for treating AD patients with intranasal insulin.

Pharmacokinetics of Intranasal versus Subcutaneous Insulin in the Mouse

“…3,7–9,13,15,18–20,25,28–37 Herein we show that IN administration achieves insulin exposure in the brain similar to SC administration of the same dose (2.4 IU), but it achieves significantly lower peripheral exposure, preventing severe hypoglycemia. Repeated IN dosing of 2.4 IU insulin was also well tolerated and resulted in increased concentrations of glucose and phosphorylated energy substrates in the brain, a potentially neuroprotective and pro-cognitive profile.…”

“…Repeated IN dosing of 2.4 IU insulin was also well tolerated and resulted in increased concentrations of glucose and phosphorylated energy substrates in the brain, a potentially neuroprotective and pro-cognitive profile. 13,18–20,25,28 …”

“…66,70–72 In AD brain samples and in cultured neurons under oxidative stress, accompanying depletion of ATP and phosphocreatine has also been detected. 21–23,73,74 IN insulin has generally been found to reverse these effects, inducing FDG-PET uptake in the brains of rodents 19,20,25 and humans 13,18,19,28 and promoting the production of neuronal ATP and phosphocreatine. 21–23,75 Renewing normal levels of ATP, phosphocreatine, and other energy substrates in the brain may broadly improve cognition in various disease states by meeting the high metabolic demand necessary to preserve neuronal function and cognition.…”

“…18,19 The neuroprotective effects of insulin appear to involve the induction or preservation of brain glucose metabolism and restoration of the energy storage molecules adenosine triphosphate (ATP) and phosphocreatine, 13,20–25 in addition to neurotrophic and anti-inflammatory effects mediated by the direct activation of insulin receptors on neurons. 26,27 When delivered to the brain, insulin has been shown to increase glucose uptake 13,18–20,25,28 and improve cognitive performance in animals, 3,7,15,16,25,29 healthy humans, 30–32 and cognitively impaired patients. 1,2,8,9,11,33–37 Given the absence of robust neuroprotective therapeutics, insulin delivery to the brain has thus emerged as a promising new therapy for multiple neurological and psychiatric disorders.…”

Shared cerebral metabolic pathology in non-transgenic animal models of Alzheimer's and Parkinson's disease

“…Although a growing body of evidence suggests that the prevailing sporadic AD and idiopathic PD are fundamentally metabolic diseases with characteristic neurodegenerative processes possibly being caused by IRBS and metabolic dysfunction (Hoyer 2004;Defelice and Ferreira 2002;de la Monte et al 2014;Chen et al 2017;Bloom et al 2018;Athauda et al 2016;Schelp et al 2017;Yang et al 2018); the cause(s) and characterisation of these metabolic alterations are still unknown. One way to understand the metabolic etiopathogenesis of sporadic/idiopathic AD and PD is to explore the onset, development and time-course of insulin signalling dysfunction and glucose metabolism in the brain of animal models that mimic these human diseases.…”