Intranasal insulin therapy for cognitive impairment and neurodegeneration: current state of the art

Abstract

Introduction Growing evidence supports the concept that insulin resistance plays an important role in the pathogenesis of cognitive impairment and neurodegeneration, including in Alzheimer's disease (AD). The metabolic hypothesis has led to the development and utilization of insulin- and insulin agonist-based treatments. Therapeutic challenges faced include the ability to provide effective treatments that do not require repeated injections and also minimize potentially hazardous off-target effects. Areas covered This review covers the role of intra-nasal insulin therapy for cognitive impairment and neurodegeneration, particularly Alzheimer's disease. The literature reviewed focuses on data published within the past 5 years as this field is evolving rapidly. The author provides evidence that brain insulin resistance is an important and early abnormality in Alzheimer's disease, and that increasing brain supply and utilization of insulin improves cognition and memory. Emphasis was placed on discussing outcomes of clinical trials and interpreting discordant results to clarify the benefits and limitations of intranasal insulin therapy. Expert Opinion Intranasal insulin therapy can efficiently and directly target the brain to support energy metabolism, myelin maintenance, cell survival, and neuronal plasticity, which begin to fail in the early stages of neurodegeneration. Efforts must continue toward increasing the safety, efficacy, and specificity of intranasal insulin therapy.

Insulin Resistance and Neurodegeneration: Progress Towards the Development of New Therapeutics for Alzheimer’s Disease

“…Intranasal delivery provides a realistic solution to these problems because with this non-invasive approach, insulin and other neurotrophins can enter the CNS and bypass the blood-brain barrier [96, 200, 201] while avoiding systemic effects. In contrast to inhalation, intranasal administration efficiently delivers drugs to ventromedial corticolimbic structures in the brain via olfactory and trigeminal nerves innervating the nasal cavity (olfactory) mucosa [202].…”

“…Although cognitive impairment and AD can be treated with either systemic or intranasal insulin, proper administration of the latter has the potential to selectively target the brain with generally high levels of safety due to the low rates of off-target side-effects such as hypoglycemia [96]. Furthermore, intranasal therapy avoids the need for multiple daily injections.…”

“…The third point is that therapeutic agents, including insulin, delivered via the intranasal route should be structurally stable, relatively resistant to degradation, and able to penetrate the nasal mucosa. Finally, the potential for developing nasal transport resistance and reduced absorbance could limit the effectiveness of intranasal therapy [96]. Therefore, to further the use of intranasal insulin and other neurotrophins to treat CNS diseases, improvements in delivery systems, means of monitoring CNS delivery and brain responses, and assessments of nasal transport resistance are needed.…”

Novel calcium-related targets of insulin in hippocampal neurons

“…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.…”

Intranasal delivery of N-terminal modified leptin-pluronic conjugate for treatment of obesity

“…In general, formulation strategies used to enhance direct nose-to-brain delivery of therapeutic proteins remain largely unexplored [72, 73]. Absorption enhancers/tight-junction modulators, bioadhesive polymers, enzyme inhibitors, and nanoparticles have been studied [74–78], aiming to improve the stability, prolong the residence time, create a local drug depot or enhance absorption across the mucosa epithelium.…”