Impact of Single or Repeated Dose Intranasal Zinc-free Insulin in Young and Aged F344 Rats on Cognition, Signaling, and Brain Metabolism

Abstract

Novel therapies have turned to delivering compounds to the brain using nasal sprays, bypassing the blood brain barrier, and enriching treatment options for brain aging and/or Alzheimer's disease. We conducted a series of in vivo experiments to test the impact of intranasal Apidra, a zinc-free insulin formulation, on the brain of young and aged F344 rats. Both single acute and repeated daily doses were compared to test the hypothesis that insulin could improve memory recall in aged memory-deficient animals. We quantified insulin signaling in different brain regions and at different times following delivery. We measured cerebral blood flow (CBF) using MRI and also characterized several brain metabolite levels using MR spectroscopy. We show that neither acute nor chronic Apidra improved memory or recall in young or aged animals. Within 2 hours of a single dose, increased insulin signaling was seen in ventral areas of the aged brains only. Although chronic Apidra was able to offset reduced CBF with aging, it also caused significant reductions in markers of neuronal integrity. Our data suggest that this zinc-free insulin formulation may actually hasten cognitive decline with age when used chronically.

Novel calcium-related targets of insulin in hippocampal neurons

“…Irrespective of the mechanism of inhibition of VGCC by insulin, it is clear that VGCC are a target of insulin in neurons. The effect described here, therefore, is likely to mediate the beneficial impact of the hormone on cognitive function following intranasal delivery in animal models (Apostolatos et al , 2012; Adzovic et al , 2015; Anderson et al , 2016; Maimaiti et al , 2016) and in early AD subjects (Reger et al , 2006; Reger et al , 2008; Craft et al , 2012; Freiherr et al , 2013; Rosenbloom et al , 2014; Claxton et al , 2015). Indeed, according to the calcium hypothesis of aging and dementia (Landfield, 1987; Khachaturian, 1989; Alzheimer's Association Calcium Hypothesis, 2017), reducing calcium levels in postsynaptic neurons is a favorable approach to offset cognitive decline in aging and AD (see below).…”

“…The intranasal route of insulin administration raises insulin acutely in the central nervous system without much risk of peripheral hypoglycemia (Kern et al , 1999; Ott et al , 2014; Lochhead et al , 2015; Anderson et al , 2016; Maimaiti et al , 2016). 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).…”

“…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.…”

A Ketogenic Diet Improves Cognition and Has Biochemical Effects in Prefrontal Cortex That Are Dissociable From Hippocampus

“…This has been shown to enhance cognition in older adults with memory impairments (Reger et al, 2008). In rats, however, chronic intranasal insulin administration failed to improve behavior in old animals and lead to reductions in markers of neuronal integrity (Anderson et al, 2017). Moreover, enhancing insulin receptor sensitivity pharmacologically, however, has produced mixed results regarding benefits to cognitive function in old age.…”

Alfalfa-derived HSP70 administered intranasally improves insulin sensitivity in mice

“…Human studies (Goetzl et al, 2015;Gancheva et al 2015;Di Domenico et al 2010) support the translational relevance of the HSP70 potential and CNSmediated effects on metabolism. Work to date has focused on insulin, but the results of intranasal administration on cognition are mixed in rodent models (Maimaiti et al 2016;Anderson et al 2017). Systemic upregulation of HSP70 improves cognition in a rat AD model (Zare et al 2015), which combined with the human data documenting CNS HSP70 deficiencies positions local aHSP70 delivery by the intranasal method as a strategy worth pursuing for both AD and T2DM.…”