Pharmacokinetics and pharmacodynamics of intranasal insulin in a rat brain

Background and Purpose: Understanding of the insulin-mediated effects on signalling and metabolism is important not only for fundamental knowledge of insulin's action in the brain but also for elucidating the mechanism of therapeutic potential in neurodegenerative disorders with underlying brain metabolic dysfunction. One of the main goals of this research is to clarify and explore the time-dependent regular insulin distribution and activity in the rat brain following intranasal administration. Experimental Approach: Male Wistar rats were given insulin (2 IU) intranasally and were killed 3, 7.5, 15, 30, 60 and 120 min after administration. Control animals were killed without intranasal administration. Insulin, C-peptide and glucose concentrations were measured in plasma and cerebrospinal fluid (CSF), while levels and activity of the insulin signal transduction network were measured in brain and epithelia. Key Results: Insulin immediately distributed to all brain regions after intranasal administration and was rapidly utilized and/or metabolized. Intranasal insulin positively influences insulin secretion seen as increment of C-peptide and insulin in the periphery and in distinctive brain regions. Secondary activation of AMP-activated protein kinase and calcium/calmodulin-dependent protein kinase occurred, perhaps due to brain region-dependent negative-feedback mechanisms on the overstimulated insulin signalling pathway. Conclusion and Implications: The insulin dose was likely too high and caused its transport back to epithelia through unknown mechanisms (most likely by transporter), which could be of relevance for human dose reduction. Possible beneficial insulin action could be due to overstimulation of the insulin-signalling pathway with subsequent inactivation through insulin receptor substrate phosphorylation at Ser307.