Intranasal Insulin and Gangliosides Correct Cognitive Impairments and Signaling Pathways in the Hippocampus of Rats with Type 2 Diabetes Mellitus

Insulin controls both systemic glucose homeostasis and functional brain activity. In type 2 diabetes mellitus (DM2), insulin content and the activity of the insulin signaling system in the brain decreases, causing metabolism disorders, including brain glucose hypometabolism, and cognitive dysfunctions. Brain insulin deficiency can be compensated by intranasal insulin administration (IIA). The effectiveness of IIA in correcting brain functions can be improved by combining it with intranasal administration of substances having neuroprotective properties, e.g., complex glycosphingolipids, gangliosides. This work aimed to evaluate the effectiveness of separate and combined IIA and intranasal ganglioside administration (IGA) in correcting cognitive impairments in Wistar rats with DM2 using the Morris water maze (MWM), as well as the analysis of hippocampal expression of proteins (BDNF, GLUT1, GLUT3, GLUT4, GFAP, PSD95) and activity of protein kinases (Akt, GSK3β, ERK1/2) involved in learning and long-term memory formation. Both IIA and IGA improved spatial orientation of DM2 rats in the MWM, with the effects of separate or combined IIA and IGA being similar. Due to combined IIA and IGA, the activity of effector protein kinases Akt and ERK1/2 persisted at the same level as in controls, whereas IIA monotherapy led to a reduced level of their phosphorylation. The combined therapy also increased the level of GSK3β phosphorylation at Ser 9 , which is protective against tauropathy. Thus, combined IIA and IGA improves the functional state of the insulin system’s components in the brain of DM2 rats, although not enhancing significantly the effects of IIA on long-term memory.