CORRECTION OF COGNITIVE IMPAIRMENTS AND SIGNALING PATHWAYS IN THE HIPPOCAMPUS OF RATS WITH TYPE 2 DIABETES MELLITUS USING INTRANASALLY ADMINISTERED INSULIN AND GANGLIOSIDES

Abstract

Insulin controls both systemic glucose homeostasis and the functional activity of the brain. Insulin content and the activity of the insulin signaling system decreases in the brain in diabetes mellitus type 2 (DM2). It gives rise to disorders of energy metabolism, including hypometabolism of glucose in the brain, and to cognitive dysfunctions. The deficiency of hormone in the brain can be restored by intranasally administered insulin (IAI). It is also reasonable to use it in combination with substances with neuroprotective properties, including complex glycosphingolipids gangliosides, in order to increase the effectiveness of IAI for the correction of brain functions. Intranasal way of ganglioside delivery (IAG) to the brain can be explored as well. The aim of the research comprised the evaluation of efficiency of separate and combined IAI and IAG use to correct the cognitive impairment in Wistar rats with DM2 using the Morris water maze (MWM) and analysis of expression of proteins (BDNF, GLUT-1, GLUT-3, GLUT -4, GFAP, PSD95) and activity of protein kinases (Akt, GSK3β, ERK1/2) involved in learning and long-term memory formation in the hippocampus. IAI and IAG improved spatial orientation of rats with DM2in the MWM, and the effect of combined use of IAI and IAG was similar to the effect of each substance used separately. Owing to combined IAI and IAG the activity of effector protein kinases (Akt and ERK1/2) was maintained at the same level as in control rats while IAI monotherapy resulted in the reduced level of their phosphorylation. The level of GSK3β phosphorylation at Ser9 was also increased after combined treatments with insulin and gangliosides which is protective against tauropathy. Thus, the combined application of IAI and IAG improves the functional state of the components of the insulin system in the brain of rats with DM2, although it does not significantly enhance the effects of IAI on long-term memory.