Low-Molecular-Weight NGF Mimetic Corrects the Cognitive Deficit and Depression-like Behavior in Experimental Diabetes

Abstract

Based on the comorbidity of diabetes, depression, and dementia and recognizing that a deficiency of the nerve growth factor (NGF) is involved in all of these kinds of pathologies, we studied the effect of the mimetic of dimeric dipeptide NGF loop 4, GK-2, on a model of streptozotocin-induced type 2 diabetes in C57Bl/6 mice. GK-2 [hexamethylenediamide bis-(N-monosuccinyl-glutamyl-lysine)] was synthesized at the V.V. Zakusov Scientific Research Institute of Pharmacology. The study revealed the ability of GK-2 to ameliorate hyperglycemia induced by streptozotocine (STZ 100 mg/kg i.p.) in C57Bl/6 mice, to restore learning ability in the Morris Water Maze test, and to overcome depression after both intraperitoneal (0.5 mg/kg) and peroral (5 mg/kg) long-term administration. The presence of the listed properties and their preservation in the case of peroral treatment determines the prospects of research. Taking into account the previous findings on the ability of GK-2 to selectively activate PI3K/Akt, these data suggest that Akt-signaling is sufficient for pancreatic beta cell function. GK-2 has been shown to exhibit pronounced neuroprotective activity. The coexistence of neuroprotective and antidiabetic effects is in agreement with the fundamental concept holding that the function of neurons and pancreatic beta cells is controlled by similar mechanisms.