Antidiabetic activity of dipeptide mimetics of NGF, BDNF, and NT-3 in a streptozotocin-induced diabetes model in mice and rats

Parent neurotrophinCodeNeurotrophin loopThreshold dose (mg/kg, ip)Activation of post-receptor signaling cascadesAntihyperglycemic activity, percent of the maximum possible effect (%)
PI3K/AktMAPK/ERKPLC-γ1
NGFGK-2 [56]40.5++ns++90
BDNFGSB-106 [53]40.5+++++42
GSB-214 [53]10.5+ns++84
GTS-201 [53]2Not activens+++ns
NT-3GTS-301 [54]40.1ns++++53

ip: intraperitoneally; NGF: nerve growth factor; BDNF: brain-derived neurotrophic factor; NT-3: neurotrophin-3; MAPK/ERK: mitogen-activated protein kinase/extracellular signal-regulated kinase; PLC-γ1: phospholipase C-gamma; GK-2: bis-(monosuccinyl-L-glutamyl-L-lysine) hexamethylenediamide; GSB-106: bis-(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide; GSB-214: bis-(N-monosuccinyl-L-methionyl-L-serine) heptamethylenediamide; GTS-201: bis-(N-hexanoyl-L-seryl-L-lysine) hexamethylenediamide; GTS-301: bis-(N-monosuccinyl-L-asparaginyl-L-asparagine) hexamethylenediamide; +: the effect is inferior to the full-length neurotrophin in terms of intensity and/or duration; ++: the effect is comparable to the full-length neurotrophin in terms of intensity and duration; ns: non-significant. All effects not labeled as “ns” are statistically significant. The table shows the most pronounced antihyperglycemic effects of the compounds, achieved during treatment or its discontinuation. These effects are presented as percentages of the maximum possible effect and are provided as average values. The antihyperglycemic effect of the reference drug Metformin (300.0 mg/kg, orally) in the same experimental design reached up to 85% of the maximum possible