The effects of dipeptide mimetics of NGF, BDNF, and NT-3 on pain sensitivity in the tail flick and hot plate tests in mice and rats
| Parent neurotrophin | Code | Neurotrophin loop | Threshold dose, (mg/kg, ip) | Activation of post-receptor signaling cascades | Pain threshold compared to the control group 24 h after administration of the compound (%) | ||
|---|---|---|---|---|---|---|---|
| PI3K/Akt | MAPK/ERK | PLC-γ1 | |||||
| NGF | GK-2 [37] | 4 | 1.0 | ++ | ns | ++ | 144(analgesia) |
| GK-6 [37] | 1 | 2.0 | + | + | + | 62(algesia) | |
| BDNF | GSB-106 [98] | 4 | 0.1 | + | ++ | ++ | 144(analgesia) |
| GSB-214 | 1 | Not active | + | ns | ++ | ns | |
| NT-3 | GTS-301 [99] | 4 | 0.01 | ns | ++ | ++ | 120(analgesia) |
| GTS-302 | 0.1 | ++ | ++ | + | 110(analgesia) | ||
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; GK-6: bis-(N-aminocaproyl-glycyl-L-lysine) hexamethylenediamide; GSB-106: bis-(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide; GSB-214: bis-(N-monosuccinyl-L-methionyl-L-serine) heptamethylenediamide; GTS-301: bis-(N-monosuccinyl-L-asparaginyl-L-asparagine) hexamethylenediamide; GTS-302: bis-(N-gamma-oxybutyryl-L-glutamyl-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. Effects of mimetics on pain thresholds are presented as average values. Morphine, used as a reference drug, increased pain thresholds by 200% in the same experimental setup, and this effect persisted for 1 h after its administration