主催: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
会議名: WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
開催地: Kyoto
開催日: 2018/07/01 - 2018/07/06
There is a growing body of evidence indicating the role of nerve growth factor (NGF) in recovery after stroke. NGF has been reported to improve recovery in rodents subjected to experimental stroke even when administered beginning 24 hours after surgery [Zhu W. et al., 2011; Yang J. et al., 2011]. However, clinical application of NGF requires solving two major problems: effective CNS delivery and limitation of adverse effects.
The dimeric dipeptide, bis(N-succinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2), was created based on the most exposed outside fragment of NGF loop 4 beta-turn sequence [Ru Patent 2410392, 2010; CN Patent CN 102365294 B, 2016]. It was established that GK-2 activates the NGF-specific TRKA receptors and PI3K/AKT signaling pathway that is mainly involved in neuroprotection, without activation of the MAPK/ERK pathway associated with the development of hyperalgesia [Gudasheva T.A. et al., J Biomed Sci. 2015]. In vitro GK-2 exhibited neuroprotective activity (10-5-10-9M) in the conditions of H2O2- or glutamate- induced toxicity [Gudasheva T.A. et al., Dokl Biochem Biophys. 2010]. In vivo GK-2 was active in models of Parkinson's disease, Alzheimer's disease, cerebral ischemia and diabetes mellitus in doses 0.01 - 5 mg/kg, ip and 5-10 mg/kg, per os [Seredenin S.B., Gudasheva T.A., Zh Nevrol Psikhiatr. 2015]. It was found that GK-2 has no side effects accompanying NGF treatment namely hyperalgesia and weight loss.
The purpose of this work was an expanded study the pharmacological effects of GK-2 in a rat model of transient middle cerebral artery occlusion.
It was found that GK-2 at subchronic administration (7 days) after experimental stroke, significantly decreases infarct volumes (by 20-60%) and improves the neurological status in a wide range of doses (0.5-10 mg/kg, ip). GK-2, like NGF, had a wide "therapeutic window". The dipeptide was active when the treatment beginning 1, 4, 6, 8 and even 24 hours after reperfusion. Effectiveness of GK-2 at a delayed start of administration suggests that the dipeptide has neuroregenerative properties.
Thus, GK-2 is a promising agent for post-stroke therapy. To date, the full cycle of preclinical studies of GK-2 has been successfully completed.
This work was supported by RFBR, 18-015-00228 and RSF, 18-15-00381
