An experimental evaluation of the therapeutic window of the neuroprotective activity of a low-molecular nerve growth factor mimetic GK-2

Abstract

It was found that GK-2 at a daily dose of 1 mg/kg, intraperitoneally, during 7 days statistically significantly reduces brain infarct volume by 20-60% at the first injection from 4 to 24h, with the highest effect 6-8 hours after surgery. Thus, the 'therapeutic window' of GK-2 detected in the experiment is no less than 24 hours, which exceeds the existing neuroprotective agents.

A Nerve Growth Factor Dipeptide Mimetic Stimulates Neurogenesis and Synaptogenesis in the Hippocampus and Striatum of Adult Rats with Focal Cerebral Ischemia

“…The dimeric dipeptide mimetic of nerve growth factor loop 4, GK-2, administered subchronically and starting 6 and 24 h after surgery statistically significantly restores the reduced proliferation of neuronal stem cells in the hippocampus and increases the proliferative activity in the striatum, according to the Ki67 marker, in an experimental ischemic stroke caused by transient occlusion of the middle cerebral artery. Based on the previously obtained data on the improvement in the neurological status of rats receiving GK-2 under conditions similar to those of the present experiment [17], we may suggest that stimulation of proliferative activity by the dipeptide leads, at least primarily, to neurogenesis. The effect of GK-2 increases the number of synaptic contacts being reduced after surgery, which was assessed using the postsynaptic marker PSD-95, upon administration starting 6 h after surgery and increases this indicator when the first administration occurrs 24 h after surgery.…”

“…These findings indicate the ability of the NGF mimetic to stimulate a proliferative activity in the hippocampus of the ischemic brain. Based on previously obtained data on the improvement in the neurological status of rats receiving GK-2 (administration starting 6 and 24 h after surgery) under the same conditions as in this experiment [17], we suggest that dipeptide-induced stimulation of proliferative activity leads, at least predominantly, to neurogenesis. This is also supported by published data indicating that the full-length NGF stimulates hippocampal neurogenesis, increasing the proliferative activity and promoting the survival of neuroblasts in the dentate gyrus of the hippocampus [5, 9].…”

“…To assess the contribution of neuroregeneration to the protective effects of GK-2 in an experimental stroke, we compared our biochemical data with the results of a previous morphological study [17] on the role of GK-2 in reducing the volume of an ischemic brain injury. All dipeptide effects were evaluated on the 7 th day after surgery (see Table).…”

“…In support of the in vitro data, GK-2, unlike the full-length protein, did not cause hyperalgesia and weight loss in in vivo experiments [14]. A study of the neuroprotective effect of GK-2 in a model of ischemic stroke caused by transient occlusion of the middle cerebral artery in rats showed that the dipeptide statistically significantly reduced the amount of brain injury if the onset of therapeutic administration started between 4 and 24 h, with the strongest effect (60%) being observed if the first administration occured 6 h after surgery [17]. Preservation of the GK-2 activity when its first administration occurs 24 h after a simulated ischemic stroke is probably not explained by its neuroprotective properties, because the infarction area has fully formed by that time [18].…”

Low‐molecular mimetics of nerve growth factor and brain‐derived neurotrophic factor: Design and pharmacological properties

“…Notably, GK-2 was effective at the start of administration 1, 4, 6, 8, and even 24 h after surgery in this model. 89 The authors explain the restoration effects of GK-2 firstly administered 24 h after ischemic stroke by neuroregenerative properties of the dipeptide due to the activation of neurogenesis. GK-2 was revealed to stimulate neurogenesis in hippocampus and striatum in experimental ischemic stroke.…”