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

Abstract

The nerve growth factor (NGF) and its mimetics, which have neuroprotective and neuroregenerative properties, are attractive candidates for developing new drugs for brain injury therapy. A dipeptide mimetic of NGF loop 4, bis(N-succinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2), developed at the Zakusov Research Institute of Pharmacology, has the NGF-like ability to activate TrkA receptors, but unlike NGF, GK-2 activates mainly the PI3K/AKT pathway associated with neuroprotection and has no effect on the MAPK cascade associated with hyperalgesia, the main side effect of NGF. That GK-2 possesses neuroprotective activity has been observed in various models of cerebral ischemia. GK-2 was found to statistically significantly reduce the cerebral infarct volume in experimental stroke, even at treatment onset 24 h after injury. This suggests that GK-2 possesses neuroregenerative properties, which may be associated with the activation of neurogenesis and/or synaptogenesis. We studied the effect of GK-2 on neurogenesis and synaptogenesis in experimental ischemic stroke caused by transient occlusion of the middle cerebral artery in rats. GK-2 was administered 6 or 24 h after surgery and then once a day for 7 days. One day after the last administration, proliferative activity in the hippocampus and striatum of the affected hemisphere was assessed using Ki67 and synaptogenesis in the striatum was evaluated using synaptophysin and PSD-95. Ki67 immunoreactivity, both in the striatum and in the hippocampus of the ischemic rats, was found to have dropped by approximately 30% compared to that in the sham-operated controls. Synaptic markers - synaptophysin and PSD-95 - were also statistically significantly reduced, by 14 and 29%, respectively. GK-2 in both administration schedules completely restored the level of Ki67 immunoreactivity in the hippocampus and promoted its increase in the striatum. In addition, GK-2 restored the level of the postsynaptic marker PSD-95, with the therapeutic effect amounting to 70% at the start of its administration after 6 h, and promoted restoration of the level of this marker at the start of administration 24 h after an experimental stroke. GK-2 had no effect on the synaptophysin level. These findings suggest that the neurotrophin mimetic GK-2, which mainly activates one of the main Trk receptor signaling pathways PI3K/ AKT, has a stimulating effect on neurogenesis (and, probably, gliogenesis) and synaptogenesis in experimental cerebral ischemia. This effect may explain the protective effect observed at the start of dipeptide administration 24 h after stroke simulation.

Protective Effects of PGC-1α Activators on Ischemic Stroke in a Rat Model of Photochemically Induced Thrombosis

“…PGC-1α activation has been shown to mediate the neuroprotective effects of BDNF [ 17 ]. Currently, studies are underway for the creation of neuropeptide mimetics that are resistant to the action of peptidases and can cross the BBB [ 40 , 41 , 42 ]. One of these drugs is the synthetic peptide Semax (a fragment of adrenocorticotrophin (ACTH) 4 – 7 conjugated with the C-terminal tripeptide Pro-Gly-Pro), which has been used as a nootropic and neuroprotective drug [ 43 , 44 ].…”

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

“…GK-2 was revealed to stimulate neurogenesis in hippocampus and striatum in experimental ischemic stroke. 90 Neuroprotective effects of GK-2 were also demonstrated in a number of other experimental models.…”

GAP-43 and BASP1 in Axon Regeneration: Implications for the Treatment of Neurodegenerative Diseases

“…NGF and BDNF bind tropomyosin receptor kinase A and B, respectively, to initiate cell survival signaling via the PI3K/Akt pathway ( Nguyen et al, 2010 ; Figure 1 ). In rodent models of stroke and TBI, the activation of NGF and BDNF signaling was shown to promote neuroprotection, synaptogenesis, and neurogenesis ( Wu et al, 2008 ; Qi et al, 2014 ; Gudasheva et al, 2019 ). Such beneficial upregulation of NGF and BDNF was accompanied by an increase in GAP-43 levels when optogenetic stimulations were provided after stroke ( Cheng et al, 2014 ).…”