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.
Хорошо известно, что нейротрофины фактор роста нервов (NGF) и мозговой нейротрофический фактор (BDNF) участвуют в процессах обучения и памяти. В НИИ фармакологии имени В. В. Закусова сконструированы и синтезированы димерные дипептидные миметики 1-й (ГК-6) и 4-й (ГК-2) петель NGF, 1-й (ГСБ-214), 2-й (ГТС-201) и 4-й (ГСБ-106) петель BDNF, активирующие in vitro соответственно TrkA- или TrkB-рецепторы. При инкубации в культуре клеток НТ-22 в течение 5 – 180 мин были зарегистрированы различия в активации сигнальных путей PI3K/AKT, MAPK/ERK и PLC-γ1. Целью данной работы было изучение мнемотропной активности оригинальных миметиков NGF и BDNF в тесте распознавания нового объекта у крыс. Дипептиды вводили однократно внутрибрюшинно. Установлено, что ГК-2 (0,5 и 1,0 мг/кг) и ГСБ-214 (0,1 и 1,0 мг/кг), активирующие сигнальные пути PI3K/AKT и PLC-γ1 без влияния на MAPK/ERK, статистически значимо улучшали долговременную память. Соединения ГК-2 и ГСБ-214 представляются перспективными для дальнейшей разработки в качестве средств коррекции нарушений памяти.
We compared the effects of GK-2 (dimeric dipeptide mimetic of nerve growth factor) and Mexidol (standard preparation for the therapy of stroke) on rat model of transient occlusion of the middle cerebral artery. GK-2 and Mexidol were administered intraperitoneally in the most active doses (1 and 100 mg/kg, respectively) 6 h after surgery and then once a day for 6 days. The preparations reduced the volume of cerebral infarction (by 60 and 30%, respectively). At the same time, GK-2 had a pronounced and statistically more reliable effect in a dose that is lower by two orders of magnitude. In addition, GK-2 significantly reduced the neurological deficit in the limb placement test, while Mexidol was ineffective in this test.
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