Activity of compound GSB-106, a low-molecular mimetic of loop 4 of the brain neurotrophic factor (BDNF), was studied in experimental morphine withdrawal syndrome simulated in outbred rats. Single and subchronic (5 intraperitoneal injections) administration of GSB-106 in a dose of 0.1 mg/kg significantly reduced the total index of morphine withdrawal syndrome by 55.2 and 45.6%, respectively. GSB-106 reduced the severity of some behavioral signs (piloerection, gnashing of teeth, wet-dog shaking, and runaway attempts), but had no effect on mechanical allodynia formed in the rats with dependence. Subchronic treatment with GSB-106 prevented the increase in the content of ΔFosB (product of early response gene) in the striatum induced by morphine withdrawal. The results confirmed the concept on the involvement of neurotrophins, specifically BDNF and its analogs, in the mechanisms associated with the formation of opiate dependence.

The effects of a peptide anxiolytic Selank synthesized on the basis of the endogenous peptide tuftsin on memory impairment and content of brain-derived neurotrophic factor (BDNF) in brain structures were analyzed in outbred rats receiving 10% ethanol as the only source of fluid for 30 weeks. In the object recognition test, Selank (0.3 mg/kg a day, 7 days, intraperitoneally) produced a cognitive-stimulating effect in 9 months rats not exposed to ethanol (p<0.05) and prevented the formation of ethanol-induced memory and attention disturbances (p<0.01) developing during alcohol withdrawal. In ex vivo experiments, Selank prevented ethanol-induced increase in BDNF content in the hippocampus and frontal cortex (p<0.05). These results indicate positive effects of the tuftsin analogue on age-related memory disturbances associated with chronic alcohol intoxication and confirm the involvement of the neurotrophin mechanism related to BDNF production into the effect of Selank.

With a water crisis bearing down on us, incredible materials that can suck water from even arid desert air could quench our thirst, says Nic Fleming

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.

Experiments on Wistar rats using a model of type 2 diabetes induced by streptozotocin (STZ) at a dose of 40 mg/kg addressed the effects of the proline-containing dipeptide noopept (the ethyl ester of N-phenylacetyl-L-prolylglycine) on nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) contents. Untreated diabetic rats showed 59% and 33% decreases in NGF content in the pancreas and liver, respectively, while BDNF contents decreased by 30% and 40% in the pancreas and liver, respectively, as compared with controls. Noopept given to diabetic rats at a dose of 0.5 mg/kg for 14 days increased the NGF content in the pancreas by 48% compared with untreated diabetic rats and produced a 19% increase in the NGF content in the liver as compared with the control group. Noopept given to diabetic rats normalized BDNF content in the pancreas but had no effect on the decreased level in the liver. The data obtained here identify one of the mechanisms of the antidiabetic action of noopept described in our previous reports.

Сконструирован и синтезирован димерный дипептидный миметик 2-й петли мозгового нейротрофического фактора гексаметилендиамид бис-(N-гексаноил-серил-лизина), ГТС-201. Он обладает нейропротекторной активностью в концентрациях 10–5 – 10–8 М на культуре иммортализованных гиппокампальных нейронов линии НТ-22 в условиях окислительного стресса, вызванного Н2О2. Методом Вестерн-блот анализа показано, что он активирует TrkB рецепторы и Erk, но не активирует Akt. ГТС-201, в отличие от ранее синтезированного димерного дипептидного миметика 4-й петли ГСБ-106 не обнаруживал антидепрессивную активность в тесте Порсолта на мышах BALB/c в дозах 0,1; 1,0 и 5,0 мг/кг при внутрибрюшинном введении. Полученные результаты подтверждают ранее выдвинутую Гудашевой Т. А. и Середениным С. Б. оригинальную гипотезу о возможности дивергенции функций нейротрофинов с помощью низкомолекулярных миметиков их отдельных петлеобразных структур.

A dimeric dipeptide mimetic of brain-derived neurotrophic factor loop 2, bis-(N-hexanoyl-seryl-lysine) hexamethylenediamide or GTS-201, was designed and synthesized. It exhibited neuroprotective activity at concentrations of 10–5 – 10–8 M in HT-22 immortalized hippocampal neuronal cell culture under H2O2-induced oxidative stress. Western-blot analysis showed that it activated TrkB receptors and Erk but not Akt. GTS-201 did not exhibit antidepressant activity in a Porsolt forced swim test on BALB/c mice at i.p. doses of 0.1, 1.0, and 5.0 mg/kg, in contrast with previously synthesized GSB-106, a dimeric dipeptide mimetic of loop 4. The results confirmed the previous original hypothesis about the possible discrimination of neurotrophin functions by low-molecular-mass mimetics of their separate loops.

On culture of hippocampal HT-22 cells line it is shown that dimeric dipeptide mimetiks of different Loops of NGF realize their action via specific neurotrophic TrkA-receptor and selective activate post-receptor intracellular signal ways. Mimetiks of 1th (GK-6 (10-6M)) and the 3rd Loops (GTS-115 ((10-6M)) evoke activation of two main signal cascades - PI3/Akt and MAP/Erk, while mimetic the 4th loop of NGF (GK-2 (10-8M)) only one - a PI3/Akt-way.

On culture of hippocampal HT-22 cells line it is shown that dimeric dipeptide mimetiks of different Loops of NGF realize their action via specific neurotrophic TrkA-receptor and selective activate post-receptor intracellular signal ways. Mimetiks of 1th (GK-6 (10-6M)) and the 3rd Loops (GTS-115 ((10-6M)) evoke activation of two main signal cascades - PI3/Akt and MAP/Erk, while mimetic the 4th loop of NGF (GK-2 (10-8M)) only one - a PI3/Akt-way.

Alzheimer's disease (AD), a neurodegenerative disorder, is caused by amyloid-beta oligomers (AβOs). AβOs induce cell death by triggering oxidative stress and mitochondrial dysfunction. A recent study showed that AβO-induced oxidative stress is associated with extracellular signal-regulated kinase (ERK)–dynamin related protein 1 (Drp1)-mediated mitochondrial fission. Reactive oxygen species (ROS) are regulated by antioxidant enzymes, especially peroxiredoxins (Prxs) that scavenge H2O2. These enzymes inhibit neuronal cell death induced by various neurotoxic reagents. However, it is unclear whether Prx5, which is specifically expressed in neuronal cells, protects these cells from AβO-induced damage. In this study, we found that Prx5 expression was upregulated by AβO-induced oxidative stress and that Prx5 decreased ERK–Drp1-mediated mitochondrial fragmentation and apoptosis of HT-22 neuronal cells. Prx5 expression was affected by AβO, and amelioration of oxidative stress by N-acetyl-l-cysteine decreased AβO-induced Prx5 expression. Prx5 overexpression reduced ROS as well as RNS and apoptotic cell death but Prx5 knockdown did not. In addition, Prx5 overexpression ameliorated ERK–Drp1-mediated mitochondrial fragmentation but Prx5 knockdown did not. These results indicated that inducible Prx5 expression by AβO plays a key role in inhibiting both ERK–Drp1-induced mitochondrial fragmentation and neuronal cell death by regulating oxidative stress. Thus, Prx5 may be a new therapeutic agent for treating AD.