Neuroprotective effect of dipeptide AVP(4-5)-NH2 is associated with nerve growth factor and heat shock protein HSP70.

In vitro experiments demonstrated the neuroprotective effect of dipeptide pGlu-Asn-NH2, which corresponded to the N-terminal fragment of the major vasopressin metabolite AVP(4-9). The dipeptide in concentrations of 10(-5)-10(-7) M prevented death of HT-22 immortalized hippocampal neurons under conditions of oxidative stress and protected PC-12 rat pheochromocytoma cells from neurotoxic compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. pGlu-Asn-NH2 in a concentration of 10(-6) M increased the content of endogenous neuroprotective substances, neurotrophin NGF and heat shock protein HSP70 in HT-22 cells. Our results indicate that this dipeptide can be used for the therapy of Parkinson's disease.

[Effect of afobazole on the accumulation of free radical oxidation products and the catalase activity in rats with cerebral ischemia].

The influence of afobazole on the accumulation of free radical oxidation products (reactive oxygen species, ROS) and on the activity of antioxidative enzyme catalase was studied in striatum and cortex of rats under cerebral ischemia damage conditions. Afobazole showed a tendency to decrease the extent of ROS accumulation in the cortex. In striatum, the intensity of ROS accumulation in rats after ischemia wasa reliably lower as compared to that in control rats, but afobazole produced a partial recovery of this parameter. Afobazole induced an increase in the catalase activity in the cortex of rats with ischemia. In contrast, afobazole did not change the activity of this enzyme in striatum (where it was also decreased by ischemia). Thus, afobazole increased the resistance of neuron membrane structures to free radical oxidation in cortex and striatum and stimulated the catalase activity in the cortex in rats with global reversible cerebral ischernia.

Neuroprotective properties of afobazol in vitro.

The effects of a novel selective anxiolytic afobazol on survival of HT-22 neurons were studied in the model of oxidative stress and glutamate toxicity. In both models, the neuroprotective effect of afobazol was established.

NO-dependent mechanisms of adaptation to hypoxia.

In studying NO-dependent mechanisms of resistance to hypoxia, it was shown that (1) acute hypoxia induces NO overproduction in brain and leaves unaffected NO production in liver of rats; (2) adaptation to hypoxia decreases NO production in liver and brain; and (3) adaptation to hypoxia prevents NO overproduction in brain and potentiates NO synthesis in liver in acute hypoxia. Dinitrosyl iron complex (DNIC, 200 microg/kg, single dose, iv), a NO donor, decreases the resistance of animals to acute hypoxia by 30%. Nomega-nitro-L-arginine (L-NNA, 50 mg/kg, single dose, ip), a NO synthase inhibitor, and diethyl dithiocarbamate (DETC, 200 mg/kg, single dose, iv), a NO trap, increases this parameter 1.3 and 2 times, respectively. Adaptation to hypoxia developed against a background of accumulation of heat shock protein HSP70 in liver and brain. A course of DNIC reproduced the antihypoxic effect of adaptation. A course of L-NNA during adaptation hampered both accumulation of HSP70 and development of the antihypoxic effect. Therefore, NO and the NO-dependent activation of HSP70 synthesis play important roles in adaptation to hypoxia.

[NO-Dependent mechanisms of adaptation to hypoxia]. / NO-zavisimye mekhanizmy adaptatsii k gipoksii.

Studies of nitrogen oxide (NO)-dependent mechanisms of organism resistance to hypoxia demonstrate that (1) acute hypoxia induces NO hyperproduction in the brain and does not affect NO production in the liver; (2) adaptation to hypoxia decreases NO production in the liver and brain; and (3) adaptation to hypoxia prevents NO hyperproduction in the brain and enhances NO synthesis in the lever during acute hypoxia. An NO donor--dinytrosyl iron complexes (DCI, 200 micrograms/kg, single intravenous (i.v.) introduction)--decreases animal resistance to acute hypoxia by 30%, while introduction of an NO synthase inhibitor--N- nitro-L-arginine (NNA, 50 micrograms/kg, single intraperitoneal (i.p.) introduction)--and an NO trap--diethyldithiocarbamate (DETC, 200 mg/kg, single i.p. introduction)--increases the resistance 1.3 and 2 times, respectively. Adaptation to hypoxia is realized against a background of accumulation of heat shock proteins HSP70 in the liver and brain. Course treatment with DCI reproduces the antihypoxic effect of adaptation to hypoxia. Course treatment with NNA during adaptation to hypoxia prevents both accumulation of HSP70 and development of the antihypoxic effect. Hence, No and NO-dependent activation of HSP70 synthesis play an important role in adaptation to hypoxia.

[Nitric oxide as a factor in the antihypoxic effect of adaptation to physical loading]. / Oksid azota kak faktor antigipoksicheskogo éffekta adaptatsii k fizicheskoi nagruzke.

It is known that adaptation to exercise enhances the organism resistance to acute hypoxia. However the mechanism of this cross protective effect have been insufficiently studied. The analysis of literature suggests that NO may play a role in the development of the antihypoxic effect of adaptation to exercise. The aim of the present study was to test this hypothesis: first, by evaluating the influence of NO donor and NO-synthase inhibitor on the antihypoxic effect of adaptation to exercise and, second, by evaluating the changes of NO production in acute hypoxia and after a course of adaptation to exercise. It was shown that the NO donor could both reproduce and considerably (three times) potentiate the antihypoxic effect of adaptation to exercise. At the same time, the NO-synthase inhibitor completely suppressed the development of the protective antihypoxic effect of adaptation. After adaptation to exercise, the cerebral NO production was unchanged, while the hepatic NO production doubled. Acute hypoxia induced a biphase change in tissue NO production; initial increase (twofold in the brain) preceded a decrease (by 25% in liver and 37% in the brain as compared to the control). Therefore, the increased NO production following adaptation to exercise can underlie the antihypoxic effect of such an adaptation.

[The protective effect of a NO-synthase inhibitor in heat shock]. / Zashchitnyi éffekt ingibitora NO-sintazy pri teplovom shoke.

Acute hypotension related to the excessive production of a potent endogenous vasodilator nitric oxide (NO) is a most important link of heat shock pathogenesis. It was shown that inhibition of inducible NO-synthase by N(W)-nitro-L-arginine (L-NNA) at 10 mg/kg reduces the mortality of animals due to heat shock, prevents the fall of arterial blood pressure and abnormal inhibition of constriction and stimulation of dilation reactions related to NO hyperproduction. A total blockade of NO synthesis by L-NNA at 300 mg/kg did not exert a protective effect from heat shock. The data obtained suggest the importance of inducible NO-synthase in heat shock pathogenesis and show promise for the application of selective inhibition of inducible NO-synthase at pathological states related to NO hyperproduction.

Nitric oxide donor induces HSP70 accumulation in the heart and in cultured cells.

As our group has shown, the NO-synthase inhibitor L-NNA decreased 2-3 times heat shock-induced synthesis of the heat shock protein HSP70 (FEBS Lett. 370 (1995) 159-162). It was suggested that NO is involved in such induction. In the present study, it was found that (1) injection of the NO donor dinitrosyl iron complex (DNIC) into rats results in accumulation of HSP70 in the heart; (2) heat shock is accompanied by increased generation of NO (EPR assay) and HSP70 accumulation in cultured cells; (3) DNIC induces HSP70 accumulation in cultured cells not exposed to heat shock.