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P.5.073 Neuroprotective activity ofproproten in experimental model of cerebral hemorrhagic stroke
Poster Sessions 2) vinpocetine-treated (2 mg/kg/day i.p.), 3) nimodipinetreated (0.5mg/kg/day i.p.) and 4) cinnarizine-treated (1 mg/kg/day-i.p.). The duration of treatment was 7 days up to the appropriate term of HK. Local cerebral blood (1CBF) was measured through the trepan hole above parietal cortex using laser-Doppler flowmeter. The sensitivity of cerebral vessels to CO2 was defined by registering ICBF during hypercapnic inhalation test and by counting the coefficient of reactivity of cerebral vessels (RCVco2). Results: We observed a decrease of sensitivity of cerebral vessels to CO2, which was most vividly expressed on 30th day of I-IK [RCVco 2= 1.996±0.058 in control, and 1.7354-0.089 in I-IK30 group (p <0.01)]. V-treatment increased the RCVco2 [in HK30+V group RCVco2=l.8854-0.090 (p<0.05)]. Opposite to this, C-treatment decreased RCVco2 in late periods of HK [in HK45 group RCVco2=l.990+0.074 and in I-IK45+C group 1.840±0.077 (p <0.05); in I-IK60 group RCVco2 = 1.940+0.076 and HK60+C group 1.708+0.079 (p<0.01)]. At the same time, no significant decrease of RCVco2 in the I-IK45+N and I-IK60+N groups was observed. Conclusion: The results of this study suggest that HK is a factor decreasing sensitivity of cerebral vessels to CO2, which is one of the signs of altered regulation of cerebral circulation in HK. At the same time, we showed that V-treatment can improve these shifts, but C- and to a lesser extent N-treatment have opposite effect, especially in late periods of HK. Generally, V-treatment is a more effective prevention of cerebrovascular shifts in I-IK than N- or C-treatment.
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Memory restoring and neuroprotective effects of dipeptide noopept in a photochemical stroke model
G.A. Romanova1, EM. Shakova1, T.A. Gudasheva2, R.U. Ostrovskaya2, T.A. Voronina2. 1Institute of General Pathology and Pathophysiology, 2Zakusov State Institute of Pharmacology, Russian Academy of Medical Sciences, 8 Baltiyskaya, 125315, Moscow, Russia Cognition deficit is a typical symptom of stroke. N-phenylacetyl-L-prolylglycine ethyl ester (GVS-111, noopept) was developed among other acetyl-prolinecontaining dipeptides as a topological analogue of the cognition enhancer, piracetam [1]. The aim of this study was to evaluate the effect of noopept on passive avoidance performance (PA) and size of lesion in photochemically induced local cortical thrombosis, known to be the model of ischemic stroke.
$241
The photothrombosis of rat's prefrontal cortex provokes a selective deficit of PA performance. Repetitive testing of this reflex on day nine after the operation revealed diminishing of the latency of the dark compartment entering in comparison to sham-operated rats (P < 0.01). Noopept, administered in a dose of 0.5mg/kg intravenously for nine postoperative days, was found to improve the performance in the PA test - the latency of this response increased comparing with saline-treated ischemized rats (P <0.01). The effect of noopept was demonstrated also in another schedule of the experiment. The acquisition of PA in rats took place after phototrombosis of prefrontal cortex, when noopept was administered for eight days before and three days during learning. In this case noopept administered postoperatively, before the learning, also improve the performance of PA comparing to ischaemic damaged saline-treated rats (P <0.05 in U-test). Judging by the morphological assessment the treatment with noopept causes statistically significant diminution of the volume of the lesioned cortical tissues, testifying to its neuroprotective effect. These experiments provide evidence that this dipeptide being administered systemically possesses both cognition restoring and neuroprotective properties.
References [1] Seredenin S.B., Voronina T.A., Gudasheva T.A. et al., 1995. Biologically active N-acylprolyldipeptides having antianmestic, antihypoxic and anorexigenic effects. USA Patent 5,439,930.
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Neuroprotective activity of proproten in experimental model of cerebral hemorrhagic stroke
S.A. Sergeeva, LL. Dugina, A.V. Martyushev-Poklad, O.I. Epstein. Materia Medica Holding, Research-andProduction Company, 3 Samotechniy per 9, Moscow, 127473, Russia The development of treatments for hemorrhagic stroke has focused both on reestablishing blood flow to ischemic areas as quickly as possible (antithrombotics or thrombolytics) and on protecting neurons from cytotoxic events (neuroprotective therapies). Proproten, ultra-low doses of antibodies to S-100 protein for oral use, was shown to protect brain tissue against focal cerebral ischemia in a model of photochemically induced thrombosis. The aim of the present work is to study neuroprotective activity of proproten in an experimental model of hemorrhagic stroke.
Poster Sessions
s242
Cerebral brain posttraumatic hematoma was modeled in rats according to Makarenko et al. (2002). White outbred
rats (200-220g) received either proproten (2.5ml/kg, i.g.) or nimodipine (0.Img/kg, i.g.) daily for 14 days. Animals were tested on day I, day 3, day 7 and day 14 after operation. The effect of drugs on neurologic deficit (McGrow scale), cognitive impairment (passive avoidance test) and emotional status (open field test, elevated plusmaze) was assessed. Sham-operated animals were used as controls. Because of hemorrhagic brain damage 50% of the animals in the vehicle-treated group had died by day 14 (proproten - 30%; nimodipine - 40%). Proproten as well as nimodipine ameliorated neurologic deficit preventing both severe and non-severe impairments. Proproten improved retention in the rat passive avoidance paradigm: on day 14 proproten increased both retention latency and number of animals remembering punishments (3.5 times, p<0.05). On the contrary, there was no statistically significant improvement of memory in nimodipine-treated animals on day 14. Besides, proproten eliminated excessive anxiety and myorelaxation in rats after hemorrhagic stroke. Influence of proproten on the survival of rots after hemorrhagic stroke Day 1 n/N
Sham-operated Stroke+vehicle(2.5ml/kg) Stroke+proproten (2.5ml/kg) Stroke+nimodipine (0.1mg/kg)
Day 3
% n/N
0/10 0 1/10" 10 0/10 0 0/10 0
0/10 2/10 1/10 2/10
Day 7
Day 14
% n/N
% n/N
%
0 20 10 20
0 30 20 30
0 50* 30 40
0/10 3/10 2/10 3/10
0/10 5/10 3/10 4/10
*Difference significant at p < 0.05 (vs sham-operated animals).
To conclude, proproten was effective in improving neurological outcome after hemorrhagic stroke. Proproten benefits hemorrhagic stroke treatment by improving neurologic recovery and attenuating memory deficit. Unlike nimodipine, proproten moderated effects of hemorrhagic brain trauma on cognition and anxiety.
References [1] Makarenko A.N., Kositsyn N.S., Pasikova N.V., Svinov M.M. Simulation of local cerebral hemorrhage in different brain structures of experimental animals. Zh. Vyssh Nerv. Deiat. Im. I.P. Pavlova 2002; 52: 765.
~New
antiischemicdrug composition
E.V. Lunshina, N.R. Mirzoyan. Laboratory of
Pharmacology of Cerebrovascular Disorders, Zakusoo State Institute of Pharmacology Russian Academy of Medical Sciences, Baltiyskaya str. 8, 125315 Moscow, Russia Pharmacotherapy of cerebrovascular ischemic disorders is an actual problem of modern medicine. At the RAMS Institute of Pharmacology we elaborated a new antiischemic drug composition (containing pyrrolidone and pyroglutamic acid) having neuroprotective effect in rats with focal brain ischemia produced by middle cerebral artery occlusion [1,2]. The aim of the investigation was to study cerebrovascular and neuroprotective characteristics and neurotransmitter mechanisms of action of the composition. The experiments were made in anesthetized rats and cats. The local cerebral blood flow in rats was registered by laser doppler flowmeter, regional blood flow in cats was registered by ultrasonic flowmeter. The experiments showed that the drug composition (pyrrolidone and pyroglutamic acid) increased brain microcirculation in rats and cerebral blood flow in cats. Effects of the novel drug composition containing pyroglutamic acid and pyrrolidone on the cerebral circulation were estimated after global recurrent brain ischemia and in the model of ischemic state during radial gravitational overloads. Global transient ischemia was produced by both carotid artery occlusion for 10 min and hemorrage from femoral artery down to 40-50mmHg. The experiments showed that following global brain ischemia drug composition effects on cerebral circulation were more pronounced than those observed in intact rats (52.0±12.7%, in comparison with 26.04-6.3%.). In special experiments radial gravitational overloads in craniocaudal direction, during which the pressure in cerebral arteries dropped to zero, was used as ischemic state model. The drug composition was also found to increase the rats' survival by 2.0-2.5 times in this model of ischemic state. In order to investigate neurotransmitter mechanisms of cerebrovascular effects of the composition, we examined the role of serotonin and GABA. It is known that serotonin is a potent cerebral vasoconstrictor. Our experiments showed that drug composition did not influence cerebrovascular effect of serotonin. GABA decreases the tone of cerebral vessels and increases the brain circulation. Components of the drug composition - pyrrolidone and pyroglutamic acid are biogenic derivatives of GABA and glutamic acid. So we were interested in the role of GABAA receptors of brain vessels in the ability of the composition to enhance cerebral blood flow. It was shown that, during blockade of GABAA receptor by bicucullin, pyrrolidone
•
Memory restoring and neuroprotective effects of dipeptide noopept in a photochemical stroke model
G.A. Romanova1, EM. Shakova1, T.A. Gudasheva2, R.U. Ostrovskaya2, T.A. Voronina2. 1Institute of General Pathology and Pathophysiology, 2Zakusov State Institute of Pharmacology, Russian Academy of Medical Sciences, 8 Baltiyskaya, 125315, Moscow, Russia Cognition deficit is a typical symptom of stroke. N-phenylacetyl-L-prolylglycine ethyl ester (GVS-111, noopept) was developed among other acetyl-prolinecontaining dipeptides as a topological analogue of the cognition enhancer, piracetam [1]. The aim of this study was to evaluate the effect of noopept on passive avoidance performance (PA) and size of lesion in photochemically induced local cortical thrombosis, known to be the model of ischemic stroke.
$241
The photothrombosis of rat's prefrontal cortex provokes a selective deficit of PA performance. Repetitive testing of this reflex on day nine after the operation revealed diminishing of the latency of the dark compartment entering in comparison to sham-operated rats (P < 0.01). Noopept, administered in a dose of 0.5mg/kg intravenously for nine postoperative days, was found to improve the performance in the PA test - the latency of this response increased comparing with saline-treated ischemized rats (P <0.01). The effect of noopept was demonstrated also in another schedule of the experiment. The acquisition of PA in rats took place after phototrombosis of prefrontal cortex, when noopept was administered for eight days before and three days during learning. In this case noopept administered postoperatively, before the learning, also improve the performance of PA comparing to ischaemic damaged saline-treated rats (P <0.05 in U-test). Judging by the morphological assessment the treatment with noopept causes statistically significant diminution of the volume of the lesioned cortical tissues, testifying to its neuroprotective effect. These experiments provide evidence that this dipeptide being administered systemically possesses both cognition restoring and neuroprotective properties.
References [1] Seredenin S.B., Voronina T.A., Gudasheva T.A. et al., 1995. Biologically active N-acylprolyldipeptides having antianmestic, antihypoxic and anorexigenic effects. USA Patent 5,439,930.
•
Neuroprotective activity of proproten in experimental model of cerebral hemorrhagic stroke
S.A. Sergeeva, LL. Dugina, A.V. Martyushev-Poklad, O.I. Epstein. Materia Medica Holding, Research-andProduction Company, 3 Samotechniy per 9, Moscow, 127473, Russia The development of treatments for hemorrhagic stroke has focused both on reestablishing blood flow to ischemic areas as quickly as possible (antithrombotics or thrombolytics) and on protecting neurons from cytotoxic events (neuroprotective therapies). Proproten, ultra-low doses of antibodies to S-100 protein for oral use, was shown to protect brain tissue against focal cerebral ischemia in a model of photochemically induced thrombosis. The aim of the present work is to study neuroprotective activity of proproten in an experimental model of hemorrhagic stroke.
Poster Sessions
s242
Cerebral brain posttraumatic hematoma was modeled in rats according to Makarenko et al. (2002). White outbred
rats (200-220g) received either proproten (2.5ml/kg, i.g.) or nimodipine (0.Img/kg, i.g.) daily for 14 days. Animals were tested on day I, day 3, day 7 and day 14 after operation. The effect of drugs on neurologic deficit (McGrow scale), cognitive impairment (passive avoidance test) and emotional status (open field test, elevated plusmaze) was assessed. Sham-operated animals were used as controls. Because of hemorrhagic brain damage 50% of the animals in the vehicle-treated group had died by day 14 (proproten - 30%; nimodipine - 40%). Proproten as well as nimodipine ameliorated neurologic deficit preventing both severe and non-severe impairments. Proproten improved retention in the rat passive avoidance paradigm: on day 14 proproten increased both retention latency and number of animals remembering punishments (3.5 times, p<0.05). On the contrary, there was no statistically significant improvement of memory in nimodipine-treated animals on day 14. Besides, proproten eliminated excessive anxiety and myorelaxation in rats after hemorrhagic stroke. Influence of proproten on the survival of rots after hemorrhagic stroke Day 1 n/N
Sham-operated Stroke+vehicle(2.5ml/kg) Stroke+proproten (2.5ml/kg) Stroke+nimodipine (0.1mg/kg)
Day 3
% n/N
0/10 0 1/10" 10 0/10 0 0/10 0
0/10 2/10 1/10 2/10
Day 7
Day 14
% n/N
% n/N
%
0 20 10 20
0 30 20 30
0 50* 30 40
0/10 3/10 2/10 3/10
0/10 5/10 3/10 4/10
*Difference significant at p < 0.05 (vs sham-operated animals).
To conclude, proproten was effective in improving neurological outcome after hemorrhagic stroke. Proproten benefits hemorrhagic stroke treatment by improving neurologic recovery and attenuating memory deficit. Unlike nimodipine, proproten moderated effects of hemorrhagic brain trauma on cognition and anxiety.
References [1] Makarenko A.N., Kositsyn N.S., Pasikova N.V., Svinov M.M. Simulation of local cerebral hemorrhage in different brain structures of experimental animals. Zh. Vyssh Nerv. Deiat. Im. I.P. Pavlova 2002; 52: 765.
~New
antiischemicdrug composition
E.V. Lunshina, N.R. Mirzoyan. Laboratory of
Pharmacology of Cerebrovascular Disorders, Zakusoo State Institute of Pharmacology Russian Academy of Medical Sciences, Baltiyskaya str. 8, 125315 Moscow, Russia Pharmacotherapy of cerebrovascular ischemic disorders is an actual problem of modern medicine. At the RAMS Institute of Pharmacology we elaborated a new antiischemic drug composition (containing pyrrolidone and pyroglutamic acid) having neuroprotective effect in rats with focal brain ischemia produced by middle cerebral artery occlusion [1,2]. The aim of the investigation was to study cerebrovascular and neuroprotective characteristics and neurotransmitter mechanisms of action of the composition. The experiments were made in anesthetized rats and cats. The local cerebral blood flow in rats was registered by laser doppler flowmeter, regional blood flow in cats was registered by ultrasonic flowmeter. The experiments showed that the drug composition (pyrrolidone and pyroglutamic acid) increased brain microcirculation in rats and cerebral blood flow in cats. Effects of the novel drug composition containing pyroglutamic acid and pyrrolidone on the cerebral circulation were estimated after global recurrent brain ischemia and in the model of ischemic state during radial gravitational overloads. Global transient ischemia was produced by both carotid artery occlusion for 10 min and hemorrage from femoral artery down to 40-50mmHg. The experiments showed that following global brain ischemia drug composition effects on cerebral circulation were more pronounced than those observed in intact rats (52.0±12.7%, in comparison with 26.04-6.3%.). In special experiments radial gravitational overloads in craniocaudal direction, during which the pressure in cerebral arteries dropped to zero, was used as ischemic state model. The drug composition was also found to increase the rats' survival by 2.0-2.5 times in this model of ischemic state. In order to investigate neurotransmitter mechanisms of cerebrovascular effects of the composition, we examined the role of serotonin and GABA. It is known that serotonin is a potent cerebral vasoconstrictor. Our experiments showed that drug composition did not influence cerebrovascular effect of serotonin. GABA decreases the tone of cerebral vessels and increases the brain circulation. Components of the drug composition - pyrrolidone and pyroglutamic acid are biogenic derivatives of GABA and glutamic acid. So we were interested in the role of GABAA receptors of brain vessels in the ability of the composition to enhance cerebral blood flow. It was shown that, during blockade of GABAA receptor by bicucullin, pyrrolidone