8 research outputs found
ΠΠ΅ΠΉΡΠΎΠΏΡΠΎΡΠ΅ΠΊΡΠΈΠ²Π½ΡΠ΅ ΡΠ²ΠΎΠΉΡΡΠ²Π° ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΠΎΠ³ΠΎ ΡΡΡΠ°Π½Π° - ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΡ ΠΠΠ-276 Π½Π° ΠΌΠΎΠ΄Π΅Π»ΠΈ Π³Π΅ΠΌΠΎΡΡΠ°Π³ΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΠΈΠ½ΡΡΠ»ΡΡΠ°
The study of the neuroprotective properties new original compound GIZH-276 and evaluate changes activities of prolyl endopeptidase (PEP) and lactate dehydrogenase (LDH) in blood plasma of rats with post-traumatic hematoma (model of hemorrhagic stroke) is the aim of this investigation. Methodology of the study: Modeling of hemorrhagic stroke (HS) was carried out using the creation of intracerebral post-traumatic hematoma with the introduction of autologous blood into the site of injury. Assay of enzymes activities in plasma was carried out with fluorescent (PEP) and ultraviolet (LDH) methods. The results of the study: GIZH-276 at dose of 10 mg/kg (7 days, intraperitoneally) has a pronounced neuroprotective effect, attenuating neurological deficits in rats with hemorrhagic stroke 24 hours, 7 and 14 days after surgery and statistically significantly increasing the number of surviving rats by 14 days of observation. The weakening of neurological deficit and death of animals is accompanied by decreased activity of enzymes LDH and PEP, which indicates the improvement of security of brain tissue oxygen and reducing neuroinflammation. Conclusion: Safety and neuroprotective effect of GIZH-276 on the model of hemorrhagic stroke may be partially due to positive effect on inflammatory and hypoxia during the development of secondary brain damage in stroke.Π¦Π΅Π»ΡΡ Π½Π°ΡΡΠΎΡΡΠ΅Π³ΠΎ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ Π±ΡΠ»ΠΎ ΠΈΠ·ΡΡΠ΅Π½ΠΈΠ΅ Π½Π΅ΠΉΡΠΎΠΏΡΠΎΡΠ΅ΠΊΡΠΈΠ²Π½ΡΡ
ΡΠ²ΠΎΠΉΡΡΠ² Π½ΠΎΠ²ΠΎΠ³ΠΎ ΠΎΡΠΈΠ³ΠΈΠ½Π°Π»ΡΠ½ΠΎΠ³ΠΎ ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΡ ΠΠΠ-276 Ρ Π±ΠΈΠΎΡ
ΠΈΠΌΠΈΡΠ΅ΡΠΊΠΎΠΉ ΠΎΡΠ΅Π½ΠΊΠΎΠΉ Π΅Π³ΠΎ Π²Π»ΠΈΡΠ½ΠΈΡ Π½Π° Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΡΠ΅ΡΠΌΠ΅Π½ΡΠΎΠ² ΠΏΡΠΎΠ»ΠΈΠ»ΡΠ½Π΄Π΅ΠΏΠ΅ΠΏΡΠΈΠ΄Π°Π·Ρ (ΠΠΠ ΠΈ Π»Π°ΠΊΡΠ°ΡΠ΄Π΅Π³ΠΈΠ΄ΡΠΎΠ³Π΅Π½Π°Π·Ρ (ΠΠΠ) Π² ΠΏΠ»Π°Π·ΠΌΠ΅ ΠΊΡΠΎΠ²ΠΈ ΠΊΡΡΡ Ρ ΠΏΠΎΡΡΡΡΠ°Π²ΠΌΠ°ΡΠΈΡΠ΅ΡΠΊΠΎΠΉ Π³Π΅ΠΌΠ°ΡΠΎΠΌΠΎΠΉ, ΠΌΠΎΠ΄Π΅Π»ΡΡ Π³Π΅ΠΌΠΎΡΡΠ°Π³ΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΠΈΠ½ΡΡΠ»ΡΡΠ°. ΠΠ΅ΡΠΎΠ΄ΠΈΠΊΠ° ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ: ΠΌΠΎΠ΄Π΅Π»ΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ Π³Π΅ΠΌΠΎΡΡΠ°Π³ΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΠΈΠ½ΡΡΠ»ΡΡΠ° ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ΠΎ Ρ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½ΠΈΠ΅ΠΌ ΠΌΠ΅ΡΠΎΠ΄ΠΈΠΊΠΈ ΡΠΎΠ·Π΄Π°Π½ΠΈΡ ΠΈΠ½ΡΡΠ°ΡΠ΅ΡΠ΅Π±ΡΠ°Π»ΡΠ½ΠΎΠΉ ΠΏΠΎΡΡΡΡΠ°Π²ΠΌΠ°ΡΠΈΡΠ΅ΡΠΊΠΎΠΉ Π³Π΅ΠΌΠ°ΡΠΎΠΌΡ Ρ Π²Π²Π΅Π΄Π΅Π½ΠΈΠ΅ΠΌ Π°ΡΡΠΎΠΊΡΠΎΠ²ΠΈ Π² ΠΌΠ΅ΡΡΠΎ ΠΏΠΎΠ²ΡΠ΅ΠΆΠ΄Π΅Π½ΠΈΡ. Π€Π»ΡΠΎΡΠΈΠΌΠ΅ΡΡΠΈΡΠ΅ΡΠΊΠΈ, ΡΠ»ΡΡΡΠΎΡΠΈΠΎΠ»Π΅ΡΠΎΠ²ΡΠΌ ΠΌΠ΅ΡΠΎΠ΄ΠΎΠΌ ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ΠΎ Π±ΠΈΠΎΡ
ΠΈΠΌΠΈΡΠ΅ΡΠΊΠΎΠ΅ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠ΅ Π²Π»ΠΈΡΠ½ΠΈΡ ΠΠΠ-276 Π½Π° Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΡΠ΅ΡΠΌΠ΅Π½ΡΠΎΠ² ΠΠΠ ΠΈ ΠΠΠ Π² ΠΏΠ»Π°Π·ΠΌΠ΅ ΠΊΡΠΎΠ²ΠΈ ΠΊΡΡΡ Ρ ΠΠ. Π Π΅Π·ΡΠ»ΡΡΠ°ΡΡ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ: Π²ΡΡΠ²Π»Π΅Π½ΠΎ, ΡΡΠΎ ΠΠΠ-276 Π² Π΄ΠΎΠ·Π΅ 10 ΠΌΠ³/ΠΊΠ³ (7 Π΄Π½Π΅ΠΉ, Π²Π½ΡΡΡΠΈΠ±ΡΡΡΠΈΠ½Π½ΠΎ) ΠΎΠΊΠ°Π·ΡΠ²Π°Π΅Ρ Π²ΡΡΠ°ΠΆΠ΅Π½Π½ΡΠΉ Π½Π΅ΠΉΡΠΎΠΏΡΠΎΡΠ΅ΠΊΡΠΈΠ²Π½ΡΠΉ ΡΡΡΠ΅ΠΊΡ, ΠΎΡΠ»Π°Π±Π»ΡΡ Π½Π΅Π²ΡΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈΠΉ Π΄Π΅ΡΠΈΡΠΈΡ Ρ ΠΊΡΡΡ Ρ Π³Π΅ΠΌΠΎΡΡΠ°Π³ΠΈΡΠ΅ΡΠΊΠΈΠΌ ΠΈΠ½ΡΡΠ»ΡΡΠΎΠΌ ΡΠ΅ΡΠ΅Π· 24 Ρ, 7 ΠΈ 14 ΡΡΡ. ΠΏΠΎΡΠ»Π΅ ΠΎΠΏΠ΅ΡΠ°ΡΠΈΠΈ ΠΈ ΡΡΠ°ΡΠΈΡΡΠΈΡΠ΅ΡΠΊΠΈ Π΄ΠΎΡΡΠΎΠ²Π΅ΡΠ½ΠΎ ΡΠ²Π΅Π»ΠΈΡΠΈΠ²Π°Ρ ΡΠΈΡΠ»ΠΎ Π²ΡΠΆΠΈΠ²ΡΠΈΡ
ΠΊΡΡΡ ΠΊ 14-ΠΌ ΡΡΡΠΊΠ°ΠΌ Π½Π°Π±Π»ΡΠ΄Π΅Π½ΠΈΡ. ΠΡΠ»Π°Π±Π»Π΅Π½ΠΈΠ΅ Π½Π΅Π²ΡΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ Π΄Π΅ΡΠΈΡΠΈΡΠ° ΠΈ Π³ΠΈΠ±Π΅Π»ΠΈ ΠΆΠΈΠ²ΠΎΡΠ½ΡΡ
ΡΠΎΠΏΡΠΎΠ²ΠΎΠΆΠ΄Π°Π΅ΡΡΡ ΡΠ½ΠΈΠΆΠ΅Π½ΠΈΠ΅ΠΌ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΡΠ΅ΡΠΌΠ΅Π½ΡΠΎΠ² ΠΠΠ ΠΈ ΠΠΠ, ΡΡΠΎ ΡΠ²ΠΈΠ΄Π΅ΡΠ΅Π»ΡΡΡΠ²ΡΠ΅Ρ ΠΎΠ± ΡΠ»ΡΡΡΠ΅Π½ΠΈΠΈ ΠΎΠ±Π΅ΡΠΏΠ΅ΡΠ΅Π½ΠΈΡ ΡΠΊΠ°Π½Π΅ΠΉ ΠΌΠΎΠ·Π³Π° ΠΊΠΈΡΠ»ΠΎΡΠΎΠ΄ΠΎΠΌ ΠΈ ΡΠΌΠ΅Π½ΡΡΠ΅Π½ΠΈΠΈ Π½Π΅ΠΉΡΠΎΠ²ΠΎΡΠΏΠ°Π»Π΅Π½ΠΈΡ. ΠΠ°ΠΊΠ»ΡΡΠ΅Π½ΠΈΠ΅: Π·Π°ΡΠΈΡΠ½ΡΠΉ, Π½Π΅ΠΉΡΠΎΠΏΡΠΎΡΠ΅ΠΊΡΠΈΠ²Π½ΡΠΉ ΡΡΡΠ΅ΠΊΡ ΠΠΠ-276 Π½Π° ΠΌΠΎΠ΄Π΅Π»ΠΈ Π³Π΅ΠΌΠΎΡΡΠ°Π³ΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΠΈΠ½ΡΡΠ»ΡΡΠ° ΠΌΠΎΠΆΠ΅Ρ Π±ΡΡΡ ΡΠ°ΡΡΠΈΡΠ½ΠΎ ΠΎΠ±ΡΡΠ»ΠΎΠ²Π»Π΅Π½ Π΅Π³ΠΎ ΠΏΠΎΠ»ΠΎΠΆΠΈΡΠ΅Π»ΡΠ½ΡΠΌ Π²Π»ΠΈΡΠ½ΠΈΠ΅ΠΌ Π½Π° Π²ΠΎΡΠΏΠ°Π»ΠΈΡΠ΅Π»ΡΠ½ΠΎΠ΅ ΠΈ Π³ΠΈΠΏΠΎΠΊΡΠΈΡΠ΅ΡΠΊΠΎΠ΅ Π·Π²Π΅Π½ΠΎ ΡΠ°Π·Π²ΠΈΡΠΈΡ Π²ΡΠΎΡΠΈΡΠ½ΡΡ
ΠΏΠΎΠ²ΡΠ΅ΠΆΠ΄Π΅Π½ΠΈΠΉ ΠΌΠΎΠ·Π³Π° ΠΏΡΠΈ ΠΈΠ½ΡΡΠ»ΡΡΠ΅
ΠΠΎΠ²ΠΎΠ΅ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΠΎΠ΅ ΠΎΠΊΡΠΈΠΌΠΎΠ² 4-Π±Π΅Π½Π·ΠΎΠΈΠ»ΠΏΠΈΡΠΈΠ΄ΠΈΠ½ΠΎΠ² ΠΠΠ-298, ΠΎΠ±Π»Π°Π΄Π°ΡΡΠ΅Π΅ ΠΏΡΠΎΡΠΈΠ²ΠΎΡΡΠ΄ΠΎΡΠΎΠΆΠ½ΠΎΠΉ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡΡ
Novel derivative of benzoylpyridine oximes - GIZH-298 (4-benzoylpyridine 0-(2-morpholinoethyl) oxime oxalate) was designed and synthesized in this work. This compound has a broad spectrum of anticonvulsant effects, eliminating primary generalized seizures in maximal electroshock (MES) and corazol antagonism tests in rodents in the doses of 0,5-100 mg/kg. LD50 for compound GIZH-298 is 316 mg/kg intraperitoneally (mouse). GIZH-298 has a large therapeutic breadth.Π Π½Π°ΡΡΠΎΡΡΠ΅ΠΉ ΡΠ°Π±ΠΎΡΠ΅ ΠΎΡΡΡΠ΅ΡΡΠ²Π»ΡΠ½ Π΄ΠΈΠ·Π°ΠΉΠ½ ΠΈ ΡΠΈΠ½ΡΠ΅Π· Π½ΠΎΠ²ΠΎΠ³ΠΎ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΠΎΠ³ΠΎ ΠΎΠΊΡΠΈΠΌΠ° 4-Π±Π΅Π½Π·ΠΎΠΈΠ»ΠΏΠΈΡΠΈΠ΄ΠΈΠ½Π° - ΠΠΠ-298 (ΠΎΠΊΡΠ°Π»Π°Ρ 0-(2-ΠΌΠΎΡΡΠΎΠ»ΠΈΠ½ΠΎΡΡΠΈΠ»)ΠΎΠΊΡΠΈΠΌΠ° 4-Π±Π΅Π½Π·ΠΎΠΈΠ»ΠΏΠΈΡΠΈΠ΄ΠΈΠ½Π°). ΠΡΠΎ ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΠ΅ ΠΎΠ±Π»Π°Π΄Π°Π΅Ρ ΠΏΡΠΎΡΠΈΠ²ΠΎΡΡΠ΄ΠΎΡΠΎΠΆΠ½ΠΎΠΉ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡΡ, ΡΡΡΡΠ°Π½ΡΡ ΠΏΠ΅ΡΠ²ΠΈΡΠ½ΠΎ-Π³Π΅Π½Π΅ΡΠ°Π»ΠΈΠ·ΠΎΠ²Π°Π½Π½ΡΠ΅ ΡΡΠ΄ΠΎΡΠΎΠ³ΠΈ Π² ΡΠ΅ΡΡΠ°Ρ
Π°Π½ΡΠ°Π³ΠΎΠ½ΠΈΠ·ΠΌΠ° Ρ ΠΌΠ°ΠΊΡΠΈΠΌΠ°Π»ΡΠ½ΡΠΌ ΡΠ»Π΅ΠΊΡΡΠΎΡΠΎΠΊΠΎΠΌ (ΠΠΠ¨) ΠΈ ΠΊΠΎΡΠ°Π·ΠΎΠ»ΠΎΠΌ Π² Π΄ΠΎΠ·Π°Ρ
0,5-100 ΠΌΠ³/ΠΊΠ³ Ρ Π³ΡΡΠ·ΡΠ½ΠΎΠ² Π²Π½ΡΡΡΠΈΠ±ΡΡΡΠΈΠ½Π½ΠΎ. ΠΠ50 ΠΏΡΠΈ Π²Π½ΡΡΡΠΈΠ±ΡΡΡΠΈΠ½Π½ΠΎΠΌ Π²Π²Π΅Π΄Π΅Π½ΠΈΠΈ Π΄Π»Ρ ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΡ ΠΠΠ-298 ΡΠΎΡΡΠ°Π²Π»ΡΠ΅Ρ 316 ΠΌΠ³/ΠΊΠ³ (ΠΌΡΡΠΈ). Π’Π°ΠΊΠΈΠΌ ΠΎΠ±ΡΠ°Π·ΠΎΠΌ, ΠΠΠ-298 ΠΈΠΌΠ΅Π΅Ρ Π±ΠΎΠ»ΡΡΡΡ ΡΠ΅ΡΠ°ΠΏΠ΅Π²ΡΠΈΡΠ΅ΡΠΊΡΡ ΡΠΈΡΠΎΡΡ
4-BENZOYLPYRIDINE OXIME DERIVATIVE (GIZH-298) VERSUS VALPROIC ACID: THE ANTICONVULSANT POTENTIAL EFFECT IN A MODEL OF EPILEPSY IN RATS WITH COBALT-INDUCED LESIONS
Objective of the research is to evaluate the anticonvulsant effect of the new original compound GIZH-298 (4-benzoylpyridine oxime derivative) versus valproic acid (VPA) in a model of epilepsy in rats with cobalt-induced lesions.Materials and methods. Modeling of epileptic status was performed using the technique of creating a chronic epileptogenic focus caused by the application of cobalt to the sensorimotor zone of the rat cortex, followed by intraperitoneal administration of homolecysteine thiolactone. Compounds GIZH-298 and VPA were introduced against the background of development of electrographic status with behavioral convulsive seizure manifestations.Results. The study revealed that GIZH-298 at a dose of 60 mg/kg (i. p.) in 50 minutes after injection reduces the number of high-amplitude generalized discharges caused by homocysteine thiolactone in the ipsilateral and contralateral cortex (46-fold decrease), in the hippocampus and hypothalamus (28-fold decrease); eliminates (in 100% of the animals) the generalized tonic-clonic seizures that arise in the advanced stage of status epilepticus. VPA at a dose of 100 mg/kg (i. p.) in 3 hours after injection significantly suppresses the EpA in all evaluated structures with the maximum value in the hypothalamus (28-fold decrease), and after 5 hours in the ipsilateral and contralateral (33-fold decrease). At the same time, VPA eliminates generalized motility of status epilepticus only in 71% of the animals and protects from death 86% of the rats.Conclusion. The compound GIZH-298 significantly earlier (for 2 hours) than the VPA (100 mg/kg) and at a lower dose (60 mg/kg) fully eliminates electrographic (in all evaluated brain structures with the greatest efficiency in the contralateral cortex and the hypothalamus) and behavioral manifestations of unfolded status epilepticus and prevents deaths in 100%
ELECTROPHYSIOLOGICAL AND NEUROCHEMICAL STUDIES OF THE MECHANISMS OF THE ANTICONVULSANT EFFECT OF THE NEW ORIGINAL COMPOUND GIZH-298
The aim of this study was to investigate the electrophysiological and neurochemical mechanisms of the anticonvulsant effect of a new original compoundΒ GIZH-298 and to define the leading structure as the target for influence compound. Materials andΒ Methods. The partial (focal) and secondary generalized seizures were modeled by methods of creation a chronic epileptic focusΒ that was causedΒ by cobalt applique on the brain of rats. The liquid chromatographyΒ (HPLC) analysis used for neurochemical study of the effect GIZH-298. There was studied the effect on metabolismΒ and quantity of biogenic amines in the brain structures of rats. Results. It was found that GIZH-298 at a dose of 60 mg / kg (i.p.) has a pronounced effect on the primary and especially secondary generalized epileptic foci in various brain structures with a primary influence on the cortex. GIZH-298 at a doseΒ of 60 mg / kg causedΒ a statistically significant increase in the content of serotonin and dopamine in the frontal cortex after 30 minutes after the administration and reduced the rate of metabolismΒ of dopamineΒ in theΒ dorsal striatum.Β Conclusion.Β The anticonvulsantΒ effectΒ GIZH-298Β is enhancedΒ with increased of epileptic system, may be due to increased synthesis of serotonin and dopamine in the cortex, and decreased metabolismΒ of the latter in the striatum