RESUMEN
OBJECTIVE: Identification of the role of oxidative stress in the development of disorders that occur in hemorrhagic stroke (HS, post-traumatic intracerebral hematoma), and the study of the effects of Mexidol on neurological and cognitive deficits in HS with an analysis of the relationship between the therapeutic effects of the drug in HS with its antioxidant effect. MATERIAL AND METHODS: The study was carried out on mature outbred male rats weighing 260-280 g. HS was created by destruction of the brain tissue in the area of the capsula interna, with the introduction of blood into the site of injury. On the 1st, 7th, and 14th days after HS modeling, death, neurological deficits (McGrow scale, rotating rod), convulsive manifestations, and cognitive impairment were recorded in rats; blood plasma and homogenates of the cerebral cortex of rats. Mexidol was administered after the HS operation: first at a dose of 150 mg/kg, intraperitoneally, for 3 days and then 75 mg/kg, orally (from the 4th to the 14th day). RESULTS: Mexidol in rats with HS significantly increases the survival rate of animals, reduces the manifestations of neurological deficits according to the McGrow scale (playpen movements, paresis of 1-4 limbs, paralysis of the lower limbs, lateral position), eliminates individual motor convulsive manifestations, restores impaired coordination of movements (rotating rod test) and improves, impaired HS, learning and memory processes. Mexidol normalizes the concentration of TBA-active products in the blood of animals and homogenates of the cerebral cortex of rats, both a day and 7 days after HS modeling. CONCLUSION: The data obtained indicate the involvement of oxidative stress as a chain of pathogenesis in the development of disorders in HS and the ability of Mexidol to alleviate neurological deficits, convulsive manifestations and cognitive impairment in HS, which is accompanied by a decrease in oxidative stress. All this justifies the importance of the use of Mexidol in patients with hemorrhagic stroke, posttraumatic intracerebral hematoma and determines the features of its therapeutic effects.
Asunto(s)
Accidente Cerebrovascular Hemorrágico , Animales , Hematoma , Masculino , Estrés Oxidativo , Picolinas , RatasRESUMEN
The influence of two aminoadamantane derivatives representing low-affinity NMDA receptor antagonists, which show antiparkinsonian-like activity both in animal models and in patients with Parkinson's disease, have been studied in vivo on mice with acute ethanol-induced disorders. N-(adamant-2-yl) hexamethyleneimine hydrochloride (himantane) in doses of 5--20 mg/kg, i.p., dose-dependently prevented ethanol-induced ataxia in CD-I mice, sedation in C57BI/6 mice, and hyperlocomotion in DBA/2 mice. At the same time, I -aminoadamantane (amantadine) in doses of 10 - 20 mg/kg, i.p., did not attenuate acute ethanol-induced (2 g/kg, i.p.) effects. Neither himantane nor amantadine influenced the duration of ethanol narcosis (5.5 g/kg, i.p.) in CD-I mice. The obtained data showed a difference of the pharmacodynamic profile of himantane as low-affinity NMDA receptor antagonist in interaction with ethanol at doses inducing behavioral disorders.
Asunto(s)
Adamantano/análogos & derivados , Adamantano/farmacología , Ataxia , Etanol/efectos adversos , Hipnóticos y Sedantes , Locomoción/efectos de los fármacos , Animales , Ataxia/inducido químicamente , Ataxia/tratamiento farmacológico , Ataxia/fisiopatología , Etanol/farmacología , Hipnóticos y Sedantes/efectos adversos , Hipnóticos y Sedantes/farmacología , Ratones , Ratones Endogámicos DBARESUMEN
Hemantane demonstrated a pronounced antiparkinsonian activity in the model of hemiparkinsonian syndrome provoked in rats by unilateral intracerebral injection of 6-hydroxydopamine, which was comparable to efficacy of levodopa in decreasing the duration of cataleptogenic state and the degree of akinesia of the contralesional forelimb assessed in the cylinder test. In the stepping test, hemantane exerted a long-term effect in contrast to levodopa, which diminished its beneficial action to the treatment day 21. In the swing test, the behavior normalized only by hemantane.
Asunto(s)
Adamantano/análogos & derivados , Antiparkinsonianos/uso terapéutico , Catalepsia/tratamiento farmacológico , Adamantano/uso terapéutico , Animales , Levodopa/uso terapéutico , Masculino , Ratas , Ratas WistarRESUMEN
Levodopa-induced heavy dyskinesia was modeled in rats with severe hemiparkinsonian syndrome induced by injection of 6-hydroxydopamine in the left medial forebrain bundle. It is established that the antidyskinetic effect of the injectable dosage form of a new antiparkinsonian drug hemantane (5 mg/kg) after a single intravenous administration is weaker than that of the most effective in clinical practice antidyskinetic drug amantadine (20 mg/kg). However, after five days of treatment, the effect of hemantane injections exceeded that of amantadine.
Asunto(s)
Adamantano/análogos & derivados , Adrenérgicos/efectos adversos , Antiparkinsonianos/efectos adversos , Discinesia Inducida por Medicamentos/fisiopatología , Levodopa/efectos adversos , Oxidopamina/efectos adversos , Trastornos Parkinsonianos/fisiopatología , Adamantano/farmacología , Adrenérgicos/farmacología , Animales , Antiparkinsonianos/farmacología , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/farmacología , Masculino , Oxidopamina/farmacología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/tratamiento farmacológico , RatasRESUMEN
A single intraperitoneal injection of MPTP neurotoxin (30 mg/kg) in C57BL/6 mice causes desynchronization of EEG with a decrease of theta-1 activity and a growth of beta activity in the interval of 15-30 Hz. Subchronic administration of the new antiparkinsonian drug hemantane (injection form) in a dose of 10 mg/kg makes the power of MPTP-induced beta oscillations less pronounced and leads to its reliable decrease within 24 h. This effect of hemantane administration was manifested during the entire period of observations.
Asunto(s)
Adamantano/análogos & derivados , Ritmo beta/efectos de los fármacos , Intoxicación por MPTP/fisiopatología , Enfermedad de Parkinson Secundaria/fisiopatología , Ritmo Teta/efectos de los fármacos , Adamantano/farmacología , Animales , Intoxicación por MPTP/tratamiento farmacológico , Masculino , Ratones , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Factores de TiempoRESUMEN
Effects of the novel antiparkinsonian drug himantane and amantadin were studied in rats with intracerebral posttraumatic hematoma. Drugs were administered first at 3.5 hours after surgery and then for 4 consecutive days. Effects were registered on days 1, 3, 7 and 14 after surgery. It was shown that both drugs significantly decreased mortality and improved motor activity, exploratory behavior and memory. Amantadin was more effective in tests for motor activity and exploratory behavior. Himantane 5 mg/kg i.p demonstrated the more pronounced activity in restoring memory. The results obtained testify for neuroprotective properties of the novel antiparkinsonian drug himantane.
Asunto(s)
Adamantano/análogos & derivados , Amantadina/uso terapéutico , Antiparkinsonianos/uso terapéutico , Hemorragia Cerebral Traumática/tratamiento farmacológico , Adamantano/uso terapéutico , Animales , Hemorragia Cerebral Traumática/psicología , Hemorragia Cerebral Traumática/rehabilitación , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Tono Muscular/efectos de los fármacos , RatasRESUMEN
Presymptomatic (premotor) stage of Parkinson's disease has been modeled in rats by intranigral bilateral injections of neurotoxin MPTP. Three weeks after surgery, rats demonstrated cognitive deficit and depressive-like behavior without definite motor impairment. Pretreatment with hemantane (10 mg/kg) and the reference drug amantadine (20 mg/kg) 5 days before MPTP and further administration during 3 weeks after MPTP preserve cognitive function and prevented depressive disturbances in rats. The antidepressive effect of hemantane was more pronounced than that of amantadine. Results obtained, together with data on hemantane mechanism of action, allow hemantane to be considered as a promising drug for the treatment of Parkinson's disease with potential to decrease the rate of disease progression when administered on early stages.
Asunto(s)
Adamantano/análogos & derivados , Antiparkinsonianos/uso terapéutico , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/prevención & control , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Adamantano/farmacología , Adamantano/uso terapéutico , Amantadina/farmacología , Amantadina/uso terapéutico , Animales , Antiparkinsonianos/farmacología , Cognición/efectos de los fármacos , Esquema de Medicación , Masculino , Neurotoxinas , Enfermedad de Parkinson Secundaria/inducido químicamente , Ratas , Factores de TiempoRESUMEN
Chronic administration of levodopa and benserazide (10 and 15 mg/kg, respectively) cause the development of dyskinesia in rats with model parkinsonian syndrome induced by injection of 6-hydroxydopamine in left substantia nigra. The chronic administration of these drugs together with amantadine (20 mg/kg) accelerates the onset of latency and increases the magnitude of dyskinesia. Chronic administration of levodopa and benserazide together with hemantane (10 mg/kg) slows down the development and decreases the magnitude of levodopa-induced abnormal involuntary movements as measured for limb, orolingual and rotatory movements.
Asunto(s)
Adamantano/análogos & derivados , Conducta Animal/efectos de los fármacos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Trastornos Parkinsonianos/tratamiento farmacológico , Sustancia Negra/efectos de los fármacos , Adamantano/administración & dosificación , Adamantano/uso terapéutico , Amantadina/administración & dosificación , Amantadina/efectos adversos , Animales , Benserazida/farmacología , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/fisiopatología , Levodopa/administración & dosificación , Levodopa/efectos adversos , Masculino , Oxidopamina/administración & dosificación , Oxidopamina/efectos adversos , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/fisiopatología , RatasRESUMEN
An association between a polymorphism of the SCN1 gene, a therapeutical target of lamotrigine, and an effective dose (a blood plasma concentration) of the drug in patients with epilepsy has been studied. Fifty patients with different forms of epilepsy have been genotyped for the SCN1 IVS5N+5 G>A polymorphism using polymerase chain reaction. The distribution of allelic variants was as follows: 23 patients had the mutant homozygous genotype (V/V), 20 - the heterozygous genotype Wt/V and 7 were homozygous for the wild allele (Wt/Wt). Mean lamotrigine doses were 85,7+/-7,4 mg/day for carriers of the Wt/Wt genotype, 113,75+/-7,13 mg/day for the Wt/V genotype and 142,4+/-15,43 mg/day for the V/V genotype. Peak plasma concentrations corresponded to effective doses were 0,6+/-0,065 mg/ml for Wt/Wt, 0,96+/-0,1 mg/ml for V/V and 0,72+/-0,1 mg/ml for Wt/V. The hypothesis on the association between the SCN1 IVS5N+5 G>A polymorphism and the effective dose (concentration) of lamotrigine was confirmed. The significantly higher frequency of the SCN1A mutation in the group of patients with epilepsy compared to the control group of Caucasians (45,5 and 21,3%, respectively) implies that this polymorphism may contribute to the pathogenesis of epilepsy.
Asunto(s)
Anticonvulsivantes/administración & dosificación , ADN/genética , Epilepsia/genética , Proteínas del Tejido Nervioso/genética , Polimorfismo Genético , Canales de Sodio/genética , Triazinas/administración & dosificación , Adolescente , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Electroforesis , Epilepsia/tratamiento farmacológico , Antagonistas de Aminoácidos Excitadores , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Lamotrigina , Masculino , Persona de Mediana Edad , Mutación , Canal de Sodio Activado por Voltaje NAV1.1 , Reacción en Cadena de la Polimerasa , Resultado del Tratamiento , Adulto JovenRESUMEN
The domestic drug himantane has been used as a monotherapy in dosage 25 mg daily during 12 weeks in patients with Parkinson's disease. Patient's state has been assessed using clinical, electromyographic, electroneuromyographic, EEG and psychometric (UPDRS and other scales) methods. The preparation used is well tolerated, induces the significant decrease of movement disorders, i.e. tremor, and exerts a positive effect on emotional and personality disturbances. The clinical changes have been confirmed by electroneuromyographic data and EEG.
Asunto(s)
Adamantano/análogos & derivados , Antiparkinsonianos/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Adamantano/uso terapéutico , Anciano , Esquema de Medicación , Electroencefalografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Temblor/diagnóstico , Temblor/tratamiento farmacológico , Temblor/fisiopatologíaRESUMEN
The neuroprotective effect of the new selective anxiolytic afobazole was evaluated in rats with ischemic stroke produced by the occlusion of the left middle cerebral artery, with simultaneous ligation of the ipsilateral carotid artery. Afobazole exhibits a protective effect in a dose range from 0.1 to 5.0 mg/kg for the first injection delayed 24 h after operation and double daily injections over the following two days.
Asunto(s)
Bencimidazoles/uso terapéutico , Encéfalo/efectos de los fármacos , Ataque Isquémico Transitorio/tratamiento farmacológico , Morfolinas/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Animales , Bencimidazoles/administración & dosificación , Encéfalo/patología , Modelos Animales de Enfermedad , Ataque Isquémico Transitorio/patología , Masculino , Morfolinas/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Ratas , Ratas WistarRESUMEN
Changes in the BDNF content in brain structures--hippocampus, hypothalamus, striatum, and frontal cortex--were determined in mice of different emotional-stress reaction phenotypes, which were subjected to emotional stress and treated by the selective anxiolytic afobazole. The changes were different in BALB/c and C57BL/6 mice. Afobazole exhibited a significant protector action against a decrease in the brain BDNF level caused by emotional stress in BALB/c mice.
Asunto(s)
Conducta Animal/efectos de los fármacos , Bencimidazoles/farmacología , Química Encefálica/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Encéfalo/metabolismo , Morfolinas/farmacología , Estrés Psicológico/metabolismo , Animales , Masculino , Ratones , Ratones Endogámicos BALB C , FenotipoRESUMEN
An investigation of bioelectrical brain activity in 32 patients with akinetic-rigid and trembling-rigid forms of Parkinson's disease was conducted before and after treatment with amantadin-sulfate on the basis of spectral-coherent EEG analysis. Comparing to controls, EEG deviations, mainly related to the main rhythm, were observed in 93.75% patients. Symptoms stabilization augmented EEG disorganization emerging in diffused spikes and sharp theta- and alpha-waves. The presence of paroxysmal activity in the form of synchronic bilateral groups of theta-waves and/or beta-waves was detected in 11 out of 32 patients, with paroxysmal activity of theta-waves being more evident in patients with a trembling PD form. In the group of patients with post treatment positive dynamics, EEG spectrum power increased in the range of alpha-beta-waves. Significant differences were mainly found in the range of beta-activity in frontal-parietal-occipital leads of the left hemisphere. The coherent analysis of EEG revealed that an amantadin-sulfate course resulted in normalization of space organization of biopotentials at the expense of a decrease of pathologically high indications of coherency for the majority of intra- and interhemisphere pairs of leads in alpha-, beta- and theta-ranges. In those regions, where the spectrum power increased in the same range, a significant decrease of the coherency indices was detected for inter hemispheric frontal-frontal, frontal-parietal and frontal-occipital leads and intracortical long connections of the left hemisphere. In amantadin-sulfate non-responders, the changes of EEG spectrum and coherency were insignificant.
Asunto(s)
Amantadina/farmacología , Amantadina/uso terapéutico , Antiparkinsonianos/farmacología , Antiparkinsonianos/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Electroencefalografía/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Adulto , Anciano , Amantadina/administración & dosificación , Antiparkinsonianos/administración & dosificación , Femenino , Lateralidad Funcional/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico , Índice de Severidad de la EnfermedadRESUMEN
The content of BDNF was measured in cerebral structures of intact C57Bl/6 and BALB/c mice in winter and spring. The level of cerebral neurotrophic factor in laboratory mice depended on genetic characteristics and chronobiological factors.
Asunto(s)
Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Factor Neurotrófico Derivado del Encéfalo/fisiología , Encéfalo/metabolismo , Estrés Fisiológico/metabolismo , Animales , Fenómenos Cronobiológicos , Masculino , Procesos Mentales/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Fenotipo , Estaciones del Año , Factores de TiempoRESUMEN
An experimental investigation of parkinsonism in rats and patients with initial forms of Parkinson's disease was performed by using methods of electromyography and electroneuromyography. Neurophysiologic peculiarities of reorganization of peripheral neuromotor apparatus and criteria for treatment efficacy were detected. The results obtained in the study allowed evaluating of an adequacy of adamantan-sulphate therapy either in the animal experiments and in patients with Parkinson's disease.
Asunto(s)
Amantadina/farmacología , Amantadina/uso terapéutico , Dopaminérgicos/farmacología , Dopaminérgicos/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Animales , Modelos Animales de Enfermedad , Electromiografía/instrumentación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/efectos de los fármacos , Enfermedad de Parkinson/diagnóstico , Ratas , Índice de Severidad de la EnfermedadRESUMEN
The activity of the adamantane derivative PK-Merz and the new aminoadamantane derivative hemantane was studied by methods of electromyography and electroneuromyography in rats with a model of Parkinson syndrome induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The toxin produced an increase in the pulse conduction velocity (PCV) in the motor fibers of peripheral nerves and a decrease in the amplitude and frequency of the maximum muscle stress curve. A singe administration of both PK-Merz and hemantane produced unidirectional changes in the neuromyographic parameters and reduced the PCV down to a level in the control group. These results give ground for the clinical investigation of hemantane.
Asunto(s)
Adamantano/análogos & derivados , Adamantano/farmacología , Antiparkinsonianos/farmacología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/inervación , Trastornos Parkinsonianos/fisiopatología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Modelos Animales de Enfermedad , Electromiografía , Masculino , Músculo Esquelético/fisiopatología , Trastornos Parkinsonianos/inducido químicamente , RatasRESUMEN
N-(Adamant-2-yl)hexamethyleneimine hydrochloride (hemantane) is a new potential antiparkinsonian drug with a complex mechanism of action. The drug exhibits the properties of a low-affinity blocker of the ion channels of NMDA receptors, increases the dopamine content in striatum, and inhibits monoamine oxidases (MAO-B). This combination of properties suggests that hemantane can also possess neuroprotector properties. In this context, the ability of hemantane to prevent from the development of MPTP neurotoxin action on the locomotor activity in mice and the EEG activity in rats has been studied. Preliminary single (and the more so, repeated over a period of 5 days) peroral administration of hemantane in a dose of 10 mg/kg significantly reduced the manifestations of MPTP-induced oligokinesia in C57BL/6 mice. Acute of subchronic (7-day) pretreatment with hemantane prevented the development of EEG changes typical of parkinsonism. The results of statistical EEG data processing showed that a systemic introduction of MPTP (30 mg/kg) on the background of hemantane pretreatment produced no reliable changes against control characteristics. Thus, hemantane is capable of protecting experimental animals from MPTP neurotoxicity.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Adamantano/análogos & derivados , Adamantano/uso terapéutico , Antiparkinsonianos/uso terapéutico , Administración Oral , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , RatasRESUMEN
Chronic administration of a low dose of reversible monoamine oxidase (MAO) B inhibitors isatin or himantane (20 mg/kg) to mice during 21 day did not influence the enzyme activity assayed in isolated brain mitochondria. However in vivo sensitivity of brain MAO B to irreversible mechanism-based inhibitor deprenyl injected to animals right after the last administration of the reversible inhibitor sharply decreased. This suggests accumulation of these compounds (or their metabolites?) in the brain accompanied by increased protection of active site of MAO B against specific irreversible inhibitor. deprenyl. In vitro inhibition of MAO B activity in mitochondria isolated from brain of mice treated with isatin or himantane was somewhat higher than in control mitochondria. The latter suggests that long-term treatment of animals with reversible easily dissociating inhibitors may influence regulatory properties of MAO B.
Asunto(s)
Adamantano/análogos & derivados , Adamantano/farmacología , Encéfalo/efectos de los fármacos , Isatina/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/efectos de los fármacos , Selegilina/farmacología , Animales , Encéfalo/enzimología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Effect of the new potential antiparkinsonian drug hemantane (N-(adamant-2-yl)hexamethyleneimine hydrochloride) on the generative function and gonad morphology was studied in a group of male and female mongrel rats. The generative function was studied after peroral drug administration in a dose of 10 mg/kg (ED50) and 50 mg/kg (5 ED50): males were treated over a 60-day period of spermatogenesis, while females received the drug in the same doses over 15 days (three estrous cycles). The gonad morphology was studied after a 6-month treatment of experimental animals with hemantane in the same doses. It was established that the administration hemantane in indicated doses did not influence the generative function and gonad morphology in male and female rats.
Asunto(s)
Adamantano/análogos & derivados , Antiparkinsonianos/efectos adversos , Azepinas/efectos adversos , Gónadas/efectos de los fármacos , Oogénesis/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Adamantano/efectos adversos , Administración Oral , Animales , Femenino , Gónadas/embriología , Masculino , Oogénesis/fisiología , Embarazo , Ratas , Espermatogénesis/fisiologíaRESUMEN
N-2(adamantyl)hexamethyleneimine hydrochloride (hemantane) is a new potential antiparkinsonian drug targeted at several neurochemical systems. The drug exhibits the properties of a low-affinity noncompetitive blocker of the ion channels of glutamate NMDA receptors. Hemantane increases the content of dopamine in the striatum, while decreasing the level of dopamine metabolite dioxyphenylacetic acid (DOPAC). Investigation of the drug interaction with monoamine oxidases (MAOs) of the A and B types in vitro showed that hemantane acts as a weak competitive inhibitor of MAO-B (Ki = 470 +/- 70 microM) and partly protected MAO-B from irreversible inhibition by selegiline (deprenyl), while virtually not influencing the activity of MAO-A. Administered to C57BL6 mice (20-100 mg/kg), hemantane did not influence the activity of MAO-B measured in isolated cerebral mitochondria. At the same time, hemantane administered in combination with deprenyl significantly reduced activity of the latter drug and caused pronounced irreversible inhibition of mitochondrial MAO-B (comparable with the effect of deprenyl introduced alone). Therefore, inhibition of MAO-B may contribute to the spectrum of neurochemical activity of hemantane.