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.

The effects of low-affinity NMDA-receptor antagonists amantadine (1-aminoadamantane hydrochloride) and hemantane [ N -(2-adamantyl)hexamethyleneimine hydrochloride] on morphine-induced analgesia in C57Bl/6 mice were studied. Amantadine (10 and 20 mg/kg, i.p.) per se did not affect the latent period of the response in the hot-plate test while hemantane (10 and 20 mg/kg, i.p.) increased dose-dependently pain thresholds 180 and 240 min after administration. Morphine (20 mg/kg, s.c.) showed a time—effect dependence (30 – 120 min). The aminoadamantanes were administered 90 min after the opioid to assess their effects on morphine-induced antinociception. The responses of the animals were recorded for the next 2.5 h. The aminoadamantanes potentiated and extended the analgesic activity of morphine in the order of efficacy amantadine < hemantane. The results indicated that the aminoadamantanes had different capabilities to cause delayed analgesia and modulated opioid antinociceptive activity at the supraspinal level.

На клеточной модели болезни Паркинсона — цитотоксичности, индуцированной внесением в культуру клеток нейробластомы человека SH-SY5Y нейротоксина 6-гидроксидофамина (6-ГОДА), проведено сравнительное исследование защитных свойств нового противопаркинсонического препарата гимантана (N-(2-адамантил)-гексаметиленимина гидрохлорид) и амантадина при различных режимах внесения. Установлено, что гимантан в концентрации 10–7 М оказывает цитопротекторный эффект при предварительном внесении в культуральную среду до добавления 6-ГОДА и при внесении сразу же после введения нейротоксина в диапазоне концентраций 10–6 – 10–8 М. Цитопротекторный эффект амантадина в концентрациях 10–7 – 10–8 М проявился только при внесении его в культуральную среду сразу после воздействия 6-ГОДА. Полученные результаты свидетельствуют о большем нейропротекторном потенциале гимантана, чем амантадина.

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.

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.

Hemantane is a novel antiparkinsonian drug that is undergoing clinical trials. Hemantane in the dosage range 10 – 40 mg/kg demonstrated anti-inflammatory activity and decreased statistically significantly the intensity of the exudative reaction in an acetic-acid peritonitis model in mice. Hemantane (10 mg/kg) in a neuro-inflammation model induced by lipopolysaccharide injection in rats prevented loss of body mass, development of forepaw akinesia contralateral to the operation, and smell disturbance.

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.

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.

Hemantane is a novel antiparkinsonian drug that is currently at the stage of clinical trials. Hemantane in a dosage range of 10 – 40 mg/kg demonstrates anti-inflammatory activity and significantly decreases the intensity of exudative reaction in a model of acetic acid-induced peritonitis in mice. In rats with a model of neuroinflammation induced by lipopolysaccharide injection, hemantane (10 mg/kg) prevents weight loss, development of forepaw akinesia contralateral to the operation, and smell disturbance.

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.

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.

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.