[Anxiolytic and antidepressant effects of emoxipine, reamberin and mexidol in experimental diabetes mellitus]. / Anksioliticheskoe i antidepressivnoe deistvie émoksipina, reamberina i meksidola pri éksperimental'nom sakharnom diabete.

AIM: To perform a comparative study of anxiolytic and antidepressant effects of derivatives of 3-oxypyridine and succinic acid (emoxipine, reamberin and mexidol) in experimental diabetes mellitus. MATERIAL AND METHODS: An effect of emoxipine, reamberin and mexidol on manifestations of anxiety in 'elevated plus maze' (EPM) and duration of 'desperate behavior' (DB) in Porsolt test in rats with alloxan diabetes during medication course was studied. Alpha-lipoic (thioctic) acid (α-LA) was used as a reference drug. In additional experimental series, an effect of emoxipine, reamberin, mexidol and α-LA on the intensity of hyperglycemia in experimental DM was investigated. RESULTS AND CONCLUSION: All studied medications used in doses equivalent to therapeutic range in humans and administered for 14 days significantly reduced manifestations of anxiety and depression in rats with alloxan diabetes. The most pronounced anxiolytic potential was demonstrated for emoxipine that emerged as the only medication in the study that reduced manifestations of anxiety not only in comparison with 'alloxan diabetes-control' groups but also in comparison to 'intact control'. The intensity of tranquilizing activity of derivatives of 3-oxypyridine and succinic acid was similar to that of α-LA while the thymoanaleptic activity, when the drugs were administered in maximal doses to rats with experimental DM, was higher. Both emoxipine and mexidol as well as α-LA in all studied doses significantly decreased hyperglycemia in alloxan diabetes. Reamberin demonstrated only insignificant tendencies of the same trend.

[The effect of reamberin and alpha-lipoic acid on the tolerance to acute cerebral ischemia in experimental diabetes mellitus]. / Vliyanie reamberina i α-lipoevoi kisloty na ustoichivost' k ostroi tserebral'noi ishemii pri eksperimental'nom sakharnom diabete.

AIM: To study an effect of reamberin and α-lipoic acid (α-LA) on the tolerance of mice with experimental diabetes mellitus (DM) to acute cerebrovascular accident (ACVA) in mice experiments. MATERIAL AND METHODS: The authors studied mice with alloxan diabetes and subtotal and total brain ischemia. In additional experimental series, an effect of reamberin and α-lipoic acid on the tolerance to acute hypoxic hypoxia and intensity of hyperglycemia in experimental DM was studied. RESULTS AND CONCLUSION: The increased vulnerability of animals to ACVA due to hyperglycemia and increased sensitivity to acute hypoxic hypoxia was established. Reamberin and α-lipoic acid administered for 14 days in doses, which are equivalent to therapeutic range in humans, enhance the tolerance to ACVA and acute hypoxic hypoxia in mice with alloxan diabetes. These medications also decrease the intensity of hyperglycemia during concurrent insulin replacement therapy. The increased tolerance to ACVA in mice with alloxan diabetes caused by reamberin and alpha-lipoic acid is associated with an antihypoxic effect of these medications and does not depend on their effect on the intensity of hyperglycemia. Reamberin outperformed α-lipoic acid in the antihypoxic activity, protection against ACVA and the rate of onset of glucose reducing effect in experimental diabetes mellitus.

[ANTIANHEDONIC EFFECT OF 3-OXYPYRIDINE AND SUCCINIC ACID DERIVATIVES].

We performed a comparative study of the effect of original domestic derivatives of 3-oxypyri-dine and succinic acid (emoxipine, reamberin and mexidol) on measures from «sucrose preferen-ce¼ test which is used for assessment of hedonic behavior in rats. а-lipoic acid (а-LA) and amit-riptylin were used as reference medications. For the modeling of anhedonia rats received dexa-methasone (5 mg/kg subcutaneously). We established that threefold administration of emoxipine, reamberin and mexidol in doses that are equivalent to therapeutic range in humans had antianhe-donic effect and increased the measures of «preference¼ and absolute sucrose consumption. This effect was demonstrated in animals that did not receive dexamethasone as well as in rats with dexamethasone-induced anhedonia. Maximal intensity of antianhedonic effect of 3-oxypyridine and succinic acid derivatives was noted after the previous administration of dexamethasone. In rats that did not receive dexamethasone, succinate-containing medications (reamberin and mexidol) exceeded the isolated 3-oxypyridine derivative (emoxipine) in their antianhedonic potential. In case of previous dexamethasone administration 3-oxypyridine and succinic acid derivatives demonstrated equivalent antianhedonic effect that exceeded the effect of reference medications (а-LA and amitriptylin).

[Antidepressant effect of 3-oxypyridine and succinic acid derivatives (experimental study)].

OBJECTIVE: To evaluate antidepressant activity of domestic derivatives of 3-oxypyridine and succinic acid (emoxipine, reamberin and mexidol) in rats. MATERIAL AND METHODS: The influence of emoxipine, reamberin and mexidol on duration of desperate behavior of rats in Porsolt forced swim test was studied. Additionally the effect of these substances on the animal's behavior in the open field was evaluated. Amitriptyline and alpha-lipoic acid were used as reference substances. RESULTS: It was established that three administrations of any of the substances in doses corresponding to the therapeutic range in humans reduced the duration of desperate behavior in Porsolt test. Such effect of emoxipine, reamberin, mexidol and alpha-lipoic acid is indicative of their antidepressant activity. Intensity of this activity depends on the effect of these substances on the behavior in the open field. CONCLUSION: Reamberin and alpha-lipoic acid that in maximal doses either had no effect on the orientation behavior in the open field (reamberin) or suppressed it (alpha-lipoic acid) matched amitriptyline in the extent of antidepressant activity. The derivatives of 3-oxypyridine (emoxipine and mexidol) with stimulatory effect on the behavior in the open field demonstrated significantly lower ability to reduce desperate behavior than that of amitriptyline.

[Anxiolytic and antidepressant effects of 3-oxypiridine and succinic acid derivatives in alloxan diabetes].

The effects of 3-oxypyridine and succinic acid derivatives (emoxipine, reamberin and mexidol) on affective disorders in rats with alloxan diabetes were studied. The efficiency of emoxipine, reamberin and mexidol was compared to alpha-lipoic acid, which is considered a "golden standard" in treatment of diabetic neuropathies. Emoxipine, reamberin and mexidol after seven administrations in single doses, that are equivalent to therapeutic range in humans, corrected the anxiety-depressive disorders in rats with alloxan diabetes. Unlike reamberin and alpha-lipoic acid, emoxipine and mexidol corrected the affective status concurrently with the decrease in hyperglycemia. At the same time, emoxipine outperformed mexidol in tranquilizing action (in maximal doses) but yielded mexidol in the antidepressant effect (in minimal doses).

Comparative analysis of the anxiolytic effects of 3-hydroxypyridine and succinic acid derivatives.

Threefold administration of 3-hydroxypyridine derivatives emoxipine and mexidol in optimal doses corresponding to the therapeutic dose range for humans produced an anxiolytic effect and stimulated risk behavior in the elevated plus maze test in rats. These effects were most pronounced after injection of 3-hydroxypyridine derivative emoxipine. Combination of 3-hydroxypyridine cation and succinate anion in the mexidol structure led to attenuation of the anxiolytic effect and less pronounced stimulation of the risk behavior. By the anxiolytic effect and induction of risk behavior, emoxipine and mexidol were close to the reference substance amitriptyline. Reamberin, a succinic acid derivative, had no pronounced tranquilizing properties, but risk behavior induction was similar to that produced by mexidol. In contrast to other test agents, the reference substance α-lipoic acid produced anxiogenic effects and suppressed risk behavior. The obtained results suggest that Russian-made 3-hydroxypyridine derivatives emoxipine and mexidol are promising preparations for the treatment of anxiety disorders.

Dynamics of lipid peroxidation-antioxidant defense system during alloxan diabetes in rats.

We studied the dynamics of lipid peroxidation-antioxidant defense system in rat model of alloxan diabetes and compared it with disorders of carbohydrate and lipid metabolism. It was found that rats not treated with insulin developed hyperglycemia, hypertriglyceridemia, hypocholesterolemia, and hypotocoferolemia with simultaneous accumulation of circulating LPO products 96 h after the administration of alloxan. The severity of hyperglycemia and hypertriglyceridemia decreased, hypercholesterolemia developed, hypotocoferolemia returned to normal, and the tendency to LPO inhibition was observed in rats 10 days after alloxan administration against the background of previous one-week treatment with insulin. In 17 days after the induction of alloxan diabetes preceded by two-week insulin therapy, the content of lipoperoxides reduced below the normal values with simultaneous progression of hypercholesterolemia, hypertriglyceridemia and the increase in serum fructosamine.

Cerebroprotective effects of emoxipin, reamberin, and mexidol in alloxan diabetes.

The effects of original Russian preparations, derivatives of 3-hydroxypyridine and succinic acid (emoxipin, reamberin, mexidol), on the cellular composition of the cerebrocortical and diencephalic structures were studied and correlations of shifts in the cellular composition with changes in the severity of hyperglycemia in rats with alloxan diabetes were analyzed. The efficiency of 3-hydroxypyridine and succinic acid derivatives was evaluated in comparison with α-lipoic acid. Seven injections of the optimal doses of all the studied drugs prevented the neuron loss in layers I-III of the primary somatosensory cortex. In addition, emoxipin, reamberin, and α-lipoic acid prevented astrocyte loss in the neocortical surface layers and of neurons in the hypothalamic paraventricular nucleus. Reamberin limited microglial infiltration of the hippocampal field CA1. Injection of α-lipoic acid augmented the increase in astrocyte count in the paraventricular nucleus and potentiated the reduction of tigroid granularity of CA1 field neurons. Emoxipin and mexidol caused an increase in the counts of neurons and oligodendrocytes in CA1 field. By contrast, reamberin and α-lipoic acid reduced the counts of neurons and oligodendrocytes, respectively, in this hippocampal zone. More favorable effects of emoxipin and mexidol vs. reamberin and α-lipoic acid on the cellular composition of the hippocampus of rats with alloxan diabetes were explained by more effective correction of hyperglycemia under the effect of 3-hydroxypyridine derivatives.

Effect of pro- and antioxidants on insulin sensitivity and glucose tolerance.

We studied the correlation between the effect of α-lipoic acid, emoxipin, reamberin, and mexidol on LPO in vitro and the action of these drugs on insulin sensitivity and tolerance to glucose load in vivo. It was found that the preparations producing prooxidant effect in vitro (α-lipoic acid and reamberin) are characterized by pronounced insulin-potentiating activity, but only slightly increase (α-lipoic acid) or even decrease (reamberin) tolerance to glucose load. 3-Hydroxypyridine derivatives (emoxipin and mexidol) producing an antioxidant effect in vitro increase glucose tolerance, but exhibit relatively weak insulin-potentiating activity. These results suggest that differential use of the studied drugs in patients with diabetes mellitus depending on the type of the disease and individual insulin requirement is a promising trend in medical studies.