Ewa Zwierzyńska

Involvement of oxidative stress in the mechanism of cadmium-induced toxicity on rat uterus

The study was undertaken to explore whether cadmium bioaccumulation can induce oxidative stress in the uterus of rats. Cadmium (0.09, 0.9, 1.8 or 4.5mgCd/kg b.w.) was administered by gavage for 28 days. The animals were dissected on the first day and then after 90 days post exposure (second group of animals). The results show that cadmium accumulates in the uterus in a dose-dependent manner. The uterine Cd concentrations were almost the same in both groups, which is indicative of its long half-life in this organ. The accumulated cadmium caused significant changes in catalase (CAT) activity and lipid peroxidation (MDA) levels at concentrations from 0.09 to 0.35μgCd/g wet uterine tissue. In summary our results show that the induction of oxidative stress and lipid peroxidation in the uterus may play important roles in the mechanism of toxicity in this organ and may have a negative impact on reproductive processes.

A pharmaco-EEG study of the interaction between ethanol and retigabine in rabbits

Abstract Background: Retigabine is a new antiepileptic drug with multiple mechanisms of action. It may well interact with ethanol, as both have an influence on GABA-ergic and glutamate neurotransmission. Objectives: To assess the effect of retigabine, administered as single or repeated doses, on ethanol-induced changes in the bioelectric activity of selected brain structures in rabbits. Methods: 30 rabbits were used to assess the effect of retigabine on ethanol-induced changes in EEGs using the pharmaco-EEG method. Retigabine was administered p.o. as a single dose (5 mg/kg or 10 mg/kg) or repeatedly at a dose of 5 mg/kg/day for 14 days. Ethanol was injected i.v. at a dose of 0.8 g/kg 60 min after the administration of retigabine. Results: Retigabine, administered as a single high or low dose, increased the depressive effect of an acute dose of ethanol on the bioelectric activity of the frontal cortex in rabbits. These changes were also visible in the recordings from the hippocampus and midbrain reticular formation after administration of a high dose of the drug. Retigabine administered in repeated doses decreased ethanol-induced changes in the rabbit EEG recordings from the hippocampus. Conclusion: Retigabine in multiple doses decreases the sensitivity of the hippocampus to an acute dose of ethanol in rabbits. Given the role of hippocampal-related memory processes to addiction, retigabine may have therapeutic potential.

Does retigabine affect the development of alcohol dependence?—A pharmaco-EEG study

New antiepileptic drugs have been investigated for their potential role in the treatment of alcohol dependence. One of these drugs is retigabine and this study examines the effect of retigabine co-administered with ethanol on the development of alcohol dependence and the course of acute withdrawal syndrome. A pharmaco-EEG method was used to examine this impact in selected brain structures of rabbits (midbrain reticular formation, hippocampus and frontal cortex). Retigabine was administered p.o. at a dose of 5mg/kg/day with ethanol ad libitum for 6 weeks and then alone for 2 weeks during an abstinence period. Changes in bioelectric activity, which demonstrated the inhibitory effect of alcohol on the brain structures, were already visible after 2 weeks of ethanol administration. In the abstinence period, changes were of a different nature and significant neuronal hyperactivity was observed, particularly in the midbrain reticular formation and the hippocampus. This findings reveal that retigabine decreased ethanol-induced changes during both alcohol administration and abstinence periods. In particular, the modulatory effect of retigabine on the hippocampus may be a significant element of its mechanism of action in alcohol dependence therapy.

[Long-term use of estrogens: benefit or risk]

Estrogens are widely used in hormone replacement therapy, gynecology, urogynecology and rarely in dermatology. Non-therapeutic use of estrogens is very widespread. Estrogens are used as contraceptives, which cause a lot of serious side effects. A common clinical problem is skin hyperpigmentation (melasma), occurring mainly in women who take contraceptives with high doses of estrogens. But low doses of estrogens may also cause skin side effects. The mechanism of melasma development is very complicated and not fully understood. It is very likely that UV radiation and genetic background can affect melasma development. Effective therapy should lead to prevention or alleviation of relapses. Treatment should also reduce the area of lesions and improve the appearance of skin. There is no effective and universal pattern of treatment, in which only one substance or method is used. A combination of different methods is used to optimize the therapy. An important role is attributed to prevention, especially protection from UV radiation.

A pharmaco-EEG-based assessment of the interaction between ethanol and zonisamide.

AIMS Recent research suggests a potential role for a new generation of anticonvulsant drugs, including zonisamide, in the treatment of alcohol dependence. Some elements of the central mechanism of action that zonisamide has in common with ethanol, give rise to the question of whether there is an interaction between these two agents and whether there is any risk associated with the enhanced depressive effect of these agents on the central nervous system. METHODS This study uses a pharmaco-EEG method to examine the interaction of ethanol with zonisamide. The influence of zonisamide on the effect of ethanol on EEG of rabbits (midbrain reticular formation, hippocampus, frontal cortex) was determined. Zonisamide was administered p.o. as a single dose (20 or 60 mg/kg) or repeatedly at a dose of 30 mg/kg/day for 14 days. Ethanol was injected i.v. at a dose of 0.8 g/kg 180 min after the administration of zonisamide. RESULTS Ethanol caused an increase in the low frequencies (0.5-4 Hz) in the recording, as well as a marked decrease in the higher frequencies (13-30 and 30-45 Hz). Changes in the EEG recordings after zonisamide alone were more significant compared with these after repeated doses. In the hippocampus after single dose of drug the proportion of the low frequency (0.5-4 Hz) increased, whereas the proportion of high frequencies decreased. Combined administration of ethanol and zonisamide (60 mg/kg) resulted in a markedly synergistic effect in the examined structures. A beneficial effect of repeatedly administered zonisamide on ethanol-induced EEG changes was observed, especially in the hippocampus. CONCLUSION Zonisamide in repeated doses decreases the sensitivity of the hippocampus to ethanol, an observation that may be important in the treatment of alcohol addiction.

The possibility of adverse effect of Kv7-channel opener retigabine on memory processes in rats

OBJECTIVE Retigabine is a novel antiepileptic drug with a unique and complex mechanism of action which allows its use in many diseases associated with impaired neuronal activity. This study sought to examine the impact of retigabine on two types of memory in rats. METHODS Adult male Wistar rats were used to assess the effect of retigabine, administered p.o. as single (10mg/kg or 20mg/kg) or repeated doses, on spatial memory with the Morris water maze test (MWM) and emotional memory, associated with fear, with the passive avoidance test (PA). RESULTS Retigabine administered at a high single dose transiently impairs learning processes in rats. In the MWM, these changes were delayed in time and of a lesser degree when retigabine was given at low single dose. Additionally, the drug administered repeatedly for 2weeks slowed learning processes in the MWM, but this effect occurred only after 1week of administration in the PA. CONCLUSION These findings indicate that retigabine may affect memory and learning processes, especially in the first phase of administration.

The efficacy of topiramate in alcohol dependence therapy – current research and prospects of use

Alcohol dependence (AD) is a chronic and recurrent disease that is a major social and clinical problem. The Food and Drug Administration (FDA) has approved a few drugs for AD treatment like disulfiram, naltrexone and acamprosate. Their efficacy is limited and depends on many additional factors. Also therefore, new methods of therapy are still being sought. Currently, research is focused on a new generation of antiepileptic drugs that could improve the efficiency of AD treatment thanks to their multidirectional mechanism of action associated with neurotransmission systems involved in the pathogenesis of addiction. Topiramate is the most widely studied drug in this area. The results of preclinical studies showed that the drug reduces the intake of ethanol and alleviates symptoms of withdrawal syndrome in animals. The results of clinical observations in patients with AD confirmed the efStreszczenie

The Impact of Zonisamide on the Development and Course of Alcohol Dependence in Rabbits. A pharmaco-EEG study.

Aims Zonisamide is a new anti-epileptic drug whose mechanism of action is associated with neurotransmission systems also involved in the pathogenesis of addiction. Recently, the role of memory processes and the hippocampus (Hp) is underlined in dependence. In our previous study, we determined that zonisamide decreases changes in hippocampal bioelectric activity induced by a single dose of ethanol. Methods This study uses a pharmaco-EEG method to examine the impact of zonisamide on the development and course of alcohol dependence in rabbits. Quantitative changes in EEG were observed in the midbrain reticular formation, Hp and frontal cortex. Zonisamide was administered p.o. once a day at dose of 30 mg/kg/day during the entire experiment. Solutions with increasing concentrations of ethanol were administered for 6 weeks, followed by a 2-week period of abstinence. Results The long-term administration of ethanol caused characteristic changes in rabbit EEG recordings, which were associated with a shift toward lower frequencies resulting in a depressive effect on the bioelectric activity of selected brain structures. Co-administration of zonisamide and ethanol caused a reduction of ethanol-induced alterations. Changes in EEG recordings were different during period of abstinence and were associated with potent shift toward the high frequencies. Zonisamide significantly decreased encephalographic features of neuronal hyperactivity when administered during the abstinence. Conclusion Zonisamide decreases ethanol- and abstinence-induced changes in the EEG recordings. These effects may be a significant part of drugs mechanism of action in alcohol addiction therapy. Short Summary A pharmaco-EEG method was used to determine the influence of a new anti-epileptic drug zonisamide on the development and course of alcohol dependence in rabbits. The drug co-administered with ethanol decreased alcohol-induced changes in selected brain structures. Zonisamide also decreases abstinence-induced changes in the EEG recordings.

Patogeneza uzależnień – problem wciąż aktualny

Abstract Addiction is a chronic disease involving system of brain reward, motivation and memory. Its development is associated with different neurotransmitter systems. Of vital significance is dopaminergic transmission in the mesolimbic system, which is under modulatory influence of excitatory and inhibitory neurotransmitters. In this article, we discuss different concepts and hypothesis that attempt to explain mechanisms associated with addiction. According to the incentive-sensitisation view, addiction is a result of progressive neuroadaptation and is associated with sensitisation of brain systems that mediate a reward (“wanting”) but do not mediate the pleasurable effects of drugs (“liking”). In other theories, addiction is related to learning, memory processes and formation of secondary reinforcements. Recent data suggest that the hippocampus plays an important role in the pathogenesis of addiction. This brain structure is associated with memory processes, the mechanism of positive reinforcement and it also effects control of appetitive behaviour. The hippocampus is one of a few brain regions that reveals a high concentration of ghrelin receptors. Ghrelin is a hormone that enhances hippocampal synaptic plasticity and is associated with motivational and reward behaviour. The paper also presents the significance of hippocampal endocannabinoids and adverse effect of long-term psychoactive drug use on neurogenesis processes in the hippocampus. Modulatory effect on the function of this structure may impair memory processes, which are important in the mechanism of addiction.

[Retigabine - a new antiepileptic drug with a different mechanism of action].

Retigabine belongs to a new generation of antiepileptic drugs. Its mechanism of action is different from that previously known. Retigabine opens potassium channels of subfamily Kv 7, especially Kv 7.2 and Kv 7.3. The drug enhances GABA-ergic transmission. It is well absorbed from the digestive system and undergoes metabolism via glucuronidation and acetylation. There is no interaction between retigabine and other antiepileptic drugs except lamotrigine. The drug has been registered as treatment of partial onset seizures with or without secondary generalization in adults. The efficacy of retigabine is being tested in other types of seizures and disorders characterized by neuronal hyperexcitability. Neuroprotective activity of retigabine is also being researched.