Caffeine impairs anticonvulsant effects of levetiracetam in the maximal electroshock seizure threshold test in mice.

OBJECTIVES: Caffeine is the most widely used psychoactive substance in the world. Animal studies indicate that acute caffeine exposure at high doses may induce seizures and diminish the anticonvulsant activity of antiepileptic drugs (AEDs) at much lower doses. The aim of the current study was to assess the effect of caffeine on the anticonvulsant action of levetiracetam (LEV) and vigabatrin (VGB). METHODS: The anticonvulsant activity of LEV and VGB was examined in the maximal electroshock seizure threshold test in mice (MEST test). All drugs were administered intraperitoneally by single injections, and caffeine was applied at doses capable of interfering with AEDs. Effects of caffeine exposure on AEDs were also investigated in tests of memory and motor performance. RESULTS: Caffeine reduced the protective effect of LEV against electroconvulsions. Total brain concentration of LEV was unaffected by caffeine as well as inversely; LEV had no significant impact on the brain caffeine concentration, suggesting a pharmacodynamic nature of the interaction between LEV and caffeine in the MEST test. VGB at applied doses did not affect the convulsive threshold. Administration of VGB, but not LEV, alone or in combination with caffeine, impaired memory retention. In the chimney test, the combined treatment with AEDs and caffeine did not cause motor coordination impairment. CONCLUSIONS: It is suggested that caffeine may negatively affect the anticonvulsant action of LEV in patients with epilepsy.

Effect of caffeine on the anticonvulsant action of pregabalin against electroconvulsions in mice.

BACKGROUND: Experimental data indicate that caffeine (CAF) can reduce the anticonvulsant activity of antiepileptic drugs (AEDs) in animal models of seizures. The purpose of the current study was to examine the effect of CAF on the protective action of pregabalin (PGB) against electroconvulsions in mice. METHODS: Maximal electroshock seizure (MES) test was used in the current study. In addition, the combined treatment with CAF and PGB was assessed in the passive avoidance task (long-term memory) and the chimney test (motor coordination). Drugs were injected intraperitoneally (ip) as single injections. CAF was administered at doses reported to compromise the anticonvulsant action of AEDs in mice. RESULTS: CAF at a dose of 23.1 mg/kg reduced the anticonvulsant action of PGB in the MES test. The brain concentration of PGB was not significantly changed by CAF and vice versa. In the chimney test, CAF (23.1 mg/kg) protected mice against PGB-induced motor coordination impairment. CONCLUSIONS: Regarding seizure control, it might be suggested that patients with epilepsy treated with PGB should avoid taking CAF. The estimated total brain concentration of PGB and CAF does not suggest a pharmacokinetic interaction as an explanation for these results.

Neurophysiological maturation in adolescence - vulnerability and counteracting addiction to alcohol.

The results of contemporary studies confirm the formation of two neural networks in the brain during the period of adolescence. The first is defined as emotional, located in the limbic system, develops earlier, quicker, and more intensively than the second one in the prefrontal cortex, called the judgement network, which fulfils the role of control and inhibition of emotional reactions. The domination of the emotional network in adolescence is manifested by hyperactivity of the limbic system, accompanied by intensified undertaking of courageous, reckless, risky, or even sometimes dangerous actions, so very characteristic in the maturation. The aim of the article is to present the state of the art in the field of latest achievements in experimental neurophysiology related to the maturation of the structural end functional processes in adolescents, and to alcohol vulnerability. Alcohol effect initiation starts in early adolescence, and therefore is connected with alcohol abuse and addiction in adulthood, which confirms the necessity for provision of an early prophylactic protection for juveniles, even before entering the phase of early adolescence. Some electrophysiological characteristics, such as low P3 amplitude of the Event-Related Potential (ERP) and Event-Related Oscillations (EROs), are manifested by their high risk offspring, and are considered to be biological markers (endophenotypes) of a predisposition to develop alcohol use disorders. Electroencephalographic oscillations induced within the range of the theta and delta waves (Event-Related Oscillation- ERO), considered as endophenotypes and markers of increased vulnerability for addiction, present three groups of genes and three types of neurotransmitters, with gamma aminobutyric acid, acetylcholine and glutamate as neurotransmitters in the central nervous system. A new research approach consisting in the application of electroencephalographic methods and techniques in developmental and genetic studies of the conditioning of varied vulnerability, and especially increased preferences for alcohol tasting and abuse in adolescence, provide unique possibilities for comprehensive and deepened studies which may contribute to the prevention of alcohol addiction, the genesis of which, to a great extent, is related with the effect of causative environmental and genetic factors during adolescent development.

Event-related potentials (ERP) and SGIP1 gene polymorphisms in alcoholics: relation to family history of alcoholism and drug usage.

OBJECTIVE: The electrophysiological characteristics may serve as valuable biomarkers for the genetic vulnerability underlying alcoholism. The purpose of this study was to evaluate the potential associations between single nucleotide polymorphisms (SNPs) located in the SGIP1 gene and the theta ERP quantitative traits. METHOD: The theta band (4-7 Hz) visual ERP occurring in the P300 response in the resting EEG were examined to explore the electrophysiological effects of alcohol on the brain in five regions: frontal, central, parietal, temporal and occipital in patients with alcohol addiction. In addition, we tested the potential associations between single nucleotide polymorphisms (SNPs) located in the SGIP1 gene and ERP quantitative traits. RESULTS: We found that the amplitude of the auditory P300 response differed considerably among groups of alcoholics in the frontal, central and temporal areas of the brain and it was lower in the studied brain regions in alcoholics in comparison to non-alcoholics. However, among subjects in the young adult group (GR-1) there was no statistical difference in amplitude of P300 response with control subjects in all studied brain regions in comparison with non-alcoholics. Moreover, we revealed that SNP rs10889635 had a significant effect on P300 amplitude in the central and temporal regions. The reduced P300 amplitude was in AA carriers in comparison to both carriers of GG and GA alleles. CONCLUSION: The present study demonstrated a possible association of target P300 evoked theta and of alcohol dependence with SNPs from the gene SGIP1 in the region of rs10889635, but further studies are required.

Homocysteine, antioxidant vitamins and lipids as biomarkers of neurodegeneration in Alzheimer's disease versus non-Alzheimer's dementia.

INTRODUCTION AND OBJECTIVE: Evidence for the benefit of antioxidants' based therapeutic intervention in dementia are inconsistent. Parallel studies in disease forms of dementia different than Alzheimer's are even less conclusive. In this study, the role of serum levels of homocysteine (tHcy), lipids and antioxidants in predicting the risk of cognitive decline in Alzheimer's disease (AD) versus non-Alzheimer's dementias (n-AD). The objective was to add to the ongoing cumulative research to establish the biochemical baseline for potential nutri-therapeutic intervention in different forms of dementia. MATERIALS AND METHOD: 65 participants with dementia (DP-s) were divided into two groups: ADP--patients with Alzheimer's disease and n-ADP--patients with dementia of a different etiology than primary neurodegenerative dementia in the course of Alzheimer's disease. Cognitive function was assessed by Mini-Mental State Examination (MMSE) and related to plasma levels of tHcy, folate, vitamins B-6, B-12, lipids and vitamins A and E for both groups. Also examined were associations between cognitive impairment and several variables (age, education, duration of dementia) that might confound nutrition-cognition associations. RESULTS: A significant reduction in serum vitamin A levels and elevation of total cholesterol levels were shown for the DP-s group compared to those in the control group. Moreover, significant differences were found in MMSE data and serum vitamin E and tHcy levels between patients with ADP and n-ADP. The scores for MMSE showed a correlation with the vitamin E levels and duration of dementia in the ADP group and/or correlation with tHcy, levels of vitamins A and/or E, and duration of dementia in the n-ADP group. CONCLUSIONS: The results obtained suggest that elevated serum tHcy and decreased levels of vitamins A and E are associated with an increased risk of non-Alzheimer's dementias, although further studies involving a larger cohort are now needed to verify these results.

Epigenetic regulation in drug addiction.

The interaction between environmental signals and genes has now taken on a clear molecular form as demonstrated by stable changes in chromatin structure. These changes occur through activation or repression of specific gene programmes by a combination of chromatin remodelling, activation and enzymatic modification of DNA and histones as well as nucleosomal subunit exchange. Recent research investigating the molecular mechanisms controlling drug-induced transcriptional, behavioural and synaptic activity has shown a direct role for chromatin remodelling--termed as epigenetic regulation--of neuronal gene programmes and subsequent addictive behaviour arising from it. Recent data suggest that repeated exposure to certain drugs promotes changes in levels of histone acetylation, phosphorylation and methylation, together with alterations in DNA methylation levels in the neurons of the brain reward centre, localised in the Nucleus Accumbens (NAc) region of the limbic system. The combination of acetylating, phosphorylating and methylating H3 and H4 histone tails alter chromatin compaction thereby promoting altered levels of cellular gene expression. Histone modifications, which weaken histone interaction with DNA or that promote recruitment of transcriptional activating complexes, correlate with permissive gene expression. Histone deacetylation, (which strengthen histone: DNA contacts), or histone methylation, (which recruits repressive complexes to chromatin), promote a state of transcriptional repression. Using animal models, acute cocaine treatment increases H4 acetylation at acutely regulated gene promoters, whereas H3 acetylation appears to predominate at chronically induced promoters. Chronic cocaine and alcohol treatment activate and repress many genes such as FosB, Cdk5, and Bdnf, where their dysregulation, at the chromatin level, contribute to the development and maintenance of addiction. Following drug exposure, it is still unknown, howver, how long these changes in chromatin structure persist in affecting neuronal function, but some do so for life.

Clinical utility of adjunctive retigabine in partial onset seizures in adults.

In ~30% of epileptic patients, full seizure control is not possible, which is why the search for novel antiepileptic drugs continues. Retigabine exhibits a mechanism of action that is not shared by the available antiepileptic drugs. This antiepileptic enhances potassium currents via Kv7.2-7.3 channels, which very likely results from destabilization of a closed conformation or stabilization of the open conformation of the channels. Generally, the pharmacokinetics of retigabine are linear and the drug undergoes glucuronidation and acetylation. Results from clinical trials indicate that, in the form of an add-on therapy, retigabine proves an effective drug in refractory epileptic patients. The major adverse effects of the add-on treatment are dizziness, somnolence, and fatigue. This epileptic drug is also considered for other conditions - neuropathic pain, affective disorders, stroke, or even Alzheimer's disease.