Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ethanol is a potent inhibitor of the N-methyl-D-aspartate (NMDA)-receptor subtype of glutamate receptor in a number of brain areas. The mechanism of ethanol action has been investigated by means of patch-clamp recording of ionic currents and fura-2 measurement of intracellular Ca2+ concentration in cell culture systems; the subunit composition of NMDA receptors and their influence on the effect of ethanol was determined by molecular biology methods. Ethanol does not appear to interact with NMDA either at the glutamate recognition site of the receptor, or at any of the hitherto known multiple modulatory sites, such as the glycine or polyamine site. Moreover, ethanol does not cause an open channel block by itself and fails to interact with Mg2+ at the site where it causes open channel block. The ability of ethanol to inhibit responses to NMDA is dependent on the subunit combination of NMDA receptors. The NR1/NR2A and NR1/NR2B combinations are preferentially sensitive to ethanol inhibition. Chronic treatment with ethanol leads to an increase of the NMDA receptor number at the transcriptional and posttranscriptional level; the receptor function is also facilitated. This causes withdrawal-type seizures after termination of chronic treatment with ethanol. The inhibition of NMDA receptors by ethanol leads to the depression of excitatory synaptic potentials mediated by this type of excitatory amino acid receptor. Ethanol-induced disturbances in certain regions of the brain, i.e. hippocampus, nucleus accumbens or locus coeruleus may lead to cognitive disorders or drug dependence. Brain slices containing the locus coeruleus may be used as an in vitro test system to investigate the addictive properties of ethanol.
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PMID:Ethanol-induced inhibition of NMDA receptor channels. 1040 99

Cocaine abuse is a significant problem not only in the general population but also among pregnant women. Since cocaine readily crosses the placenta and is metabolized slowly in fetuses, they can be exposed to significant levels of cocaine for long periods. In humans the most common consequences of cocaine abuse during pregnancy include premature birth, lower birth weight, respiratory distress, bowel infarctions, cerebral infarctions, reduced head circumference, and increased risk of seizures. Behaviorally these newborns show an increased degree of "tremulousness," crying and irritability, and are over-reactive to environmental stimuli. Within a month these behaviors have recovered dramatically, but not to normal levels. Thus while there are a number of abnormalities associated with cocaine-exposed neonates, they are not imminently debilitating or life-threatening. However, the long-term consequences of this prenatal cocaine exposure remain to be elucidated. We have examined a rat model for neurochemical, neuroanatomical and behavioral changes resulting from prenatal cocaine exposure. Since cocaine is known to act by blocking the inactivation of the neurotransmitters dopamine, serotonin and norepinephrine, our studies have focused on brain dopamine (DA) and serotonin (5-HT) pathways. In this model system we have found neurochemical changes that are present at birth and that return to normal as the rat ages--similar to the recovery observed in infants. However, there are other neurochemical, anatomical and behavioral changes that persist after birth which may provide insights into the long-term consequences. It is hoped that by understanding the changes occurring in this rat model we will be better prepared to devise pharmacological interventions to circumvent the secondary consequences of prenatal cocaine exposure. These consequences might include increased susceptibility to drug addiction, seizures, depression, schizophrenia, Parkinson's disease, etc.
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PMID:Prenatal cocaine exposure. 1091 32

Ibogaine, a putative antiaddictive drug, is remarkable in its apparent ability to downgrade withdrawal symptoms and drug craving for extended periods of time after a single dose. Ibogaine acts as a non-competitive NMDA receptor antagonist, while NMDA has been implicated in long lasting changes in neuronal function and in the physiological basis of drug addiction. The purpose of this study was to verify if persistent changes in NMDA receptors could be shown in vivo and in vitro after a single administration of ibogaine. The time course of ibogaine effects were examined on NMDA-induced seizures and [3H] MK-801 binding to cortical membranes in mice 30 min, 24, 48, and 72 h post treatment. Ibogaine (80 mg/kg, ip) was effective in inhibiting convulsions induced by NMDA at 24 and 72 hours post administration. Likewise, [3H] MK-801 binding was significantly decreased at 24 and 72 h post ibogaine. No significant differences from controls were found at 30 min or 48 h post ibogaine. This long lasting and complex pattern of modulation of NMDA receptors prompted by a single dose of ibogaine may be associated to its antiaddictive properties.
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PMID:Long-lasting ibogaine protection against NMDA-induced convulsions in mice. 1105 45

Bicuculline-insensitive receptors for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), GABAB receptors, are a distinct subclass of receptors that mediate depression of synaptic transmission and contribute to neuronal inhibition. When activated, these receptors reduce transmission at excitatory and inhibitory synapses, as a result of an increase in K+ conductance, or a decrease in voltage-dependent Ca2+ currents. They are also linked to G-proteins, or intracellular effector systems in a very complex manner. The recent development of highly specific and potent agonists and antagonists for these receptors has led to a much better understanding of their physiology and pharmacology, including their heterogeneity, as well as their molecular biology. Over the past year, expression and cloning studies have contributed to major advances in characterizing GABAB receptor structure, with the discovery of the amino acid sequences of GABABR1a/R1b splice variants and GABABR2 receptors. These isoforms are widely distributed throughout the nervous system, and can be functionally expressed. Importantly, GABABR2 receptors can form a heteromeric assembly with GABABR1 proteins to operate as a heterodimer that displays robust coupling to inward-rectifying K+ channels, as well as inhibition of forskolin-stimulated adenylate cyclase activity. Further insights underlying the mechanisms of GABAB receptor functions can now be gained, leading ultimately to the therapeutic potential of drugs acting at these sites. It is increasingly clear that new information on GABAB receptor molecular structure will provide a plethora of targets for pharmaceutical intervention in areas such as drug addiction, nociception and absence seizures. This review summarizes the renewed efforts, and highlights the recent advances emerging in this field.
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PMID:Recent advances in GABAB receptors: from pharmacology to molecular biology. 1126 57

Neuropeptide Y (NPY) is a 36-amino-acid peptide that exhibits a large number of physiological activities in the central and peripheral nervous systems. NPY mediates its effects through the activation of six G-protein-coupled receptor subtypes named Y(1), Y(2), Y(3), Y(4), Y(5), and y(6). Evidence suggests that NPY is involved in the pathophysiology of several disorders, such as the control of food intake, metabolic disorders, anxiety, seizures, memory, circadian rhythm, drug addiction, pain, cardiovascular diseases, rhinitis, and endothelial cell dysfunctions. The synthesis of agonists and antagonists for these receptors could be useful to treat several of these diseases.
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PMID:Neuropeptide Y and its receptors as potential therapeutic drug targets. 1241 94

Knowledge of the neural mechanisms underlying the development of benzodiazepine (BZ) dependence remains incomplete. The gamma-aminobutyric acid (GABA(A)) receptor, being the main locus of BZ action, has been the main focus to date in studies performed to elucidate the neuroadaptive processes underlying BZ tolerance and withdrawal in preclinical studies. Despite this intensive effort, however, no clear consensus has been reached on the exact contribution of neuroadaptive processes at the level of the GABA(A) receptor to the development of BZ tolerance and withdrawal. It is likely that changes at the level of this receptor are inadequate in themselves as an explanation of these neuroadaptive processes and that neuroadaptations in other receptor systems are important in the development of BZ dependence. In particular, it has been hypothesised that as part of compensatory mechanisms to diazepam-induced chronic enhancement of GABAergic inhibition, excitatory mechanisms (including the glutamatergic system) become more sensitive [Behav. Pharmacol. 6 (1995) 425], conceivably contributing to BZ tolerance development and/or expression of withdrawal symptoms on cessation of treatment, including increased anxiety and seizure activity. Glutamate is a key candidate for changes in excitatory transmission mechanisms and BZ dependence, (1) since there are defined neuroanatomical relationships between glutamatergic and GABAergic neurons in the CNS and (2) because of the pivotal role of glutamatergic neurotransmission in mediating many forms of synaptic plasticity in the CNS, such as long-term potentiation and kindling events. Thus, it is highly possible that glutamatergic processes are also involved in the neuroadaptive processes in drug dependence, which can conceivably be considered as a form of synaptic plasticity. This review provides an overview of studies investigating changes in the GABAergic and glutamatergic systems in the brain associated with BZ dependence, with particular attention to the possible differential involvement of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors in these processes.
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PMID:Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence. 1272 68

Neuroactive steroids demonstrate pharmacological actions that have relevance for a host of neurological and psychiatric disorders. They offer protection against seizures in a range of models and seem to inhibit certain stages of drug dependence in preclinical assessments. The present study was designed to evaluate two endogenous and one synthetic neuroactive steroid that positively modulate the gamma-aminobutyric acid (GABA(A)) receptor against the increase in sensitivity to the convulsant effects of cocaine engendered by repeated cocaine administration (seizure kindling). Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) and ganaxolone (a synthetic derivative of allopregnanolone 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) were tested for their ability to suppress the expression (anticonvulsant effect) and development (antiepileptogenic effect) of cocaine-kindled seizures in male, Swiss-Webster mice. Kindled seizures were induced by daily administration of 60 mg/kg cocaine for 5 days. All of these positive GABA(A) modulators suppressed the expression of kindled seizures, whereas only allopregnanolone and ganaxolone inhibited the development of kindling. Allopregnanolone and pregnanolone, but not ganaxolone, also reduced cumulative lethality associated with kindling. These findings demonstrate that some neuroactive steroids attenuate convulsant and sensitizing properties of cocaine and add to a growing literature on their potential use in the modulation of effects of drugs of abuse.
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PMID:Protective efficacy of neuroactive steroids against cocaine kindled-seizures in mice. 1292 65

Topiramate, a novel anticonvulsant drug, has CNS depressant activity including enhancement of GABAergic inhibitory synaptic transmission. Drugs of this pharmacological spectrum might have utility in assuaging drug addiction. This study analyzes the ability of TPM to reduce withdrawal signs in the kindling model of ethanol dependence: chronic intermittent ethanol (CIE) rats. After CIE, persistent withdrawal signs are shown by an increased seizure susceptibility to the convulsant drug pentylenetetrazol and increased anxiety measured on the elevated plus-maze. Topiramate increased significantly the PTZ seizure threshold in CIE but not in control rats. On the elevated plus-maze, Topiramate was markedly more effective in CIE rats than in controls. Topiramate may have a therapeutic efficacy in treating alcohol withdrawal symptoms.
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PMID:Topiramate attenuates withdrawal signs after chronic intermittent ethanol in rats. 1510 59

Cigarette smoking represents one of the most preventable causes of death worldwide. However, success rates for stopping smoking are disappointingly low and are associated with high relapse rates. There is a need for a successful form of smoking cessation therapy. Bupropion is an effective therapy for smoking cessation and is recommended as first-line treatment in both US and UK guidelines. Its mechanism of action in smoking cessation is unclear, although it is thought that dopaminergic pathways are involved in the 'reward' circuit of drug dependence. Seizures are an important adverse effect of bupropion and care is needed when used in other conditions or with other medication that can lower the seizure threshold. Bupropion has been shown to be a cost-effective therapy for smoking cessation.
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PMID:Bupropion: risks and benefits. 1625 59

Birth asphyxia is one of the common causes of mortality and morbidity in neonates and the incidence is 2-9 per 1,000 live borns. The present work is a retrospective hospital based observational study. Babies born at B.P. Koirala Institute of Health Sciences, Dharan, Nepal during the period from April 2002 to April 2003 with gestational age >or=37 weeks with Apgar score <or=6 at 5 minutes were included in the study. The aim was to study the clinical profile, the acid base parameters and the outcome of asphyxiated newborns. Babies with congenital defects, evidence of infection and maternal drug addiction were excluded from the study. All babies were resuscitated according to the guidelines of American Heart Association. Data on 50 birth asphyxia cases were tabulated and analysed. There were 10 (20%) cases of severe birth asphyxia (Apgar score: 1-3 ) and 40 (80%) cases of moderate birth asphyxia (Apgar score: 4-6). Staging of hypoxic ischaemic encephalopathy (HIE) was performed according to Sarnat's staging. Thirty percent of these cases presented with various stages of HIE and the incidence was higher in low Apgar score group. The common presentations of HIE cases had depressed neonatal reflexes, seizures, lethargy, and pupillary abnormalities. The common acid base disturbance was metabolic acidosis which was observed only in babies with HIE-3. Two neonates (4%) died during the hospital stay due to multiorgan failure and severe metabolic acidosis.
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PMID:Outcome of newborns with birth asphyxia. 1655 70


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