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)

Catalase is one of the enzymes that convert hydrogen peroxide (H2O2) to H2O presenting a protective role against free radicals. In this study, catalase activity was determined in homogenates of striatum (ST) and prefrontal cortex (PFC) in order to examine the participation of oxidative stress (OS) on cocaine actions in mice brain. Male Swiss mice were injected (i.p.) with cocaine at low (10 and 30 mg/kg) and high doses (90 mg/kg), and observed for 1 h. After cocaine overdose (90 mg/kg) some animals presented only status epilepticus (SE) while others died after seizures. These animals were dissected and divided in two groups, SE and death. Catalase activity was also determined after pretreatment with the anticonvulsant drug, diazepam, alone or injected before cocaine 90 mg/kg, and after seizures induced by a high dose of bupropion, a known inhibitor of NE and DA reuptake used for comparison. Results showed a decrease in catalase activity of the PFC and ST after SE and death induced by cocaine and bupropion overdoses. Cocaine at low doses decreased the enzyme activity only in ST. Diazepam treatment alone and before cocaine overdose did not interfere with catalase activity. This reduction in catalase activity may reflect an increase in H2O2 content in PFC and ST. Previous data reports that H2O2 inhibits dopamine transporter activity, suggesting that the decrease in catalase activity may potentiate the toxic mechanism of drugs that inhibit monoamines reuptake. As far as we know, this is the first report showing an involvement of OS in the cocaine's central mechanism of action.
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PMID:Cocaine alters catalase activity in prefrontal cortex and striatum of mice. 1608 63

Growing evidence indicates that both seizure (glutamate) and cocaine (dopamine) treatment modulate synaptic plasticity within the mesolimbic region of the CNS. Activation of glutamatergic neurons depends on the localized translation of neuronal mRNA products involved in modulating synaptic plasticity. In this study, we demonstrate the dendritic localization of HuR and HuD RNA-binding proteins (RBPs) and their association with neuronal mRNAs following these two paradigms of seizure and cocaine treatment. Both the ubiquitously expressed HuR and neuronal HuD RBPs were detected in different regions as well as within dendrites of the brain and in dissociated neurons. Quantitative analysis revealed an increase in HuR, HuD and p-glycogen synthase kinase 3beta (GSK3beta) protein levels as well as neuronal mRNAs encoding Homer, CaMKIIalpha, vascular early response gene, GAP-43, neuritin, and neuroligin protein products following either seizure or cocaine treatment. Inhibition of the Akt/GSK3beta signaling pathway by acute or chronic LiCl treatment revealed changes in HuR, HuD, pGSK3beta, p-Akt, and beta-catenin protein levels. In addition, a genetically engineered hyperdopaminergic mouse model (dopamine transporter knockout) revealed decreased expression of HuR protein levels, but no significant change was observed in HuD or fragile-X mental retardation protein RBPs. Finally, our data suggest that HuR and HuD RBPs potentially interact directly with neuronal mRNAs important for differentiation and synaptic plasticity.
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PMID:Activity-dependent expression of ELAV/Hu RBPs and neuronal mRNAs in seizure and cocaine brain. 1901 79

The topic of alcohol withdrawal syndrome (AWS), including delirium tremens and especially seizures, is reviewed. From mice and rat studies, it is known that both N-methyl-d-aspartate (NMDA) and gamma-aminobutyric acid (GABA) receptors are involved in AWS. During alcohol intoxication chronic adaptations of NMDA and GABA receptors occur, and during alcohol withdrawal a hyperexcitable state develops. In studies on humans, during intoxication the NMDA receptors are activated and mediate tonic inhibition. In withdrawal, a rebound activation of these receptors occurs. Both GABA-A and GABA-B receptors, especially the alpha2 subunit of GABA-A receptors, are also likely involved. Homocysteine increases with active drinking, and in withdrawal, excitotoxicity likely is induced by a further increase in homocysteine, viewed as a risk factor for AWS and also as a screening tool. The dopamine transporter gene is also associated with AWS. Characteristics involves changes in the ECG, especially an increase in QT interval, and EEG changes, including abnormal quantified EEG, at times periodic lateralized epileptiform discharges, and especially seizures, usually occurring 6-48h after the cessation of drinking. Therapy has emphasized benzodiazepines, mainly diazepam and lorazepam, but more standard antiepileptic drugs, like carbamazepine and topiramate, are also effective and safe.
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PMID:Alcohol withdrawal seizures. 1924 88

Dopamine neurotransmission has been a key player in attempts to identify genetic factors involved in alcohol dependence. The dopamine transporter terminates dopaminergic neurotransmission, making the gene encoding the transporter (SLC6A3/DAT1) an attractive candidate in clinical studies on alcohol dependence. We conducted a systematic review of 18 studies examining associations between polymorphisms in DAT1 and alcohol dependence. The DAT1 variable number tandem repeat, the most frequent studied polymorphism in DAT1, did not show a direct association with alcohol dependence in general. Several, but not all, studies found that the DAT1 variable number tandem repeat (9-repeat allele) was associated with alcohol-withdrawal symptoms, such as seizures and delirium tremens. We discuss shortcomings, such as lack of power and disregarding moderating variables, as well as future challenges of gene association studies.
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PMID:Polymorphisms in the dopamine transporter gene (SLC6A3/DAT1) and alcohol dependence in humans: a systematic review. 1945 Jan 32

AIM: Several lines of evidence indicate that the dopaminergic system may play a role in the propagation of epileptic seizures and, indeed, DOPA metabolism impairment has recently been demonstrated in PET studies of ring chromosome 20 [r(20)] patients. We conducted a study looking for correlations between r(20) mosaicism, other clinical variables and both pre-synaptic dopamine transporter (DAT) expression and post-synaptic D2 receptor density. METHODS: Five patients with r(20) and epilepsy were enrolled in the study. DAT expression and D2 density were measured by single photon emission tomography (SPECT) imaging with 185 MBq of [123I]ioflupane and [123I]IBZM, respectively, on different days. Linear correlations between r(20) mosaicism, clinical variables and binding of [123I]ioflupane or [123I]IBZM were examined. RESULTS: A significant correlation between seizure frequency and r(20) mosaicism was detected (r=0.903, P<0.05), along with a negative correlation between r(20) mosaicism and binding of [123I]ioflupane in the putamen and in the caudate nucleus (r=-0.692 and r=-807; P<0.05). Seizure frequency was positively correlated with post-synaptic D2 density (r=0.925, P<0.05). CONCLUSION: Striatal neurons are involved in r(20) epilepsy; the relationship found between r(20) mosaicism and DAT expression suggests that drugs acting on the dopaminergic system could have a place in the treatment of this rare form of epilepsy.
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PMID:Exploring dopaminergic activity in ring chromosome 20 syndrome: a SPECT study. 2058 11

Experiments were designed to evaluate different variables of the dopaminergic system in the temporal cortex of surgically treated patients with temporal lobe epilepsy (TLE) associated with mesial sclerosis (MTLE, n=12) or with cerebral tumor or lesion (n=8). In addition, we sought to identify dopaminergic abnormalities in those patients with epilepsy that had comorbid anxiety and depression. Specifically, we investigated changes in dopamine and its metabolites, D1 and D2 receptors, tyrosine hydroxylase (TH) and dopamine transporter. Results obtained from patients with epilepsy were compared with those found in experiments using autopsy material. The neocortex of patients with MTLE demonstrated high D1 expression (1680%, p<0.05) and binding (layers I-II, 31%, p<0.05; layers V-VI, 28%, p<0.05), and decreased D2 expression (77%, p<0.05). The neocortex of patients with TLE secondary to cerebral tumor or lesion showed high expression of D1 receptors (1100%, p<0.05), and D2-like induced activation of G proteins (layers I-II, 503%; layers III-IV, 557%; layers V-VI, 964%, p<0.05). Both epileptic groups presented elevated binding to the dopamine transporter and low tissue content of dopamine and its metabolites. Analysis revealed the following correlations: a) D1 receptor binding correlated negatively with seizure onset age and seizure frequency, and positively with duration of epilepsy; b) D2 receptor binding correlated positively with age of seizure onset and negatively with duration of epilepsy; c) dopamine transporter binding correlated positively with duration of epilepsy and frequency of seizures; d) D2-like induced activation of G proteins correlated positively with the age of patients. When compared with autopsies and patients with anxiety and depression, patients without neuropsychiatric disorders showed high D2-like induced activation of G proteins, an effect that correlated positively with age of patient and seizure onset age, and negatively with duration of epilepsy. The present study suggests that alterations of the dopaminergic system result from epileptic activity and could be involved in the physiopathology of TLE and the comorbid anxiety and depression.
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PMID:Dopamine abnormalities in the neocortex of patients with temporal lobe epilepsy. 2196 55

In clinical practice, patients with epilepsy are frequently associated with psychiatric disorders, including cognitive impairment, depression, and attention deficit hyperactivity disorder. In fact, patients with epilepsy often take centrally acting drugs, such as antidepressants and anxiolytics; however, it remains unclear whether epilepsy is associated with psychiatric function. The present study examined the effect of kindled epileptic seizures on depression-like behavior in mice. The immobility time of pentylenetetrazol-kindled mice was as long as the immobility time of the controls in both a forced swimming test and a tail suspension test. Bupropion (10mg/kg, i.p.) decreased the duration of immobility in the forced swimming test of pentylenetetrazol-kindled mice, while having no significant effect in controls. Furthermore, atomoxetine (2mg/kg, i.p.) caused a significant decrease in the duration of immobility in the tail suspension test of the pentylenetetrazol-kindled mice, while having no significant effect in controls. Using immunohistochemistry, it was shown that there was no significant change in dopamine transporter levels in the striatum; however, norepinephrine transporter was significantly increased in the perirhinal cortex of the pentylenetetrazol-kindled mice. These results suggested that bupropion (in low doses) and atomoxetine are good candidates for the treatment of patients with epilepsy who suffer from psychiatric symptoms. Furthermore, this mechanism may be involved in the change of norepinephrine transporter expression, at least in the perirhinal cortex.
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PMID:Regulatory role of the dopamine and norepinephrine transporters in pentylenetetrazol-kindled mice: association with effect of antidepressants. 2204 20

The prevalence of attention-deficit hyperactivity disorder (ADHD) in the USA is estimated at approximately 4-9% in children and 4% in adults. It is estimated that prescriptions for ADHD medications are written for more than 2.7 million children per year. In 2010, US poison centers reported 17,000 human exposures to ADHD medications, with 80% occurring in children <19 years old and 20% in adults. The drugs used for the treatment of ADHD are diverse but can be roughly separated into two groups: the stimulants such as amphetamine, methylphenidate, and modafinil; and the non-stimulants such as atomoxetine, guanfacine, and clonidine. This review focuses on mechanisms of toxicity after overdose with ADHD medications, clinical effects from overdose, and management. Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin. The primary clinical syndrome involves prominent neurological and cardiovascular effects, but secondary complications can involve renal, muscle, pulmonary, and gastrointestinal (GI) effects. In overdose, the patient may present with mydriasis, tremor, agitation, hyperreflexia, combative behavior, confusion, hallucinations, delirium, anxiety, paranoia, movement disorders, and seizures. The management of amphetamine, dextroamphetamine, and methylphenidate overdose is largely supportive, with a focus on interruption of the sympathomimetic syndrome with judicious use of benzodiazepines. In cases where agitation, delirium, and movement disorders are unresponsive to benzodiazepines, second-line therapies include antipsychotics such as ziprasidone or haloperidol, central alpha-adrenoreceptor agonists such as dexmedetomidine, or propofol. Modafinil is not US FDA approved for treatment of ADHD; however, it has been shown to improve ADHD signs and symptoms and has been used as an off-label pharmaceutical for this diagnosis in both adults and children. The mechanism of action of modafinil is complex and not fully understood. It is known to cause an increase in extracellular concentrations of dopamine, norepinephrine, and serotonin in the neocortex. Overdose with modafinil is generally of moderate severity, with reported ingestions of doses up to 8 g. The most common neurological effects include increased anxiety, agitation, headache, dizziness, insomnia, tremors, and dystonia. The management of modafinil overdose is largely supportive, with a focus on sedation, and control of dyskinesias and blood pressure. Atomoxetine is a selective presynaptic norepinephrine transporter inhibitor. The clinical presentation after overdose with atomoxetine has generally been mild. The primary effects have been drowsiness, agitation, hyperactivity, GI upset, tremor, hyperreflexia, tachycardia hypertension, and seizure. The management of atomoxetine overdose is largely supportive, with a focus on sedation, and control of dyskinesias and seizures. Clonidine is a synthetic imidazole derivative with both central and peripheral alpha-adrenergic agonist actions. The primary clinical syndrome involves prominent neurological and cardiovascular effects, with the most commonly reported features of depressed sensorium, bradycardia, and hypotension. While clonidine is an anti-hypertensive medication, a paradoxical hypertension may occur early with overdose. The clinical syndrome after overdose of guanfacine may be mixed depending on central or peripheral alpha-adrenoreceptor effects. Initial clinical effects may be drowsiness, lethargy, dry mouth, and diaphoresis. Cardiovascular effects may depend on time post-ingestion and may present as hypotension or hypertension. The management of guanfacine overdose is largely supportive, with a focus on support of blood pressure. Overdose with ADHD medications can produce major morbidity, with many cases requiring intensive care medicine and prolonged hospital stays. However, fatalities are rare with appropriate care.
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PMID:Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management. 2375 86

Over the past 35 years or so, PET brain imaging has allowed powerful and unique insights into brain function under normal conditions and in disease states. Initially, as PET instrumentation continued to develop, studies were focused on brain perfusion and glucose metabolism. This permitted refinement of brain imaging for important, non-oncologic clinical indications. The ability of PET to not only provide spatial localization of metabolic changes but also to accurately and consistently quantify their distribution proved valuable for applications in the clinical setting. Specifically, glucose metabolism brain imaging using (F-18) fluorodeoxyglucose continues to be invaluable for evaluating patients with intractable seizures for identifying seizure foci and operative planning. Cerebral glucose metabolism also contributes to diagnosis of neurodegenerative diseases that cause dementia. Alzheimer disease, dementia with Lewy bodies, and the several variants of frontotemporal lobar degeneration have differing typical patterns of hypometabolism. In Alzheimer disease, hypometabolism has furthermore been associated with poorer cognitive performance and ensuing cognitive and functional decline. As the field of radiochemistry evolved, novel radioligands including radiolabeled flumazenil, dopamine transporter ligands, nicotine receptor ligands, and others have allowed for further understanding of molecular changes in the brain associated with various diseases. Recently, PET brain imaging reached another milestone with the approval of (F-18) florbetapir imaging by the United States Federal Drug Administration for detection of amyloid plaque accumulation in brain, the major histopathologic hallmark of Alzheimer disease, and efforts have been made to define the clinical role of this imaging agent in the setting of the currently limited treatment options. Hopefully, this represents the first of many new radiopharmaceuticals that would allow improved diagnostic and prognostic information in these and other clinical applications, including Parkinson disease and traumatic brain injury.
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PMID:An overview of PET neuroimaging. 2409 12

In Belgian Malinois dogs, a 38-base pair variable number tandem repeat in the dopamine transporter gene (SLC6A3) is associated with behavior changes in Malinois. By additional sequencing in SLC6A3, we identified an intronic 12-nucleotide poly(A) insertion ("PolyA(22)") before the terminal exon that was associated with seizure, "glazing over" behaviors, and episodic biting behaviors in a sample of 138 Malinois. We next investigated whether PolyA(22) was associated with 1) increased locomotor activity and 2) response to novelty. Using a sample of 22 Malinois and 25 dogs of other breeds, dogs' activity was monitored in a novel and non-novel environment while wearing activity monitoring collars. All dogs were more active in novel compared with non-novel environments, and Malinois were more active overall than other breeds. There was an effect of PolyA(22) genotype on activity levels, and this effect appeared to underlie the difference detected between Malinois and other breeds. There was no effect of PolyA(22) genotype on the relative decrease in activity between novel and non-novel environments for either group or all dogs considered together. In addition to an association between PolyA(22) and owner reports of seizure, "glazing over" behaviors, and episodic biting behaviors, these findings support an effect of PolyA(22) on dopamine transporter function related to activity. Further investigation is required to confirm mechanistic effects of PolyA(22) on SLC6A3. The complex polygenic nature of behavior and the range of behaviors associated with this insertion predict that effects are likely also modified by additional genetic and environmental factors.
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PMID:Differences in behavior and activity associated with a poly(a) expansion in the dopamine transporter in Belgian Malinois. 2437 13


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