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PubMed2006

Focal glucose hypermetabolism in interictal state of West syndrome.

This report concerns two siblings from a tetrad, both of whom had West syndrome with atypical findings on positron emission tomography using [(18)F] fluorodeoxyglucose. One manifested periventricular leukoencephalopathy, and the other had periventricular leukoencephalopathy as well as porencephaly because of fetal distress and brain parenchymal hemorrhage in the neonatal period. They developed West syndrome at the age of 9 months. Fluorodeoxyglucose-positron emission tomography study performed after cessation of their seizures revealed an increase in glucose metabolism. The corresponding region presented low-level accumulation in [(11)C]flumazenil positron emission tomography. The patients remained seizure-free for more than 1 month, and their electroencephalograms only occasionally disclosed sporadic paroxysmal discharges. Because of the decreased density of benzodiazepine receptor in these lesions, the activity of the excitatory neuron system may overexpress that of the inhibitory neuron system, thus resulting in epileptogenesis of the lesions. It is suggested that fluorodeoxyglucose and flumazenil-positron emission tomography revealed functional abnormalities and that epileptogenesis of these patients is still active even when the patient is seizure-free and there are mild epileptogenic discharges on electroencephalogram.

Brain↗
PubMed2006

Intranasal midazolam vs rectal diazepam in acute childhood seizures.

One hundred eighty-eight seizure episodes in 46 children were randomly assigned to receive treatment with rectal diazepam and intranasal midazolam with doses of 0.3 mg/kg body weight and 0.2 mg/kg body weight, respectively. Efficacy of the drugs was assessed by drug administration time and seizure cessation time. Heart rate, blood pressure, respiratory rate, and oxygen saturation were measured before and after 5, 10, and 30 minutes following administration of the drugs in both groups. Mean time from arrival of doctor to drug administration was 68.3 +/- 55.12 seconds in the diazepam group and 50.6 +/- 14.1 seconds in the midazolam group (P = 0.002). Mean time from drug administration to cessation of seizure was significantly less in the midazolam group than the diazepam group (P = 0.005). Mean heart rate and blood pressure did not vary significantly between the two drug groups. However, mean respiratory rate and oxygen saturation differed significantly between the two drug groups at 5, 10, and 30 minutes after drug administration. Intranasal midazolam is preferable to rectal diazepam in the treatment of acute seizures in children. Its administration is easy, it has rapid onset of action, has no significant effect on respiration and oxygen saturation, and is socially acceptable.

Acute Disease↗
PubMed2005

Benzodiazepine effects on licking responses for sodium chloride solutions in water-deprived male rats.

The aim of this study was to investigate, for the first time, the effects of a centrally active benzodiazepine receptor agonist, midazolam maleate, on the microstructure of licking responses for a range of sodium chloride (NaCl) solutions in mildly water-deprived male rats. Doses of midazolam were chosen (0.3-3.0 mg/kg. i.p.) which have been characterised in studies of licking responses for several different kinds of nutrients. NaCl concentrations (0.075 M-0.45 M) were chosen to cover a range of taste preferences and acceptability. A brief-contact testing session was employed to focus on the initial determinants of licking responses (i.e. taste palatability), and to minimise any contribution of post-ingestional effects. The results indicate the midazolam significantly increased the total number of licks recorded across all salt concentrations, but that it had no effect on the number of bouts of licking. Instead, midazolam specifically enhanced the mean duration of licking bouts, an effect that was most evident at the weaker but more acceptable NaCl concentrations (0.075 M and 0.15 M). In addition, midazolam diminished the intrabout rate of licking across all salt concentrations. These results confirm that benzodiazepines can exert a specific pattern of effects on the microstructure of licking for salt solutions. They are discussed in terms of the oropharyngeal stimulation controlling intake and the palatability or "liking" hypothesis for the effects of benzodiazepines on taste stimuli, and indicate that the hypothesis is applicable to salt solution ingestive behaviour.

Analysis of Variance↗
PubMed2004

Effects of single and repeated phencyclidine administration on [3H]flunitrazepam binding in rat brain.

Repeated administration of phencyclidine (PCP) induces behavioral sensitization to dopaminergic neural transmission. This phenomenon has been implicated in the pathophysiology of schizophrenia. Recently, GABAergic agonists have been shown to reduce behavioral activity induced by enhanced dopaminergic neural transmission, which is mediated by the GABA(A)/benzodiazepine (BZD) receptor complex. Thus, to investigate the role of BZD receptors during induction and expression of behavioral sensitization in PCP-sensitized animals, the effects of both single and repeated PCP administration on BZD receptors in rat brain were examined using in vitro quantitative autoradiography. Repeated PCP administration failed to significantly alter levels of [3H]flunitrazepam (FNZ) binding in any of the regions examined. However, significant increases in levels of [3H]FNZ binding were found in the nucleus accumbens and ventral pallidum 1 h after single administration of PCP. These results suggest that BZD binding sites may not play important roles in the development of PCP-induced sensitization at several sites of GABA(A)/BZD receptor complex, while changes in GABA function in the nucleus accumbens differ from other areas following single administration of N-methyl-D-aspartate (NMDA) antagonist.

Animals↗
PubMed2005

Double-blind, comparative study of cyamemazine vs. bromazepam in the benzodiazepine withdrawal syndrome.

Cyamemazine is an anxiolytic antipsychotic, which reduces ethanol withdrawal symptoms. Here, we investigated if cyamemazine can be also effective as substitute drug to facilitate benzodiazepine withdrawal. A total of 168 patients treated with benzodiazepines for at least 3 months and with a <18 score in the Hamilton Anxiety Rating Scale (HARS) were included in the study. Previous benzodiazepine treatment was withdrawn, and patients were randomized to a 4-week treatment with cyamemazine (25-50 mg q.d.) or bromazepam (3-6 mg q.d.), followed by 2 weeks of placebo. The primary efficacy variable was the maximal anxiety rebound as measured with the HARS during the 42 days of treatment. No statistically significant differences between treatment groups were found for the extent or incidence of rebound anxiety. Considering all dropout patients as withdrawal failures, after 6 months of follow-up, 56/84 patients in the cyamemazine group (66.7%) and 55/84 patients in the bromazepam group (65.5%) were successfully withdrawn. 28 patients in the cyamemazine group and 18 in the bromazepam group had an adverse event, including anxiety, insomnia, dry mouth and somnolence. No extra-pyramidal symptoms were reported. In conclusion, cyamemazine was comparable to bromazepam in ensuring successful benzodiazepine withdrawal and in controlling the acute benzodiazepine withdrawal syndrome. Cyamemazine may be useful to facilitate benzodiazepine withdrawal in those patients where bromazepam substitution is not appropriate.

Adolescent↗
PubMed2005

A three-year follow-up study of patients with the respiratory subtype of panic disorder after treatment with clonazepam.

The demographic, clinical and therapeutic features of the respiratory subtype of panic disorder (PD) versus the non-respiratory subtype were studied in a prospective design. Sixty-seven PD outpatients (DSM-IV), who had previously been categorized into respiratory (n=35) and non-respiratory (n=32) subgroups, were openly treated with clonazepam for a 3-year period. The principal measure of efficacy was the number of panic attacks, obtained from the Sheehan Panic and Anticipatory Anxiety Scale. In the first 8 weeks of treatment (acute phase), the respiratory subtype group had a significantly faster response to clonazepam. During the follow-up (weeks 12-156), the two subgroups did not differ significantly in the number of panic attacks experienced from baseline to end point. Patients in the respiratory subtype were characterized by a later onset of disorder and a family history of PD. Patients in the non-respiratory subgroup had a significantly higher number of past depressive episodes than those in the respiratory subgroup. The respiratory subgroup had a faster response after 8 weeks of treatment and an equivalent response in the 3-year follow-up period. Clonazepam had a sustained therapeutic effect over the entire treatment period.

Adult↗
PubMed2004

Determination of language dominance with near-infrared spectroscopy: comparison with the intracarotid amobarbital procedure.

PURPOSE: To determine the efficacy of near-infrared spectroscopy (NIRS) in identifying the hemisphere associated with language by measuring changes in bilateral lateral inferior frontal blood flow during a word generation task in epilepsy surgery patients and healthy volunteers. METHODS: Sixteen patients who underwent the intracarotid amobarbital procedure (IAP) and eight healthy right-handed/right-footed individuals were tested with NIRS during a word generation paradigm. RESULTS: Increases in lateral inferior frontal total hemoglobin concentrations agreed with the IAP in 11 of 16 patients, including 2 of 3 with right hemisphere (atypical) speech dominance (P = 0.13). NIRS revealed increases in lateral inferior frontal total hemoglobin concentrations congruent with language dominance predicted by handedness/footedness in 18 of 24 subjects, including 100% of healthy right-handed subjects (P = 0.02). CONCLUSION: NIRS is a simple, non-invasive, safe modality for measuring cerebral blood flow. Further research and development of testing procedures and instrumentation are needed before routine implementation in pre-surgical testing.

Adult↗
PubMed2004

Full neurologic recovery after fulminant thrombotic thrombocytopenic purpura with status epilepticus.

Thrombotic thrombocytopenic purpura (TTP) is an ischemic vasculopathy frequently associated with neurological dysfunction including seizures. However, status epilepticus (SE) has rarely been reported in this condition. We report on a 70-year-old woman with fulminant TTP who developed convulsive SE despite high therapeutic serum levels of phenytoin and phenobarbital. Her electroencephalogram (EEG) was characterized by bilateral independent periodic lateralizing epileptiform discharges (BIPLEDs) propagating into clinical and electrographic seizures. She recovered completely after intensive plasmapheresis and treatment with pentobarbital induced coma for 5 days. This case illustrates that aggressive treatment with pentobarbital and plasmapheresis may prevent permanent neurologic deficits when TTP is complicated by SE and that periodic lateralizing epileptiform discharges (PLEDs) in this syndrome can be the manifestation of a reversible ischemic insult.

Aged↗
PubMed2006

alpha2delta and the mechanism of action of gabapentin in the treatment of pain.

Gabapentin is a drug that has been widely used in the treatment of chronic pain states. Despite its widespread usage, it is only recently that light has been shed on the mechanism of action of this agent. In the current review, the authors document the pharmacological, biochemical and molecular information that has led to the identification of the alpha2delta1 auxilliary subunit of voltage gated calcium channels as the target for this drug's actions.

Amines↗
PubMedDate not supplied

Multiple functions of type 10 17beta-hydroxysteroid dehydrogenase.

Human 17beta-hydroxysteroid dehydrogenase type 10 (17beta-HSD10) is a mitochondrial enzyme encoded by the SCHAD gene, which escapes chromosome X inactivation. 17Beta-HSD10/SCHAD mutations cause a spectrum of clinical conditions, from mild mental retardation to progressive infantile neurodegeneration. 17Beta-HSD10/SCHAD is essential for the metabolism of isoleucine and branched-chain fatty acids. It can inactivate 17beta-estradiol and steroid modulators of GABA(A) receptors, and convert 5alpha-androstanediol into 5alpha-dihydrotestosterone (DHT). Certain malignant prostatic epithelial cells contain high levels of 17beta-HSD10, generating 5alpha-DHT in the absence of testosterone. 17Beta-HSD10 has an affinity for amyloid-beta peptide, and might be linked to the mitochondrial dysfunction seen in Alzheimer's disease. This versatile enzyme might provide a new drug target for neuronal excitability control and for intervention in Alzheimer's disease and certain cancers.

17-Hydroxysteroid Dehydrogenases↗
PubMed2005

Don't worry 'B' happy!: a role for GABA(B) receptors in anxiety and depression.

GABA, the main inhibitory neurotransmitter in the brain, regulates many physiological and psychological processes. Thus, dysfunction of the GABA system is implicated in the pathophysiology of several neuropsychiatric disorders, including anxiety and depression. However, the role of GABA(B) receptors in behavioural processes related to these disorders has not been resolved. GABA(B) receptors are G-protein-coupled receptors that function as heterodimers of GABA(B(1)) and GABA(B(2)) subunits. In addition to highly selective agonists and antagonists, novel GABA(B) receptor tools have been developed recently to further assist elucidation of the role of GABA(B) receptors in CNS function. These include mice that lack functional GABA(B) receptors, and novel positive modulators of the GABA(B) receptor. In this review, we discuss evidence that points to a role of GABA(B) receptors in anxiety and depression.

Animals↗
PubMed2004

Organophosphate-induced convulsions and prevention of neuropathological damages.

Such organophosphorus (OP) compounds as diisopropylfluorophosphate (DFP), sarin and soman are potent inhibitors of acetylcholinesterases (AChEs) and butyrylcholinesterases (BChEs). The acute toxicity of OPs is the result of their irreversible binding with AChEs in the central nervous system (CNS), which elevates acetylcholine (ACh) levels. The protective action of subcutaneously (SC) administered antidotes or their combinations in DFP (2.0 mg/kg BW) intoxication was studied in 9-10-weeks-old Han-Wistar male rats. The rats received AChE reactivator pralidoxime-2-chloride (2PAM) (30.0 mg/kg BW), anticonvulsant diazepam (2.0 mg/kg BW), A(1)-adenosine receptor agonist N(6)-cyclopentyl adenosine (CPA) (2.0 mg/kg BW), NMDA-receptor antagonist dizocilpine maleate (+-MK801 hydrogen maleate) (2.0 mg/kg BW) or their combinations with cholinolytic drug atropine sulfate (50.0 mg/kg BW) immediately or 30 min after the single SC injection of DFP. The control rats received atropine sulfate, but also saline and olive oil instead of other antidotes and DFP, respectively. All rats were terminated either 24 h or 3 weeks after the DFP injection. The rats treated with DFP-atropine showed severe typical OP-induced toxicity signs. When CPA, diazepam or 2PAM was given immediately after DFP-atropine, these treatments prevented, delayed or shortened the occurrence of serious signs of poisoning. Atropine-MK801 did not offer any additional protection against DFP toxicity. In conclusion, CPA, diazepam and 2PAM in combination with atropine prevented the occurrence of serious signs of poisoning and thus reduced the toxicity of DFP in rat.

Acetylcholinesterase↗
PubMed2003

Treatment of perioral dystonia with botulinum toxin in 4 cases of Meige's syndrome.

OBJECTIVE: We describe the treatment of 4 patients (median age, 53.5 years) with incapacitating perioral dystonia and insufficient response to peroral medication. Their general treatment with clonazepam and anticholinergics was supplemented by intramuscular injections with botulinum toxin A (20-40 U) in the orbicularis oris muscle, guided by electromyography (EMG). STUDY DESIGN: Perioral dystonia and treatment effect were assessed by using subjective global and visual analog scales, examiner-based video movement counts and rating scales, and quantitative EMG. t Tests were used for statistical analysis. RESULTS: The result of the intramuscular botulinum toxin A injections was characterized by the patients as "much improved"; correspondingly, dystonia was significantly reduced in visual analog scale scores, on examiner-based assessments, and in recordings of EMG. The side effects were few and short-lasting. CONCLUSION: Incapacitating perioral dystonia in Meige's syndrome may be safely controlled by recurrent EMG-guided botulinum toxin A injections in the orbicularis oris muscle, in combination with general medication.

Botulinum Toxins, Type A↗
PubMed2005

Effects of antiepileptic drugs on attention as assessed by a five-choice serial reaction time task in rats.

Patients with epilepsy can have impaired cognitive abilities. Antiepileptic drugs (AEDs) may contribute to the cognitive deficits observed in patients with epilepsy, and have been shown to induce cognitive impairments in healthy individuals. However, there are few systematic data on the effects of AEDs on specific cognitive domains. We have previously evaluated a number of AEDs with respect to their effects on working memory. The purpose of the present study was to evaluate the effects of AEDs on attention as measured by five-choice serial reaction time behavior in nonepileptic rats. The GABA-related AEDs triazolam, phenobarbital, and chlordiazepoxide significantly disrupted performance by increasing errors of omission, whereas tiagabine, valproate, and gabapentin did not. The sodium channel blocker carbamazepine increased errors of omission at relatively high doses, whereas the sodium channel blockers phenytoin, topiramate, and lamotrigine were without significant effect. Levetiracetam had no effect on attention. The disruptions produced by triazolam, phenobarbital, chlordiazepoxide, and carbamazepine were similar in magnitude to the effects of the muscarinic cholinergic receptor antagonist scopolamine. The present results indicate that AEDs can disrupt attention, but there are differences among AEDs in the magnitude of the disruption in nonepileptic rats, with drugs that enhance GABA receptor function producing the most consistent disruption of attention.

Animals↗
PubMed2004

p62 is involved in the mechanism of Mallory body formation.

p62 is a scaffolding protein that binds to polyubiquitin. It is involved in the degradation of proteins by the proteasome. To determine if p62 is critical in the development of Mallory bodies (MBs), primary culture hepatocytes from drug-primed mice were studied and the results were compared with normal hepatocytes. Gene-specific gripNA (gp62) was added to the medium of the primary cultures of the hepatocytes to inhibit the expression of p62. Overexpression of p62 was achieved by transfecting the hepatocytes with a plasmid containing green fluorescent protein (GFP) fused p62 (p62-GFP). Gp62 dramatically inhibited MB formation by 94% in drug-primed hepatocytes. The cells transfected with gp62 had decreased protein levels of p62, ubiquitin (Ub), and cytokeratin 8 (CK8). Overexpression of p62 accelerated and enhanced MB formation by 339% in drug-primed hepatocytes. Overexpression of p62 in normal mouse hepatocytes induced MB-like aggresomes that were stained by Ub but not by CK8. The results indicate that p62 is involved in the mechanism of MB formation.

Animals↗
PubMed2005

The role of laminin-integrin signaling in triggering MB formation. An in vivo and in vitro study.

It is still unclear as to how hepatocytes perceive external factors and transduce the signals which initiate MB formation. To investigate this phenomenon, the model of MB formation in liver in vivo and in primary culture of hepatocytes derived from drug-primed mice was used. Control mice were fed the control diet (group 1). MBs were induced in the livers of mice fed diethyl-1, 4-dihydro-2, 4, 6-trimethyl-3, 5-pyridinedicarboxylate (DDC) for 10 weeks (group 2). The induced MBs completely disappeared after the withdrawal of DDC for 4 weeks (group 3). Newly formed MBs were numerous after DDC was refed for 1 week (group 4). Relative mRNA abundance was determined by quantitative real-time RT-PCR in the liver from the mice. The expression of integrin alpha(6) and beta(2) was significantly increased in the livers of DDC-treated (group 2) and drug refed mice (group 4), when compared with the livers from controls (group 1) and DDC-withdrawn (group 3) mice. The increased mRNA of these two integrin genes was associated with the increased expression of laminin (a ligand for integrin alpha(6)beta(1) and alpha(6)beta(4)), Icam1 (a ligand of alphaLbeta2), Src, MEKK1, and ERK1. Primary cultures of isolated DDC-primed hepatocytes (group 4 mice were withdrawn from DDC-CMZ for 4-6 weeks) produced significantly more MBs on laminin-coated coverslips compared with plastic uncoated, fibronectin-, collagen-, or fibrinogen-coated coverslips. U0126, an inhibitor of MEK1 protein, significantly reduced the phosphorylated forms of ERK1/2 and MB formation in vitro. In conclusion, the current study revealed an association between MB formation and integrin-mediated signaling in vivo. The data indicate that laminin-integrin signaling which activates ERK, triggered MB formation in vitro, and an inhibitor of the signaling cascade reduced MB formation.

Animals↗
PubMed2006

Physiology and gene regulation of the brain NPY Y1 receptor.

Neuropeptide Y (NPY) is one of the most prominent and abundant neuropeptides in the mammalian brain where it interacts with a family of G-protein coupled receptors, including the Y(1) receptor subtype (Y(1)R). NPY-Y(1)R signalling plays a prominent role in the regulation of several behavioural and physiological functions including feeding behaviour and energy balance, sexual hormone secretion, stress response, emotional behaviour, neuronal excitability and ethanol drinking. Y(1)R expression is regulated by neuronal activity and peripheral hormones. The Y(1)R gene has been isolated from rodents and humans and it contains multiple regulatory elements that may participate in the regulation of its expression. Y(1)R expression in the hypothalamus is modulated by changes in energetic balance induced by a wide variety of conditions (fasting, pregnancy, hyperglycaemic challenge, hypophagia, diet induced obesity). Estrogens up-regulate responsiveness to NPY to stimulate preovulatory GnRH and gonadotropin surges by increasing Y(1)R gene expression both in the hypothalamus and the pituitary. Y(1)R expression is modulated by different kinds of brain insults, such as stress and seizure activity, and alteration in its expression may contribute to antidepressant action. Chronic modulation of GABA(A) receptor function by benzodiazepines or neuroactive steroids also affects Y(1)R expression in the amygdala, suggesting that a functional interaction between the GABA(A) receptor and Y(1)R mediated signalling may contribute to the regulation of emotional behaviour. In this paper, we review the state of the art concerning Y(1)R function and gene expression, including our personal contribution to many of the subjects mentioned above.

Alcohol Drinking↗

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