Appropriate Shocks and Mortality in Patients With Versus Without Diabetes With Prophylactic Implantable Cardioverter Defibrillators.

OBJECTIVE: Diabetes increases the risk of all-cause mortality and sudden cardiac death (SCD). The exact mechanisms leading to sudden death in diabetes are not well known. We compared the incidence of appropriate shocks and mortality in patients with versus without diabetes with a prophylactic implantable cardioverter defibrillator (ICD) included in the retrospective EU-CERT-ICD registry. RESEARCH DESIGN AND METHODS AND RESULTS: A total of 3,535 patients from 12 European EU-CERT-ICD centers with a mean age of 63.7 ± 11.2 years (82% males) at the time of ICD implantation were included in the analysis. A total of 995 patients (28%) had a history of diabetes. All patients had an ICD implanted for primary SCD prevention. End points were appropriate shock and all-cause mortality. Mean follow-up time was 3.2 ± 2.3 years. Diabetes was associated with a lower risk of appropriate shocks (adjusted hazard ratio [HR] 0.77 [95% CI 0.62-0.96], P = 0.02). However, patients with diabetes had significantly higher mortality (adjusted HR 1.30 [95% CI 1.11-1.53], P = 0.001). CONCLUSIONS: All-cause mortality is higher in patients with diabetes than in patients without diabetes with primary prophylactic ICDs. Subsequently, patients with diabetes have a lower incidence of appropriate ICD shocks, indicating that the excess mortality might not be caused primarily by ventricular tachyarrhythmias. These findings suggest a limitation of the potential of prophylactic ICD therapy to improve survival in patients with diabetes with impaired left ventricular function.

Pharmacological characterisation of MDI-222, a novel AMPA receptor positive allosteric modulator with an improved safety profile.

PURPOSE: There is considerable interest in positive allosteric modulators (PAMs) of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) subtype of ionotropic glutamate receptors as therapeutic agents for a range of cognitive and mood disorders. However, the challenge is to increase AMPA receptor (AMPAR) function sufficient to enhance cognitive function but not to the extent that there are mechanism-related pro-convulsant or convulsant side effects. In this present study, we report the preclinical pharmacology data for MDI-222, an AMPAR PAM which enhances cognition but has a much reduced side-effect (i.e. convulsant) liability relative to other molecules of this mechanism. METHODS: The pharmacological effects of MDI-222 were characterised in in vitro and in vivo preclinical electrophysiology, efficacy (cognition), side-effect (pro-convulsant/convulsant), tolerability and toxicity assays. RESULTS: We demonstrate that MDI-222 is an AMPAR PAM, since it enhanced AMPAR function in vitro at human (hGluA1-4) and rat (rGluA2) homomeric receptors, and potentiated hetero-oligomeric AMPARs in rat neurons. MDI-222 enhanced electrically evoked AMPAR-mediated synaptic transmission in the anaesthetised rat at 10 mg/kg (administered intravenously) and did not significantly lower the seizure threshold in the pro-convulsant maximal electroshock threshold test (MEST) at any dose tested up to a maximum of 30 mg/kg (administered by oral gavage (p.o.)). MDI-222 reversed a delay-induced deficit in novel object recognition (NOR) in rats with a minimum effective dose (MED) of 0.3 mg/kg (p.o.) following acute administration, which was reduced to 0.1 mg/kg following sub-chronic administration, and improved passive avoidance performance in scopolamine-impaired rats with a MED of 10 mg/kg p.o. On the other hand, MDI-222 was not pro-convulsant in the MEST, resulting in a therapeutic window between plasma concentrations that enhanced cognitive performance and those associated with mechanism-related side effects of ⩾1000-fold. Unfortunately, despite the excellent preclinical profile of this compound, further development had to be halted due to non-mechanism-related issues. CONCLUSIONS: We conclude that MDI-222 is an AMPAR PAM which enhances cognitive performance in rats and has a significantly improved safety profile in preclinical species.

Asylum seekers alleging torture in their countries: Evaluation of a French center.

MATERIALS AND METHODS: Over a 6-year period, 570 survivors gave consent to this study and were examined by forensic medical doctors in academic French hospital. They evaluated with the aim of cataloguing the physical evidence of torture. Sociological data, declared violence (single physical altercation, repeated physical violence less than one year or more than one year, incarceration not more than one week or more than 1 week), and method of violence (blows by blunt object, crushing, burns, electrical shocks, attempted drowning, smothering, incision, or gunshot) were studied. An association between victims' statements and physical evidence of torture was determined. RESULTS: 70% were male with an average age of 31.9 years and ages between 1 and 70 years old. Dagestan, Guinea-Conakry and Guinea-Bissau were the countries most represented among asylum seekers. Beatings were reported by 27.89%, confinement was reported by 40.22%, and repeated violence by 30.16% of refugees. The average time interval between the first assault and forensic evaluation was 53 months. Forms of torture reported included: blunt force trauma (82.51%) truncheon blows (27.50%), arm incision (30%), and burns (16.3%). Statistically, truncheon blows were experienced more often by males in confinement due to political conflict. The use of crushing methods and electrical shocks also were experienced more often by males during confinement. Victims who had received incision wounds were significantly younger. Gunshots were statistically associated with male survivors of political conflict. Men experienced drowning and electrical shocks while in confinement in the Balkans, Asia, and Russia. Electrical shocks were reported by males during confinement and in northern Caucasus countries. The association was significant between assertions of burns and the presence of cutaneous scars (p = 0.0105); similarly, assertions of incision wounds were significantly corroborated by evidence of scars (p = 0.0009). DISCUSSION: Asylum seekers assessed were usually young men. Beatings with blunt objects were the most often reported form of torture used during episodes of repeated violence and during confinement. Assertions of burns were not associated with any particular circumstances. Electrical shocks were reported during confinement and most often in countries of the northern Caucasus. Attempted drowning, smothering, and shocking were noted, but these methods typically do not leave physical evidence. Wounds resulting from burns and incisions usually leave scars that corroborate refugee statements. Torture by crushing and gunshot were reported by asylum seekers for the first time. CONCLUSION: Investigation of the types of torture and circumstances under which torture occurs is critical for efficient forensic evaluation of claims of torture experienced by asylum seekers.

Padronização do tratamento cirúrgico do trauma elétrico na fase aguda / Standardization of surgical treatment of acute electrical trauma

INTRODUÇÃO: As queimaduras elétricas correspondem de 5 a 15% dos casos de acidentes com queimaduras. A maioria está associada a acidentes do trabalho, nos quais predominam as lesões com alta voltagem (acima de 1.000 Volts), em pacientes do sexo masculino. As taxas de mortalidade variam de 2 a 15%, nos mais diversos centros de queimados. O objetivo é revisar padronização das etapas cirúrgicas na fase aguda de desbridamento (primeiros 15 dias) pela comparação de dosagem de creatofosfoquinase, hidratação venosa e fotografias para a aplicação de uma rotina de etapas cirúrgicas. MÉTODOS: Trata-se de um estudo quantitativo, prospectivo, realizado em um hospital público da cidade de Fortaleza, CE, entre julho de 2013 a dezembro de 2015. A população foi composta por adultos jovens, entre 15 e 50 anos, de ambos os sexos, vítimas de queimaduras por choque elétrico, com lesão de terceiro grau, no mínimo muscular. RESULTADOS: Foram realizados 12 procedimentos cirúrgicos de amputações nos 15 pacientes do estudo (60%). Seis pacientes não sofreram amputação (40%). Um paciente sofreu três procedimentos de amputação no mesmo membro (pododáctilo, pé e coxa esquerdos) e outro, duas amputações em membros superiores distintos. CONCLUSÃO: O tratamento na fase aguda do choque elétrico deve incluir uma imediata e adequada reposição líquida venosa, associada com procedimentos cirúrgicos de desbridamentos e de amputações, o mais precoce possível, em etapas com intervalos de 48 a 72 horas.

INTRODUCTION: Electrical burns are responsible for 5% to 15% of cases of burn accidents. The majority is associated with workplace accidents, in which high-voltage injuries (>1,000 V) predominate in male patients. The mortality rates vary from 2% to 15% in different burn centers. The objective is to review the standardization of surgical steps in the acute phase of debridement (the first 15 days) by comparison of creatine phosphokinase levels, intravenous hydration, and photographs to implement routine surgical stages. METHODS: This was a quantitative, prospective study performed in a public hospital in the city of Fortaleza, Brazil, between July 2013 and December 2015. The population was composed of young adults between 15 and 50 years, of both sexes, who experienced electrical burns, with third-degree injuries and muscle involvement. RESULTS: Of the 15 patients in the study, 9 (60%) patients underwent 13 surgical amputation procedures and 6 (40%) patients did not undergo amputation. One patient underwent three amputation procedures in the same limb (toe, foot, and thigh) and another patient underwent two amputations in the upper limbs. CONCLUSION: Treatment in the acute phase of electrical shock must include immediate and adequate intravenous fluid replacement, along with surgical procedures of debridement and amputations, as early as possible, in steps with intervals of 48 to 72 hours.

Other people as means to a safe end: vicarious extinction blocks the return of learned fear.

Information about what is dangerous and safe in the environment is often transferred from other individuals through social forms of learning, such as observation. Past research has focused on the observational, or vicarious, acquisition of fears, but little is known about how social information can promote safety learning. To address this issue, we studied the effects of vicarious-extinction learning on the recovery of conditioned fear. Compared with a standard extinction procedure, vicarious extinction promoted better extinction and effectively blocked the return of previously learned fear. We confirmed that these effects could not be attributed to the presence of a learning model per se but were specifically driven by the model's experience of safety. Our results confirm that vicarious and direct emotional learning share important characteristics but that social-safety information promotes superior down-regulation of learned fear. These findings have implications for emotional learning, social-affective processes, and clinical practice.

Use of Tasers on people with mental illness A New Zealand database study.

BACKGROUND: In 2006-2007 New Zealand police deployed the Taser X26 electro-muscular incapacitation device for a twelve month trial across four police districts. Criteria for use of the Taser included "individuals in various states of mental health crisis". AIMS: To provide a descriptive analysis of the use of Tasers by the New Zealand police; to identify those incidents that involved people in mental health emergencies; and to compare this use with that which occurred in incidents of criminal arrest. METHOD: Descriptive analysis of the police Tactical Operations Database. RESULTS: Tasers were deployed on a total of 141 people in 124 events, and discharged 19 times. Of the 141 subjects, 30 (21%) involved people in mental health emergencies. Tasers were more than twice as likely to be discharged at mental health emergencies (8 of 30; 27%) than at criminal arrests (11 of 111; 10%) (X(2)=5.69; df=1; p=0.017). There were two incidents that involved a Taser being used as part of police response to in-patient mental health services and two incidents involving mental health community residential accommodation. CONCLUSIONS: Introduction of Tasers into policing in New Zealand will disproportionately impact on people with mental illness. Guidelines are needed to manage the future use of Tasers in mental health emergencies.

Conducted electrical weapon use by law enforcement: an evaluation of safety and injury.

INTRODUCTION: Controversy persists over the safety of conducted electrical weapons (CEWs), which are increasingly used by law enforcement agencies around the world. The purpose of this study was to examine injury patterns and physiologic conditions after CEW use under real life conditions. METHODS: A retrospective, cohort design was used, examining all CEW uses by one police department during a 6-year period. Data were collected from use-of-force forms and medical records and included conditions surrounding the use of force, medical histories, and data from emergency department evaluations and hospital admissions. RESULTS: Of 1,101 individuals subjected to (Taser M26 and X26) CEW use during the study period, 92.6% were male, the average body mass index was 26.2, and the age range was 9 to 73 years. Of the 886 (80.5%) with medical records, 46.8% had a psychiatric history and 72.9% had a substance abuse history. Emergency department (ED) evaluations occurred for 295 (26.8%) incidents. Of chief complaints, 41.7% were trauma related, 26.8% were for altered mental status, and 21.7% were for psychiatric evaluation. On presentation, 17.6% had a pulse >120, 1.7% were febrile, and 30.9% were altered; 1.4% met criteria associated with "excited delirium." When laboratory workup occurred, 70.6% had positive urine toxicology and 44.8% had positive alcohol levels. Troponin I was positive for one patient. Other laboratory abnormalities were rare, although extensive evaluations were infrequently done. Admission occurred in 24.4% of ED presentations (6.5% of all subjects); of discharge diagnoses for these patients, 59.7% were psychiatric, 22.2% were for unrelated trauma, 11.1% were for restraint-related trauma, and 6.9% were for unrelated medical diagnoses. No patients died. CONCLUSIONS: Significant injuries related to 6 years of law enforcement CEW use in one city were rare. A large percentage of those subjected to CEW use had diagnoses of substance abuse and/or psychiatric conditions. Most admissions after CEW use were unrelated to law enforcement restraint.

Proepileptic phenotype of SV2A-deficient mice is associated with reduced anticonvulsant efficacy of levetiracetam.

PURPOSE: Synaptic vesicle protein 2A (SV2A) constitutes a distinct binding site for an antiepileptic drug levetiracetam (Keppra). In the present study we characterized SV2A (+/-) heterozygous mice in several seizure models and tested if the anticonvulsant efficacy of levetiracetam is reduced in these mice. METHODS: Seizure thresholds of male SV2A (+/-) mice and their wild-type littermates were assessed in pilocarpine (i.p.), kainic acid (s.c.), pentylenetetrazol (i.v.), 6-Hz and maximal electroshock models. Kindling development was compared in amygdala and corneal kindling models. Ex vivo binding of levetiracetam to SV2A was also performed. RESULTS: Long-term electroencephalography (EEG) monitoring and behavioral observations of SV2A (+/-) mice did not reveal any spontaneous seizure activity. However, a reduced seizure threshold of SV2A (+/-) mice was observed in pilocarpine, kainic acid, pentylenetetrazol, and 6-Hz models, but not in maximal electroshock seizure model. Accelerated epileptogenesis development was also demonstrated in amygdala and corneal kindling models. Anticonvulsant efficacy of levetiracetam, defined as its ability to increase seizure threshold for 6 Hz electrical stimulation, was significantly reduced (approx. 50%) in the SV2A (+/-) mice, consistently with reduced binding to SV2A in these mice. In contrast, valproate produced the same anticonvulsant effect in both SV2A (+/+) and SV2A (+/-) mice. DISCUSSION: The present results evidence that SV2A is involved in mediation of the in vivo anticonvulsant activity of levetiracetam, in accordance with its previously proposed mechanism of action. Furthermore, the present data also indicate that even partial SV2A deficiency may lead to increased seizure vulnerability and accelerated epileptogenesis.

Shocks, personality, and anxiety in patients with an implantable defibrillator.

BACKGROUND: Studies have examined the relationship between shocks and anxiety, but little is known about the role of personality. Our aim was to examine the determinants of self-reported and interviewer-rated anxiety following implantable cardioverter defibrillator (ICD) implantation. METHODS: At baseline, that is, 0-3 weeks following ICD implantation, 308 ICD patients (82% men, mean age = 62.6 years) completed the DS14 (Type D personality) and ASI (anxiety sensitivity). The STAI (self-reported symptoms of state-anxiety) was assessed at baseline and follow-up, which was 2 months following ICD implantation. At this follow-up, the HAM-A interview (interviewer-rated anxiety) was assessed in a subsample (57%); the occurrence of ICD shocks was deduced from medical records. RESULTS: Analysis of covariance (ANCOVA) for repeated measures showed a significant interaction effect between time and shocks (F = 9.27, P = 0.003) with patients who had experienced a shock experiencing higher levels of self-reported anxiety at follow-up. The main effects of Type D personality (F = 33.42, P < 0.0001) and anxiety sensitivity (F = 66.31, P < 0.0001) were significant, indicating that these patients scored higher on self-reported anxiety across time points. Multivariable linear regression analyses yielded Type D personality (beta= 0.18, P = 0.021) and anxiety sensitivity (beta= 0.19, P = 0.016), but not shocks, as independent predictors of interviewer-rated anxiety. Covariates included gender, marital status, education, age, ICD indication, cardiac history, and comorbidity. CONCLUSIONS: Type D personality and anxiety sensitivity were independent predictors of both self-reported and interviewer-rated anxiety outcomes while ICD shocks were related to an increase in levels of self-reported anxiety only. Identification and support of ICD patients with Type D personality, increased anxiety sensitivity, or shocks is important.

Failure to condition to a cue is associated with sustained contextual fear.

The acquisition of a conditioned fear response is adaptive, as it enables the organism to appropriately respond to predictors of aversive events. Consequently, the absence of predictive cues can be used as a signal for safety. We aimed to study whether deficient fear conditioning might lead to maladaptive fear. Following previous work, we predicted that failure to learn the CS-US association would result in higher contextual fear, and that participants who failed to learn would tend to exhibit higher trait anxiety. Conditioning took place in a virtual environment with two contexts. In one of the two contexts, offset of a CS (light) was associated with a shock. Each participant visited two places (a house and an apartment) in each of 12 blocks. In one of these places shocks were administered at the offset of an 8-s period of lights on (CS). The results showed that half of the participants demonstrated differential shock expectancy between situations in the shock context in which the CS was present versus absent. This indicates that these participants learned the contingencies between the shocks and both the context and the light CS. In contrast, the other half of the participants learned only the association with the context. As predicted, learning the CS-US contingency resulted in reduced self-reported fear in the absence of the CS in the danger context compared to the presence of the CS. On the other hand, participants who failed to learn the association displayed a sustained aversive state throughout the duration of the danger context. Skin conductance measures confirmed this pattern of results. Fear-potentiated startle during the threat context compared to the safe context was significant in both groups, while startle was only potentiated during the CS in the threat context in the group that learned the CS association (trend-level significant). Finally, scores on Spielberger's self-report scale of trait anxiety tended to be higher in the group of participants who did not learn the CS-shock association in the danger context compared to participants who did. In conclusion, these results confirm higher contextual fear in participants who did not acquire a conditioned response to the cue in comparison to participants who did. Also, virtual reality contexts provide a useful tool for the study of context conditioning.

The development of cued versus contextual conditioning in a predictable and an unpredictable human fear conditioning preparation.

In this human fear conditioning study, the online development of conditioned US-expectancy to discrete cues and background contexts was measured in two groups. In the paired group (n=30), the CS was systematically followed by an aversive shock (US). In the unpaired group (n=30), CS and US were presented explicitly unpaired. Using US-expectancy ratings, we replicated the basic finding already illustrated in humans with startle modulation. In the paired group, the CS elicited more US-expectancy than the context, whereas in the unpaired group, the context elicited more US-expectancy than the CS. Interestingly, we also observed a trial-by-trial development of conditioning to the context in the unpaired group as indicated by a significant linear trend. This gradual development and the evidence for the role of US-expectancy in contextual fear add to the idea that cued and contextual fear rely on the same basic associative processes.

Psychological indices and phantom shocks in patients with ICD.

INTRODUCTION: Some patients with ICDs experience the sensation of a shock in the absence of true therapy (phantom shock). We hypothesize that phantom shocks may be a manifestation of anxiety, depression or PTSD. METHODS AND RESULTS: All patients over 18 years old with an ICD were eligible to enroll in the study. The first 75 subjects who agreed to participate were enrolled and divided into three groups: ICD patients with phantom shocks (n = 19); ICD patients who had actual shocks (n = 28) and ICD patients who had no shocks (n = 28). During a clinic visit a demographic questionnaire and three psychological rating scales were administered: the Spielberger State-Trait Anxiety Inventory (STAI); the Center for Epidemiologic Studies Depression Scale (CES-D) and the Posttraumatic Stress Checklist (PCL-C). No significant differences between groups were found in gender, race, age, history of MI or cardiac surgery status. Data analysis of the psychological indices using one-way ANOVA showed that the group with phantom shocks had more depression (CES-D p = 0.011) and more anxiety (STAI p = 0.010) than the other groups. Multiple comparisons of group means showed a greater percentage of clinically depressed patients in the phantom shock group than in the other groups. CONCLUSION: Patients with phantom shocks are more likely to be clinically depressed and have higher levels of anxiety than other ICD patients, regardless of history of actual shocks.

Effect of chronic imipramine or electroconvulsive shock on the expression of mGluR1a and mGluR5a immunoreactivity in rat brain hippocampus.

Previous studies showed that chronic electroconvulsive shock (ECS) or imipramine treatment induced a subsensitivity of group I metabotropic glutamate receptors (mGluR) in hippocampus. In the present study effects of antidepressant treatment on the expression of mGluR1a and mGluR5a, belonging to the group I mGluR, were investigated in rat brain hippocampus using immunohistochemical and Western blot methods, respectively. Male Wistar rats were treated singly or chronically for 21 days with imipramine, 10 mg/kg, twice daily; with ECS (90 mA, 50 Hz, 0.5 s) every second day; or with haloperidol, 1.2 mg/kg, once daily. Appropriate controls were injected with saline. Rats were sacrificed 24 h after the last treatment and their hippocampi were taken out for analysis. It was found that the mGluR1a-immunoreactivity expression increased significantly in Ammon's horn (CA) regions after chronic ECS. The most pronounced effect was observed in the CA3. No significant effects were found after single treatment or after haloperidol. The expression of mGluR5a increased significantly after chronic imipramine in the CA1 and after chronic ECS in the CA3 region. The results obtained indicate an influence of antidepressant treatment on group I mGluR. This increase in the receptor protein level may be a compensatory mechanism developing after chronic treatment.

Plasticity in hippocampal peptidergic systems induced by repeated electroconvulsive shock.

The regulated secretion of bioactive peptides requires the coordinated actions of a variety of gene products ranging from peptide precursors to post-translational processing enzymes and the cytosolic machinery involved in vesicle exocytosis. To evaluate the role of plasticity of peptidergic processes in the clinical response to electroconvulsive treatment, we monitored expression of a peptide (neuropeptide Y, NPY), a post-translational processing enzyme (peptidylglycine alpha-amidating monooxygenase, PAM) and a cytosolic component involved in peptide secretion and neurite extension (kalirin) in the hippocampus. Adult male rats were subjected to single or repeated electroconvulsive shock. In general, levels of NPY, PAM and kalirin mRNA showed similar transient increases after acute and repeated electroconvulsive shock. In contrast, repeated, but not acute, electroconvulsive shock brought about widespread changes in protein expression. Increased amounts of NPY and PAM accumulated in mossy fibers, and dentate granule cell dendrites contained increased amounts of NPY, PAM and kalirin. CA1 pyramidal neurons expressed increased amounts of PAM and kalirin, with an accumulation of both proteins in their dendrites. Scattered interneurons contained increased levels of NPY and PAM after acute and repeated shocks. However, scattered interneurons contained increased levels of kalirin only after repeated shocks. The distinctly different effects of repeated vs. acute electroconvulsive shock support an important role for peptidergic plasticity in the therapeutic effects observed following electroconvulsive treatment.

Effects of MK-801 and electroconvulsive shock on c-Fos expression in the rat hippocampus and frontal cortex.

Both the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and electroconvulsive shock (ECS) have been reported to induce c-Fos in rat brain. However, the former has anticonvulsant and psychotomimetic effects and the latter has proconvulsant and antipsychotic effects. To understand the mode of action of these treatments, the authors examined the effect of MK-801 and the interaction between MK-801 and ECS on the induction of c-Fos in the rat hippocampus and frontal cortex. MK-801 induced c-Fos in these brain regions in a nonlinear dose-response relationship. Maximum effect was achieved with 1-2 mg/kg of MK-801. The level of c-Fos paralleled animal hyperkinetic behavior, suggesting the role of c-Fos in the induced psychotomimetic behaviors. Pretreatment with MK-801 dose-dependently attenuated both the seizures and c-Fos expression by ECS. However, at an MK-801 pretreatment dose of 8 mg/kg, which completely blocked ECS-induced seizure, the induction of c-Fos was not completely blocked, suggesting non-NMDA mediated pathways of the induction of c-Fos by ECS.

2-Chloroadenosine, a preferential agonist of adenosine A1 receptors, enhances the anticonvulsant activity of carbamazepine and clonazepam in mice.

2-Chloroadenosine (0.25-1 mg/kg) significantly raised the threshold for electroconvulsions in mice. This preferential adenosine A(1) receptor agonist (at 0.125 mg/kg) significantly potentiated the protective activity of carbamazepine against maximal electroshock-induced seizures in mice. 2-Chloroadenosine (1 mg/kg) showed also anticonvulsive efficacy against pentylenetetrazol-evoked seizures, raising the CD(50) value for pentylenetetrazol from 77.2 to 93.7 mg/kg. The drug (at 0.5 mg/kg) significantly enhanced the protective action of clonazepam in this test, decreasing its ED(50) value from 0.033 to 0.011 mg/kg. Moreover, aminophylline, a non-selective adenosine receptor antagonist (5 mg/kg), and 8-cyclopentyl-1,3-dimethylxanthine (8-CPX), a selective A(1) adenosine receptor antagonist (5 mg/kg) reversed the 2-chloroadenosine (0.125 mg/kg)-induced enhancement of the protective activity of carbamazepine and clonazepam. 2-Chloroadenosine administered alone or combined with antiepileptic drugs, caused neither motor nor long-term memory impairment. Finally, the adenosine A(1) agonist did not change the free plasma concentration of antiepileptics, so a pharmacokinetic factor is not probable. Summing up, 2-chloroadenosine potentiated the protective activity of both carbamazepine and clonazepam, which seems to be associated with the enhancement of purinergic transmission mediated through adenosine A(1) receptors.

Altered activities of rat brain metabolic enzymes in electroconvulsive shock-induced seizures.

PURPOSE: Electroconvulsive shock (ECS) induces generalized seizure activity and provides an excellent experimental model for studying the effects of global electrical stimulation on various biochemical parameters. The aim of this work was to investigate the influence of a single or repeated ECS-induced seizures on rat brain metabolism. METHODS: Experiments were carried out on female Hannover-Wistar rats divided into four groups: (a) the control group, which was intact; (b) the 1ECS group, which was killed 2 h after single ECS; (c) the 5ECS group with 24 h rest, which was killed 24 h after the fifth daily ECS; and (d) the 10ECS group with 48 h rest, which was given ECS every 48 h and killed 24 h after the tenth ECS. Activities of glutamate dehydrogenase (GLDH), aspartate-aminotransferase (AST), alanine-aminotransferase (ALT), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and creatine kinase (CK) in the frontal cortex, cerebellum, hippocampus, and pons/medulla regions were determined. RESULTS: Increased AST, ALP, LDH, and CK activities were detected in all examined regions of the 1ECS and 5ECS groups. ALT activity was increased in both these groups, except in the hippocampus of the 5ECS group, where increased GGT activity was detected. In the hippocampus of 1ECS group, GLDH activity was decreased. Increased hippocampal AST and cortical CK activities, together with increased LDH activities in the cortex, cerebellum, and pons/medulla, were found. CONCLUSIONS: ECS treatment induces region-specific changes in metabolic activity. Neither a 24-h nor a 48-h rest period between two ECSs was sufficient for complete brain recovery, although most of the observed increased enzyme activities present in 1ECS and 5ECS were not present in 10ECS.