Ethanol's antiseizure efficacy is reduced by stress.

The ability of ethanol to antagonize the electrical precipitation of seizures in an incremental electroconvulsive shock paradigm was examined in groups of stressed and control mice. In stressed mice, the dose-response curve for ethanol's antiseizure efficacy was down-shifted and right-shifted relative to controls. These data may have clinical implications with respect to the interaction between stress, ethanol, and proneness to seizures.     

An epigenetic intervention interacts with genetic strain differences to modulate the stress-induced reduction of flurazepam's antiseizure efficacy in the mouse

Stress induces changes in the endogenous tone of both GABA and NMDA receptor-mediated neurotransmission in the intact mouse. Because changes are observed 24 h after stress, epigenetically-regulated alterations in gene expression may mediate these effects. In earlier work, sodium butyrate, a centrally-active histone deacetylase inhibitor that promotes gene expression, was shown to modulate the stress-induced reduction of the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist, to antagonize electrically-precipitated seizures. In the current study, we extended this work to look at sodium butyrate's modulatory effect on stress-induced changes in the antiseizure efficacy of flurazepam, a benzodiazepine receptor agonist, in two strains of mice. Epigenetic mechanisms, genetic strain differences and a standard stress interacted to alter flurazepam's antiseizure efficacy. These data support examination and development of epigenetic treatment strategies.     

Reduction of oxotremorine-induced analgesia after chronic but not acute restraint stress

The analgesic response (tail-flick latency) induced by the muscarinic cholinergic agonist oxotremorine was investigated in DBA/2 mice exposed to acute (a single 2 h session) and chronic (2 h once daily for 10 days) restraint stress. While a single exposure to stress did not influence the antinociceptive effects of the cholinergic agonist, chronic stress induced a clear-cut reduction of the oxotremorine-induced analgesia. The results show an involvement of cholinergic mechanisms in the adaptive modulation of nociception after chronic stressful events.     

Disruption of the stress response in wastewater treatment works effluent-exposed three-spined sticklebacks persists after translocation to an unpolluted environment

The hypothalamic–pituitary–adrenal/interrenal (HPA/I) axis plays a key role in responding to biotic and abiotic challenges in all vertebrates. Recent studies have shown that the apical response of the HPI axis to stressors in three-spined sticklebacks varies in proportion to the concentration of wastewater treatment works (WWTW) effluent to which the fish are exposed. This study was conducted to determine whether between-site variation in stress responsiveness among WWTW effluent-exposed sticklebacks is persistent or reversible. Sticklebacks from eight sites in north-west England affected by WWTW effluent and exhibiting between-population variation in HPI axis reactivity, were moved to a clean-water aquarium environment. After five months in the contaminant-free environment the responsiveness of these fish to a standardised stressor was determined, by measuring the rate of stress-induced cortisol release across the gills, and compared with the responses of fish newly sampled from the eight original capture sites. Inter-site differences in the reactivity of the HPI axis, proportional to the effluent concentration at each site, persisted among the translocated female sticklebacks for at least 5 months. In male fish however, the direct relationship between stress responsiveness and site-specific effluent was not evident 5 months post-translocation. These results support previous observations that the HPA/I axis, a non-reproductive endocrine system, is vulnerable to modulation by anthropogenic factors in fish and show for the first time that, in female fish at least, this modulation is not transient. The mechanisms underlying these observations, and the implications for the fitness and resilience of affected populations, requires investigation.     

Basis of the antiseizure action of phenytoin

• 1.1. Phenytoin has been used with much clinical success against all types of epileptiform seizures, except petit mal epilepsy, for over 50 years. Its mechanism of action, however, is still open to interpretation.
• 2.2. Several potential targets for phenytoin action have been identified within the central nervous system. These include the Na-K-ATPase, the GABA_A receptor complex, ionotropic glutamate receptors, calcium channels and sigma binding sites.
• 3.3. To date, though, the best evidence hinges on the inhibition of voltage-sensitive Na⁺ channels in the plasma membrane of neurons undergoing seizure activity. Quieter nerve cells are far less affected. Moreover, the fact that phenytoin also has important cardiac antiarrthymic effects and can inhibit Na⁺ influx into cardiac cells supports the idea that the primary target of phenytoin is, indeed, the Na⁺ channel.

     

Alpha 2-adrenoceptor-mediated coronary vasoconstriction persists after exhaustion of coronary dilator reserve

The effect of intracoronary administration of the selective alpha 2-adrenoceptor agonist B-HT 920 on coronary resistance was tested in 14 open-chest dogs before and after exhaustion of coronary dilator reserve. Under both conditions B-HT 920 increased coronary resistance to the same extent: 27 +/- 4% before and 32 +/- 3% after. Administration of B-HT 920 did not affect cardiovascular haemodynamics significantly, although after exhaustion of coronary dilator reserve left ventricular dP/dtmax decreased slightly by 12 +/- 5%. While efferent cardiac sympathetic discharge remained constant during control conditions it increased by 27 +/- 7% when B-HT 920 was administered into a stenotic coronary artery. We conclude that, in contrast to observations made on alpha 1-adrenoceptors, activation of coronary alpha 2-adrenoceptors may have deleterious effects after exhaustion of coronary dilator reserve because these receptors mediate a comparable constriction in well- and under-perfused coronary vessels. Thus they are unlikely to favour a redistribution of coronary blood flow into under-perfused myocardial regions. In addition, this unfavourable effect of B-HT 920 on coronary perfusion after coronary dilator reserve has been exhausted may be further exacerbated by an increase in efferent sympathetic discharge.     

Reduction of oxidative stress and modulation of autoantibodies against modified low-density lipoprotein after rosuvastatin therapy

AIMS: To examine the effect of 24 weeks' rosuvastatin treatment on oxidative stress and changes in immune response to oxidized low-density lipoprotein (LDL). METHODS: This was an open-label study of patients in Austria receiving 10 or 40 mg rosuvastatin daily alternately during 12 and 24 weeks. Circulating concentrations of antibodies to malondialdehyde-oxidized LDL (MDA-LDL), both IgG and IgM type, to copper-oxidized LDL (Cu-OxLDL-IgG), concentrations of oxidized LDL complexed to IgG (OxLDL-IC) and markers of oxidative stress and systemic inflammation in subjects with plasma LDL cholesterol concentrations between 130 mg dl-1 and 250 mg dl-1 and triglycerides相似文献   

Elevated aluminum persists in serum and tissues of rabbits after a six-hour infusion

The half-life of aluminum was estimated in selected tissues and fluids in a representative mammal, the rabbit. After a single iv aluminum infusion, half-lives were determined by serial killing of rabbits and aluminum quantitation in selected tissues and fluids by electrothermal atomic absorption spectroscopy. Tissues and fluids demonstrating a significant increase 4 hr after the 200 mumol/kg aluminum dose were the bile, kidney, liver, lung, serum, and spleen. Aluminum concentration did not significantly increase above control in the adrenal gland, bone, heart, muscle, testis, thyroid gland, or selected central nervous system regions. Biliary aluminum concentration returned to control within 12 hr after infusion. Estimated half-lives were 113 days in spleen, 74 days in liver, 44 days in lung, 42 days in serum, 4.2 days in kidney cortex, and 2.3 days in kidney medulla. The kidney also demonstrated another half-life greatly exceeding 100 days. The results demonstrate that aluminum persists in various tissues and fluids for different lengths of time. The calculated half-life of aluminum in these tissues is substantially longer than previously estimated half-lives based on serum aluminum determination. The persistence of aluminum in the liver and other tissues may serve as a source of continuous aluminum exposure for sensitive target organs such as the brain. These calculated half-lives establish the normal rate of aluminum elimination from tissues. Future studies could determine the influence of factors such as uremia or chelation therapy on the rate of aluminum elimination from storage sites as well as serum.     

Adenosine kinase inhibitors. 2. Synthesis, enzyme inhibition, and antiseizure activity of diaryltubercidin analogues

In the preceding article (Ugarkar et al. J. Med. Chem. 2000, 43) we reported that analogues of tubercidin are potent adenosine kinase (AK) inhibitors with antiseizure activity in the rat maximum electroshock (MES) model. Despite the discovery of several highly potent AK inhibitors (AKIs), e.g., 5'-amino-5'-deoxy- 5-iodotubercidin (1c) (IC50 = 0.0006 microM), no compounds were identified that exhibited a safety, efficacy, and side effect profile suitable for further development. In this article, we demonstrate that substitution of the tubercidin molecule with aromatic rings at the N4- and the C5-positions not only retains AKI potency but also improves in vivo activity. Synthesis of such compounds entailed transformation of 4-arylamino-5-iodotubercidin analogues to their corresponding 5-aryl derivatives via the Suzuki reaction. Alternatively, 4-N-arylamino-5-arylpyrrolo[2,3-d]pyrimidine bases were constructed and then glycosylated with appropriately protected alpha-ribofuranosyl chlorides using a phase-transfer catalyst. Several compounds exhibited potent activity in the rat MES seizure assay with ED50s < or = 2.0 mg/kg, ip, and showed relatively mild side effects.     

Reduction and sensitization of CRH neuron in rat hypothalamic and extrahypothalamic regions after chronic variable stress]

The hyperactivity of corticotropin-releasing hormone (CRH) neurons of the hypothalamic and/or extrahypothalamic regions is believed to contribute to the pathophysiology of major depression in an experimental animal chronically exposed to stress. In the present study, we examined the effects of chronic variable stress (CVS) and novel stress (footshock) on the CRH immunoreactivity in the hypothalamic paraventricular nucleus (PVN) and subdivision of PVN, and the extrahypothalamic bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala (CeA). We observed a significant reduction in CRH levels in the whole PVN, lateral parvocellular part of PVN, BNST and CeA 24 hours after the last stressor of CVS for 13 days. A novel stressor after CVS caused a marked increase in CRH levels in these four regions, followed a further reduction observed 24 hours later. Since the CVS-induced modulation of CRH levels are consistent with an alteration of tyrosine hydroxylase levels in the locus coeruleus, CRH-norepinephrine (NE) interaction in the terminal projection of forebrain NE systems, PVN, BNST and CeA where NE stimulates CRII release, might contribute to the bi-directional change in CRH. The CVS-induced bi-directional changes in CRH of PVN, BNST and CeA might play a role in the formation of the pathophysiology of major depressive disorders.     

Behavioural changes after different stress paradigms: prepulse inhibition increased after physical, but not emotional stress.

Physical (PS) and emotional (ES) stress have opposite long-term effects on open field behaviour, i.e., response to novelty. PS induced a long-term reduction in locomotor activity, while ES increased it. Additionally, sensitivity to rewarding stimuli was differentially affected by PS and ES. Whether the stress effects were specific for locomotor activity and reward or if these two stress treatments also have differential effects on other behaviours and brain functions is not known. In the present study, temperature regulation, sensory gating, learning capacity, locomotor activity and coping style were examined. PS consisted of a repeated mild foot shock treatment, which the ES animals witnessed. The tests pose additional challenges, to which all groups can respond differently depending on their previous experience. All tests were performed several days after the last stress treatment. Stress effects were specifically observed on locomotor activity, startle response and prepulse inhibition (PPI). The PS animals showed a potentiated inhibition of the startle when a prepulse (PPI) was used, although the initial startle response was already significantly lower than that of controls. ES animals did not differ from controls on PPI and startle. Additionally PS animals showed an initial decrease in activity, which turned into an increase when the tests continued. ES showed a constant increase in activity compared to controls. Stress effects on the tests for other brain processes and behaviour were not found. In addition, PS animals appeared to be less sensitive to the dopamine agonist apomorphine than control animal. In summary, physical and emotional stress induce differential changes on locomotor activity, startle response and PPI. Underlying mechanisms explaining the differences in stress effects are discussed, i.e., the role of the mesolimbic dopamine system and opioid systems.     

Changes in GABAergic function after chronic chemical stress.

1. The function of the gamma-aminobutyric acid (GABA)-ergic system in certain areas of the rat brain was investigated after chronic chemical stress (exposure to either vapours 30 sec/day for 20 days). 2. GABA concentration, [3h] -GABA uptake and the activity of the synthesis enzyme glutamate decarboxylase (GAD) were measured. 3. Chronic stress: (a) reduced neuronal uptake of [3H] -GABA in the frontal cerebral cortex (43%) and increased non-neuronal uptake of [3H] -GABA in the hypothalamus (62%); (b) enhanced the activity of GAD (under subsaturating substrate concentration) in the frontal cortex (91%) and in the corpus striatum (69%); (c) did not modify GABA endogenous concentration; (d) did not affect the animals' body weight increase or produce any signs of toxicity. 4. The stimulation of GAD and reduction of [3H] -GABA neuronal uptake in the frontal cortex might suggest the stimulation of GABAergic neurotransmission induced by chronic stress in this area of the rat brain. Together with previous findings the frontal cortex would appear to be a key area in chronic stress processing.     

Adenosine kinase inhibitors. 1. Synthesis, enzyme inhibition, and antiseizure activity of 5-iodotubercidin analogues

Adenosine receptor agonists produce a wide variety of therapeutically useful pharmacologies. However, to date they have failed to undergo successful clinical development due to dose-limiting side effects. Adenosine kinase inhibitors (AKIs) represent an alternative strategy, since AKIs may raise local adenosine levels in a more site- and event-specific manner and thereby elicit the desired pharmacology with a greater therapeutic window. Starting with 5-iodotubercidin (IC50 = 0.026 microM) and 5'-amino-5'-deoxyadenosine (IC50 = 0.17 microM) as lead inhibitors of the isolated human AK, a variety of pyrrolo[2,3-d]pyrimidine nucleoside analogues were designed and prepared by coupling 5-substituted-4-chloropyrrolo[2,3-d]pyrimidine bases with ribose analogues using the sodium salt-mediated glycosylation procedure. 5'-Amino-5'-deoxy analogues of 5-bromo- and 5-iodotubercidins were found to be the most potent AKIs reported to date (IC50S < 0.001 microM). Several potent AKIs were shown to exhibit anticonvulsant activity in the rat maximal electric shock (MES) induced seizure assay.     

Reduction of paracetamol metabolism after hepatic resection

INTRODUCTION: Paracetamol is often used as an analgesic following hepatic resection. During liver resection, vascular clamping is carried out to reduce blood loss. Previous studies have described transient postoperative rises in serum aminotransferase levels and decreases in prothrombin time and factor V levels. We have examined paracetamol metabolism after liver resection. METHODS: A prospective observational study was performed. All patients undergoing liver resection were included. Propacetamol was given every 6 h. Blood samples for plasma paracetamol concentrations were collected before, 1 h after the end of the first injection (T1), just before the second injection (6 h: T6), and just before the fifth injection (24 h: T24). RESULTS: 37 patients were recruited. 13 had hepatic vascular exclusion (HVE group), 13 had portal triad clamping (PTC group) and 11 had abdominal surgery with no liver resection (NLR group: control group). At T6, the plasma paracetamol concentration in the HVE group was significantly higher than in the NLR groups; at T24, this concentration was significantly higher in the HVE group than in the NLR and PTC groups, and was higher in the PTC group than in the NLR group. Prothrombin time and factor V was significantly lower in the HVE group than in the PTC group on the first postoperative day. DISCUSSION: This study showed a reduction of paracetamol metabolism in the liver resection group with significantly increased paracetamol levels. However, the maximum mean plasma concentration reached was not clinically or toxicologically significant. For these reasons, we cannot suggest that paracetamol should or should not be avoided in patients undergoing liver resection.     

Reduction of lipid peroxidation in different rat brain areas after cabergoline treatment.

Oxidative stress and mitochondrial damage are involved in Parkinson's disease (PD). Several drugs used for PD treatment have demonstrated antioxidant properties. To evaluate the antioxidant efficacy of cabergoline, an ergot derivative with a long plasma half-life, male Wistar rats were treated with vehicle or with 2.5 mg kg(-1)and 10 mg kg(-1)of the drug three, six, or 10 times at 48-h intervals. Cabergoline decreased basal lipid peroxide levels (LPO) in the hippocampus of rats given 10 mg kg(-1)10 times, and in the striatum of rats given the same dose six or 10 times. Spontaneous LPO was inhibited in the hippocampus of rats given 10 mg kg(-1)10 times. Stimulated LPO was decreased in the striatum of rats given 10 mg kg(-1)six times and in rats given 2.5 and 10 mg kg(-1)10 times. The ability of cabergoline to reduce LPO suggests its anti-lipoperoxidative properties.     

Synthesis and antiseizure evaluation of isoindoline-1,3-dione derivatives in mice

Epilepsy is the most common serious chronic noninfective neurological condition in the world. Despite the presence of various antiepileptic drugs in the market for epileptic patients, the necessity for development and discovery of novel antiepileptic drugs is felt. In fact, only 60–70 % of patients respond to the current drugs, and a high incidence of adverse effects is also observed. In the present study, a new series of phthalimide derivatives (compounds 3a–3m) were synthesized through the reaction of phthalic anhydride and various derivatives of aniline in toluene solvent (Reflux, 24 h). Antiepileptic activity of synthesized compounds (3a–3m) was investigated using two experimental models namely, maximal electroshock (MES) and pentylenetetrazole (PTZ), and the obtained results were compared with diazepam as reference drug. Neurotoxicity of compounds was also evaluated using rotarod model. Compound 3m with para methoxy substituent exhibited the anticonvulsant activity at 15.1 ± 1.53 (12.23–17.96) mg/kg dose in MES model compared to other derivatives. Unfortunately, none of the tested compounds rendered acceptable protection in subcutaneous PTZ model.     

Oxidative stress after sulfur mustard intoxication and its reduction by melatonin: efficacy of antioxidant therapy during serious intoxication

Sulfur mustard (SM) is an important chemical warfare agent. The mechanism of SM toxicity still has not been fully recognized. However, oxidative stress and following the damaging of macromolecules in the human body is considered one of the crucial steps in SM toxicity. Rats intoxicated with pure (i.e., distilled) SM were used as a model organism. The doses, 0 (control), 5, 20, and 80?mg/kg of body weight, were applied intradermally. A hormone with strong antioxidant potency, melatonin, was applied (25 and 50?mg/kg, subcutaneously) into the other group of rats exposed with the same doses of SM. Total plasma protein, ferric-reducing antioxidant power (FRAP), thiobarbituric-acid-reactive substances (TBARS), and plasma protein carbonyls were assayed in blood plasma. A significant decrease of total plasma proteins was found for control, and the lowest dose of SM was treated with melatonin. Melatonin was also able to enhance the production of low-molecular-weight antioxidants, as the SM-intoxicated rats had significantly (P?≤?0.01) increasing FRAP levels after intoxication with SM in doses of 20 and 80?mg/kg, when compared to the control treated with melatonin. Melatonin also decreased TBARS level, representing reduced lipid peroxidation (LPO). However, LPO seems to be of less importance for SM toxic impact. The more reliable parameter was the level of total plasma protein carbonyls. The carbonyl levels were significantly increased due to SM, and the carbonylation was slowed due to melatonin intake. In conclusion, melatonin seems to be a prospective compound in reducing SM toxicity impact in the rat.     

An in vivo evaluation of the antiseizure activity and acute neurotoxicity of agmatine

Agmatine, an endogenous cationic amine, exerts a wide range of biological effects, including modulation of glutamate-activated N-methyl-D-aspartate (NMDA) receptor function in the central nervous system (CNS). Since glutamate and the NMDA receptor have been implicated in the initiation and spread of seizure activity, the capacity of agmatine to inhibit seizure spread was evaluated in vivo. Orally administered agmatine (30 mg/kg) protected against maximal electroshock seizure (MES)-induced seizure spread in rats as rapidly as 15 min and for as long as 6 h after administration. Inhibition of MES-induced seizure spread was also observed when agmatine was administered intraperitoneally. Agmatine's antiseizure activity did not appear to be dose-dependent. An in vivo neurotoxicity screen indicated that agmatine was devoid of any acute neurological toxicity at the doses tested. These preliminary data suggest that agmatine has promising anticonvulsant activity.     

Inhibitory mechanisms of gabapentin, an antiseizure drug, on platelet aggregation

Gabapentin (Neurontin) is an analogue of gamma-aminobutyric acid (GABA) that is effective against partial seizures. Gabapentin has been reported to modulate serotonin release from platelets, but the effects of gabapentin on platelet activation have not been explored. In this study, gabapentin concentration-dependently (60-240 microM) inhibited platelet aggregation in washed platelets stimulated by collagen (1 microg mL(-1)), ADP (20 microM) and arachidonic acid (60 microM). Gabapentin (120 and 240 microM) also concentration-dependently inhibited collagen (1 microg mL(-1))-induced phosphoinositide breakdown, intracellular Ca(2+) mobilization, thromboxane A(2) formation, and p38 MAPK phosphorylation in human platelets. In conclusion, the most important findings of this study suggest that gabapentin inhibits platelet aggregation, at least in part, through the phospholipase C-inositol 1,4,5-trisphosphate-thromboxane A(2)-Ca(2+) pathway. Thus, it is possible that gabapentin treatment, alone or in combination with other antiplatelet drugs, may induce or potentiate inhibition of platelet aggregation, which may affect haemostasis in-vivo.