Inhibition of Different Pain Pathways Attenuates Oxidative Stress in Glial Cells: A Mechanistic View on Neuroprotective Effects of Different Types of Analgesics.

Neuropathic pain results from trauma or diseases affecting the central nervous system (CNS) and triggers a cascade of events in different CNS parts that eventually lead to oxidative injury. This study was aimed to investigate the protective effects of some selected analgesics in neuropathic pain-induced oxidative damage in the isolated glial cells of the rat brain. In this experiment, rats were randomly divided into 5 main groups. Rats in group 1 received no medication, whereas rats in groups 2 to 5 received ASA (aspirin), celecoxib, morphine, and etanercept daily, respectively. Each main group divides into 3 subgroups: normal, sham, and neuropathic pain model rats. The glial cells of the rat brain were isolated at different time points. Our results demonstrate that neuropathic pain induces ROS generation as the major cause of mitochondrial membrane potential collapse (%∆Ψm) and lysosomal membrane rupture, which result in oxidative damage of the glial cells. In addition, ASA and celecoxib had protective effects on the neuropathic pain-induced oxidative stress markers, including ROS production, mitochondrial membrane potential collapse, and lysosomal membrane leakiness at different time points. Furthermore, the oxidative damage markers were significantly decreased by morphine and etanercept in all investigated days. Since arachidonic acid metabolites and TNF-α are produced during neuropathic pain and inflammation, it can be concluded that the inhibition of the substances production or inhibition of the ligands binding with their receptors would help to decrease the destructive effects of neuropathic pain in the glial cells of rat brain.

Evaluation of Anxiolytic, Sedative-hypnotic and Amnesic Effects of Novel 2-phenoxy phenyl-1,3,4-oxadizole Derivatives Using Experimental Models.

Benzodiazepines (BZDs) are widely used in clinical practice as anxiolytics, hypnotics, anticonvulsants and muscle relaxants. However, they have some undesired effects including memory problems. In continuing our research on novel benzodiazepine ligands, we are looking for ligands with less adverse effects. Previously, 4 novel derivatives of 2-phenoxy phenyl-1,3,4-oxadiazole were synthesized as agonists of BZD receptors. In this study, the pharmacological effects of novel compounds were evaluated. Pentobarbital induced loss of righting reflex, elevated plus maze, open-field locomotor activity and passive avoidance test were used to evaluate the sedative-hypnotic, anxiolytic and amnesic effects of compounds respectively. The results revealed that the novel compounds with NH2, SH and SCH3 substituents at the 2-position of the oxadiazole ring increase righting reflex time significantly. In the elevated plus maze test none of the derivatives increased open arm duration and open arm entry indicating no anxiolytic properties. Moreover, the novel compounds didn't influence step-down latencies in the mice. The fact that the hypnotic activity of these compounds were significantly reduced by flumazenil, confirmed that this effect is mediated by BZD receptors.

Effect of essential oils, hydrating agents, and ethanol on hair removal efficiency of thioglycolates.

BACKGROUND: The required time for hair removal by chemical depilatories has always been a concern and depends on different parameters including permeation into the hair shaft. OBJECTIVES: In an attempt to improve this process, it was decided here to investigate the possibility of decreasing depilation time of thioglycolates, widely used depilatories, using penetration enhancers. METHODS: Urea, sodium dodecyl sulfate, dimethylsulfoxide (DMSO), ethanol (75 and 96%), NaCl, and peppermint and orange oils were used as penetration enhancers, and their effect on depilatory time of thioglycolates, represented as tear resistance time (TRT) of hair shaft under a constant tensile stress, was studied. The effects of temperature and hydration on TRT were also investigated. RESULTS: Results showed that ethanol (75%), DMSO, and peppermint oil (ethanolic solution) were able to significantly reduce TRT up to two times from about 6 to 3.5 min. Other enhancers were not able to change TRT. Results also revealed that increase in temperature from 20 to 37 °C reduces TRT by about 4 times. Hydration in boiling water also reduced TRT significantly about 1.5 times. CONCLUSIONS: Present results show that it is possible to reduce depilation time by penetration enhancers. Such improvement can increase users' compliance and might provide other advantages like decreased skin irritation.

Design, Synthesis and Pharmacological Evaluation of Novel 2-[2-(2-Chlorophenoxy) phenyl]-1,3,4-oxadiazole Derivatives as Benzodiazepine Receptor Agonists.

New derivatives of 2-[2-(2-Chlorophenoxy)phenyl]-1,3,4-oxadiazole as candidates for agonistic effect on benzodiazepine receptors were synthesized. Conformational analysis and superimposition of energy minima conformers of the novel compounds on estazolam, a known benzodiazepine agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. In pharmacological evaluation, anticonvulsant activity of the compounds determined by pentylenetetrazole-induced lethal convulsion and maximal electroshock tests. The results showed that the introduction of an amino substituent in position 5 of 1,3,4- oxadiazole ring generates compound 6 that has a considerable effect. Compound 8 with a hydroxyl substituent on position 5 of 1,3,4- oxadiazole ring showed a relatively mild anticonvulsant activity, which was significantly weaker than that of diazepam and compound 6. Anticonvulsant effects of active compounds were antagonized by flumazenil, an antagonist of benzodiazepine receptors, indicating the involvement of benzodiazepine receptors in these effects.

Optimization of the simultaneous determination of imatinib and its major metabolite, CGP74588, in human plasma by a rapid HPLC method using D-optimal experimental design.

A simple, rapid and specific HPLC method has been developed and validated for the simultaneous determination of imatinib, a tyrosine kinase inhibitor, and its major metabolite, CGP74588, in human plasma. The optimization of the HPLC procedure involved several variables, of which the influences of each was studied. After a series of preliminary-screening experiments, the composition of the mobile phase and the pH of the added buffer solution were set as the investigated variables, while the resolution between imatinib and CGP74588 peaks, the retention time and the imatinib peak width were chosen as the dependent variables. Applying D-optimal design, the optimal chromatographic conditions for the separation were defined. The method proved to show good agreement between the experimental data and predictive values throughout the studied parameter range. The optimum assay conditions were achieved with a Chromolith™ Performance RP-8e 100 mm × 4.6 mm column and a mixture of methanol/acetonitrile/triethylamine/diammonium hydrogen phosphate (pH 6.25, 0.048 mol L(-1)) (20:20:0.1:59.9, v/v/v/v) as the mobile phase at a flow rate of 2 mL min(-1) and detection wavelength of 261 nm. The run time was less than 5 min, which is much shorter than the previously optimized methods. The optimized method was validated according to FDA guidelines to confirm specificity, linearity, accuracy and precision.

Novel VKORC1 mutations associated with warfarin sensitivity.

UNLABELLED: Warfarin is widely used anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders and exerts its anticoagulant effect by inhibiting the vitamin K epoxide reductase. To determine the impact of genetic variants of the vitamin K epoxide reductase complex subunit 1 gene (VKORC1) on the anticoagulant response to warfarin, polymorphisms in exon 1, exon 3, and 3'-untranslated region (3' UTR) were assessed. RESULTS: Sixty patients (34 males and 26 females) with stable INR (2-3) were selected from cardiology and anticoagulant clinic. Three VKORC1 frameshift mutations were detected. The first frameshift mutation was nucleotide deletion (91delCC) in exon 3 (1 patient). The second variation was nucleotide addition (51addCT) in exon 3 (2 patients). All the 3 patients reported bleeding during warfarin use, while no other bleeding was reported during the study period. Warfarin maintenance dose was significantly different between 3 patients with mutations and patients without mutations. The use of a fixed-dose warfarin for all patients and in range INR may not be sufficient for warfarin monitoring. Many factors including unknown ones may also play an important role in highly variable response among patients. Our data for the first time, suggested a new possible call for screening to reduce the risk of bleeding and guide for dosing.

Development and optimization of a sublingual tablet formulation for physostigmine salicylate.

This study is aimed to design and optimize a sublingual tablet formulation of physostigmine salicylate, an effective drug in Alzheimer's disease and nerve gas poisoning, by means of the D-optimal experimental design methodology. Polyvinyl pyrrolidone, lactose, starch 1500 and sodium starch glycolate were used in the formulations as independent variables. Tablets were prepared by the direct compression method and evaluated for their physical properties (tablet hardness, disintegration time and friability), which were regarded as responses in a D-optimal design. Due to the significance of the special cubic model for data fitted, compared to other models, it was used to examine the obtained results. Response surface plots were plotted to study the tablet properties and the optimized overlay plot was generated based on the results and targets considered for the responses. After verification of the optimum checkpoint formulations, an optimized formulation was chosen due to its desirable physical properties and closely observed and predicted values. Drug assay, content uniformity of the dosage unit, drug dissolution and accelerated stability studies were done on the optimum formulation as further experiments. All the obtained results complied with the requirements of a sublingual tablet formulation.

Synthesis of a quaternary bis derivative of imipramine as a novel compound with potential anti-enuretic effect.

OBJECTIVES: Imipramine has been used for over four decades (early reports in 1960s) for the treatment of nocturnal enuresis, although the reason for its effect is not clear. Imipramine is a tertiary amine, which may act both in the periphery and/or pass through the blood-brain barrier (BBB) in unionized form and exhibit a central effect. Since imipramine has anti-cholinergic properties, some believe it may exert its anti-enuretic effect by affecting peripheral cholinergic receptors, i.e. its anti-enuretic effect may be due to peripheral anti-cholinergic properties, whereas others think it can pass through the BBB and interact with central nervous system (CNS) receptors. If the anti-enuretic effect of imipramine is due to its peripheral anti-cholinergic effects, its entrance into the CNS is unnecessary. Therefore, the synthesis of a form of imipramine that can exhibit peripheral anti-cholinergic effects but does not have CNS adverse effects would have a safer drug profile in this case. On the other hand, if the anti-enuretic effect of imipramine is primarily due to its action on the CNS, a form of imipramine that cannot pass through the BBB has no effect on nocturnal enuresis treatment and thus may help to clarify the mechanism of action of imipramine in nocturnal enuresis treatment. METHODS: This article describes the synthesis and evaluation of the anti-cholinergic effect of a new bis derivative of imipramine, which contains two imipramine units in its structure. KEY FINDINGS: The compound exhibited anti-cholinergic activity comparable with that of imipramine on isolated guinea pig ileum. CONCLUSIONS: Being a quaternary ammonium, this compound is not expected to be able to cross the BBB and thus would cause fewer CNS side effects.

Radioactivity concentrations in sediments on the coast of the Iranian province of Khuzestan in the Northern Persian Gulf.

Gamma-ray spectrometric analyses were performed on sediment samples from the coast of Khuzestan province (south west of Iran, neighbor to Iraq and Kuwait) to study the concentration of natural as well as man-made radioactive sources. The coast of Khuzestan, which extends for approximately 400 km is mainly soft areas of mud flats within different ecosystems including river mouth, estuaries, creeps, and small bays. Suspended material from the Iranian rivers including Arvand (Karun), Bahmanshir, Jarrahi, and Zohreh has settled to form these extensive soft areas. Eighty three samples were taken at different points along the coast in undisturbed areas at intervals of about 5 km since Fall 2005 to Winter 2006. Collection was carried out during low-tide, where it was possible to collect sediments from the wet region that was covered by sea water during the high tide. At each of the sample sites, a sampling area of about 1 m(2) was considered. All samples were of a muddy nature, and were left to dry in open air before drying in the oven at 105 degrees C for 2-3 days to remove all water content. The average activity concentration of the radionuclides (226)Ra (30 Bq/Kg), (232)Th (11 Bq/kg), (238)U (18 Bq/kg), and (137)Cs (2.6 Bq/kg) along the shore of Khuzestan reaches are much less than the values commonly assigned as the world average. Nevertheless in case of (40)K which is a long lived naturally occurring radionuclide, the result (481 Bq/kg) was higher than the world average which could be due to a large Kuwaiti oil spill and also fallout and deposition of tremendous amount of fly ashes which resulted from ignited Kuwaiti oil fields during the 2nd Persian Gulf war (1990-91). For man-made (137)Cs and naturally occurring (232)Th, the western and eastern parts of Khuzestan shore showed higher concentrations than the middle part (Khooriat or creeps). For the long lived naturally occurring radionuclide (40)K and Gulf war (238)U (anti armor shells), there were no significant differences (P < 0.05) among the three regions.

Evaluation of interactions between cannabinoid compounds and diazepam in electroshock-induced seizure model in mice.

Several studies have shown that cannabinoids have anticonvulsant properties that are mediated through activation of the cannabinoid CB1 receptors. In addition, endogenous cannabinoid compounds (endocannabinoids) regulate synaptic transmission and dampen seizure activity via activation of the same receptors. The aim of this study was to evaluate the possible interactions between antiepileptic effects of cannabinoid compounds and diazepam using electroshock-induced model of seizure in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, fixed current intensity 35 mA, stimulus duration 0.2 s) and tonic hindlimb extension was taken as the endpoint. All experiments were performed on groups of ten mice and the number of animals who did not display seizure reported as percent protection. Intraperitoneal (i.p.) administration of diazepam (0.25-2 mg/kg) and CB1 receptor agonist WIN55212-2 (0.5-4 mg/kg) dose dependently produced an antiepileptic effect evaluated in terms of increased percentage of protection against electroshock-induced seizure. Logistic regression analysis indicated synergistic interactions in anticonvulsant action after co-administration of diazepam and WIN55212-2 in fixed-ratio combination of 3:1 (diazepam:WIN55212-2), while an additive effect was resulted after co-administration of 1:1 and 1:3 fixed-ratio combinations. Administration of various doses of the endocannabinoid reuptake inhibitor, AM404, did not produce any effect on electroshock-induced seizure. Moreover, co-administration of AM404 and diazepam did not produce significant interaction in antiepileptic properties of these compounds. Administration of the fatty acid amide hydrolase inhibitor, URB597, produced significant antiepileptic effect. Co-administration of URB597 and diazepam led to an antagonistic interaction in protection against shock-induced seizure. Co-administration of different doses of the cannabinoid CB1 receptor antagonist, AM251 did not alter the antiepileptic effect of diazepam in the electroshock-induced seizure test. These results demonstrate that endocannabinoid system participates in the modulation of seizure and combination of small doses of exogenous CB1 receptor agonists with diazepam may have effective consequences in seizure control. Furthermore, inhibiting the endocannabinoid degradation could be more efficacious in modulating seizure than preventing their uptake. This study also suggests that the effects of cannabinoids on epilepsy depend on the relative cannabinoid responsiveness of GABAergic and glutamatergic neurotransmission. While, the antiepileptic effects of cannabinoid compounds are likely by affecting excitatory glutamate neurotransmission, the antagonistic interaction between cannabinoid compounds and diazepam to protect seizure is due to the cannabinoid action on inhibitory GABAergic system.

Errors in preparation and administration of intravenous medications in the intensive care unit of a teaching hospital: an observational study.

OBJECTIVE: To determine the frequency of medication errors that occurred during the preparation and administration of IV drugs in an intensive care unit. SETTING: The study was conducted in a 12-bed intensive care unit of one of the largest teaching hospitals in Tehran. DESIGN: Data were collected over 16 randomly selected days at different medication round times, between July and September 2006. A trained observer accompanied nurses during intravenous (IV) drug rounds. Medication errors were recorded during the observation times of IV drug administration and preparation. Drugs with the highest rate of use in the intensive care unit (ICU) were selected. Details of the process of preparation and administration of the selected drugs were compared to an informed checklist which was prepared using reference books and manufacturers' instructions. RESULTS: We observed a total of 524 preparations and administrations. The calculated number of opportunities for error was 4040. The number of errors identified were 380/4040 (9.4%). Of those, 33.6% were related to the preparation process and 66.4% to the administration process. The most common type of error (43.4%) was the injection of bolus doses faster than the recommended rate. Amikacin was involved in the highest rate of error (11%) among all the selected medications. It was found that the IV rounds conducted at 9:a.m. had the highest rate of error (19.8%). No significant correlation was found between the rate of error and the nurses' age, sex, qualification, work experience, marital status, and type of working contract (permanent or temporary). CONCLUSIONS: Since our system is devoid of a well-organized reporting system, errors are not detected and consequently not prevented. Administrators need to take the initiative of developing systems that guarantee safe medication administration.

Preparation, optimization, and characterization of topotecan loaded PEGylated liposomes using factorial design.

This study reports the development of liposomal system for a potent antitumor drug, topotecan. To achieve this goal conventional and PEGylated liposomes were prepared according to a factorial design by hydration method followed by extrusion. Parameters such as type of lipid, percentage of cholesterol, percentage of phosphatidylglycerols, percentage of polyethylene glycol (PEG)-lipids, and drug to lipid molar ratio were considered as important factors for the optimizing the entrapment and retention of topotecan inside the liposomes. The size and zeta-potential of the PEGylated and conventional liposomes were measured by particle size analyzer and zeta-potentiometer, respectively. The stability and release characteristics of PEGylated liposome loaded topotecan were compared with conventional liposomes and free topotecan. The optimized PEGylated [distearoyl phosphatidylcholine (DSPC)/cholesterol/ distearoyl phosphatidylglycerol (DSPG)/ distearoyl phosphatidylethanolamine-PEG(2000) (DSPE-PEG(2000)); 7:7:3:1.28] and related conventional [DSPC/cholesterol/DSPG; 7:7:3] liposomes showed a narrow size distribution with a polydipersity index of 0.15 and 0.10, an average diameter of 103.0 +/- 13.1 and 95.2 +/- 11.10 nm, and with drug loading of 11.44 and 6.21%, respectively. Zeta-potential was -10 +/- 2.3 and -22 +/- 2.8 mV for PEGylated and conventional liposomes, respectively. The results of stability evaluation showed that the lactone ring of topotecan was notably preserved upon liposome encapsulation. PEGylated liposomes containing topotecan showed a significant decrease (P < 0.001) in release rate in comparison with conventional leptosomes. These results indicate the suitability of PEGylated liposomes in controlling topotecan release. The prepared liposomes (especially PEGylated liposomes) as those described here may be clinically useful to stabilize and deliver topotecan for the treatment of cancer.

Effects of folic acid on preschool children's appetite: randomized triple-blind clinical trial.

BACKGROUND: In recent years some Iranian pediatricians have used folic acid empirically as an appetite-enhancing drug in poor-appetite, low-weight children. Many parents have expressed their satisfaction with this treatment but until now no study has been done to confirm or exclude folic acid as an appetite enhancer. METHODS: In order to determine if complementary folic acid has any effect on preschool children's appetite, 61 3-5-year-old children (27 girls and 34 boys) whose weight/age and weight/height ratios were below the 25 centile and whose parents regarded them as having poor appetite were randomly assigned to receive either folic acid (1 mg/day) or placebo for 20 days. The primary outcome measures were any appetite changes during and 1 month after the end of the intervention, measured by means of a questionnaire completed by parents on the 20th and 60th days. Secondary measures were mean weight gain on the 30th and 60th days. RESULTS: Children who received folic supplement had a significantly better appetite on the 20th day than those who received placebo (mean difference of appetite score: 1.7; 95% confidence interval: 0.1-3.4; P = 0.04) and significantly more children receiving folic acid were reported to have increased appetite than the placebo group (P = 0.03). But 40 days after the end of the intervention there was no difference between the two groups. Weight gain did not significantly differ between groups. CONCLUSIONS: Although folic acid appears to improve preschool children's appetite, further study is necessary to determine whether it has any effect on growth as an adjunctive to management protocols of low appetite for undernourished children.

Sex differences and role of gonadal hormones on glutamate level in the nucleus accumbens in morphine tolerant rats: a microdialysis study.

Sex differences are observed in the development of tolerance to the antinociceptive effect of opioid drugs such as morphine, but the precise underlying mechanism remains unclear. There are evidences about the interaction between gonadal hormones and neuromodulatory systems including opioidergic and glutamatergic systems. We examined the sex differences and the role of gonadal hormones on the glutamate level in the nucleus accumbens in morphine tolerant rats using in vivo microdialysis. A microdialysis probe was implanted into the left nucleus accumbens core of rats and CSF (cerebrospinal fluid) dialysates were collected. The concentration of glutamate was measured by high-performance liquid chromatography with a fluorescence detector. The results showed that after chronic morphine administration, tolerance to antinociceptive effects of morphine was significantly greater in male rats (P<0.001). Sex differences in tolerance to morphine disappeared with gonadectomy of animals. There was also a significant sex difference in the glutamate level in the nucleus accumbens of morphine tolerant rats (P<0.001), ovariectomy of female rats decreased the glutamate level significantly (P<0.001), while gonadectomy did not change the glutamate level in males significantly. In conclusion, these experiments demonstrate that the excitatory amino acid release in the nucleus accumbens may be modulated by an estrogen-sensitive mechanism and play a role in the morphine analgesia and tolerance.

Antinociceptive effect of spinally administered cannabinergic and 2-adrenoceptor drugs on the formalin test in rat: possible interactions.

The current experiments were designed to study the antinociceptive effects of intrathecal (i.t.) administration of cannabinoid CB1 receptor and 2-adrenoceptor drugs in the nociceptive processing and also their receptor interactions. Different doses of a cannabinoid receptor agonist, CP 55,940, and an 2-adrenoceptor agonist, clonidine induced a dose-dependent antinociception in both phases of the formalin test.CP 55,940-induced antinociception was reduced by pretreatment of a selective cannabinoid CB1 receptor antagonist, SR 141716A, but not by pretreatment with an 2-adrenoceptor antagonist, yohimbine in both phases of the test. However, yohimbine and SR 141716A attenuated the antinociception induced by clonidine in the early phase but not in the late phase of the test. While SR 141716A by itself did not influence pain behaviour, the reversal effect of clonidine by SR 141716A indicate that clonidine stimulate the release of endocannabinoid(s). In conclusion, our findings may suggest that: (1) spinal cannabinoid and 2-adrenoceptor systems are able to induce antinociception in both phases of formalin test, and (2) the cannabinoid system may be involved in the antinociception induced by adrenoceptors in the early phase.

Design and synthesis of new 2-substituted-5-(2-benzylthiophenyl)-1,3,4-oxadiazoles as benzodiazepine receptor agonists.

A series of new 2-substituted-5-(2-benzylthiophenyl)-1,3,4-oxadiazoles was designed and synthesized as anticonvulsant agents. Conformational analysis and superimposition of energy minima conformers of the designed molecules on estazolam, a known benzodiazepine receptor agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. Electroshock and pentylenetetrazole-induced lethal convulsion tests showed that the introduction of an amino group in position 2 of 1,3,4-oxadiazole ring and a fluoro substituent at para position of benzylthio moiety had the best anticonvulsant activity. It seems this effect is mediated through benzodiazepine receptors mechanism.

Interaction between gamma-aminobutyric acid GABAB and cannabinoid CB1 receptors in spinal pain pathways in rat.

Antinociceptive effects of cannabinoids are mediated, in part, at the spinal level. Cannabinoid CB1 receptors are co-localized with dorsal horn interneurons containing gamma-aminobutyric acid (GABA). In this study, we investigated the interaction between intrathecally administered cannabinoid and GABA(B) receptor agonists and antagonists in the modulation of formalin-induced pain at the spinal level. Intrathecal pretreatment of rats with a cannabinoid receptor antagonist [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide] (SR141716A, 30 microg) decreased the analgesic effect of the intrathecal administration of the GABA(B) receptor agonist, baclofen (0.125 microg and 0.25 microg). Intrathecal administration of the GABA(B) receptor antagonist, saclofen (30 microg), 10 min before administration of the cannabinoid receptor agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxy-propyl)-cyclohexano (CP55940), did not affect the analgesia produced by the cannabinoid receptor agonist. Our results confirm that intrathecal administration of cannabinoid and GABA(B) receptor agonists have analgesic effects and that spinal antinociceptive effects of GABA(B) receptor agonists are likely through endocannabinoid modulation.

Adrenoceptor mechanisms underlying imipramine-induced memory deficits in rats.

The post-training administration of tricyclic antidepressant imipramine impairs memory consolidation in the passive avoidance task. The present study investigated the effects of intrahippocampal (i.h.) injection of adrenoceptor agents on imipramine-induced (2-8 microg/rat) amnesia. The administration of the alpha1-adrenoceptor agonist phenylephrine (0.05 microg/rat) and the alpha1-adrenceptor antagonist prazosin (0.5 microg/rat) did not alter the effect of imipramine. The lower doses of phenylephrine (0.005 and 0.015 microg/rat) impaired, while the higher dose of the drug (0.025 and 0.05 microg/rat) improved retention. The effect of phenylephrine was not altered by prazosin (0.5 and 1 microg/rat) pretreatment, although prazosin alone decreased retention latencies. The alpha2-adrenoceptor antagonist yohimbine (0.5 and 1 microg/rat) decreased the response induced by imipramine. However, the alpha2-adrenoceptor agonist clonidine (0.08 microg/rat) did not alter the effect of the drug. Clonidine (0.15 and 0.3 microg/rat) by itself decreased, while yohimbine (1 and 2 microg/rat) increased retention latencies. Yohimbine pretreatment attenuated the effect of clonidine. It is concluded that alpha2-adrenoceptor mechanism(s) may be involved in imipramine-induced impairment of memory.

Design and synthesis of 4H-3-(2-phenoxy)phenyl-1,2,4-triazole derivatives as benzodiazepine receptor agonists.

A series of new 5-substituted analogues of 4H-3-(2-phenoxy)phenyl-1,2,4-triazole and its chlorinated derivatives was designed and prepared. Conformational analysis and superimposition of energy minima conformers of the compounds on estazolam, a known benzodiazepine receptor agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. Rotarod and pentylenetetrazole-induced lethal convulsion tests showed that the introduction of an amino group in position 5 of 1,2,4-triazole ring especially in chlorinated derivatives had the best effect which was comparable with diazepam.

The role of alpha-adrenoceptors in the amnestic effect of intracerebroventricular dexamethasone.

Corticosteroids exert dual enhancing or impairing effects on cognitive functions. While their memory-enhancing effects have been well investigated, the mechanisms involved in their amnestic effects are not completely understood. Thus, we examined the role of alpha-adrenoceptors on dexamethasone-induced amnesia using step-through passive avoidance test in rat. Intracerebroventricular (i.c.v.) injection of dexamethasone (5 and 10 microg per rat) decreased the retention latencies. Likewise, intraperitoneal administration of alpha(2)-adrenoceptor agonist clonidine (0.1-0.3 mg kg(-1)) but not alpha(2)-adrenoceptor antagonist yohimbine (0.5-2 mg kg(-1)) decreased the retention latency. Yohimbine pre-treatment decreased the amnestic effects of dexamethasone or dexamethasone plus clonidine. On the other hand, intraperitoneal administration of alpha(1)-adrenoceptor agonist phenylephrine (0.5-2 mg kg(-1)) per se increased, while prazosin at 2 mg kg(-1) decreased the retention latency. Administration of phenylephrine before dexamethasone completely reversed the amnestic effect of the latter, while prozosin did not affect dexamethasone-induced amnesia. These data suggest that dexamethasone may induce its amnestic effect through activation of alpha(2)-adrenoceptors, leading to decreased alpha(1)-adrenergic activity.