Anticonvulsant Activity of Essential Oil From Leaves of Zhumeria majdae (Rech.) in Mice: The Role of GABAA Neurotransmission and the Nitric Oxide Pathway

The essential oil from the leaves of Zhumeria majdae Rech. (ZMEO) has been shown to have several beneficial effects in the clinic. In this work we examined the anticonvulsant activities of ZMEO in an experimental mouse model of seizure and aimed to identify any possible underlying mechanisms. ZMEO (5, 10, 20, and 40 mg/kg intraperitoneally (i.p.)) or diazepam, as the reference anticonvulsant drug (25, 50 and 100 µg/kg i.p.), were administered 60 minutes prior to pentylenetetrazol (PTZ) injection (intravenously (i.v.) or i.p.) and changes in threshold, latency, and frequency of clonic seizure were examined. The PTZ i.p.-induced model of seizure was also applied for examining the protective effects of ZMEO pretreatment against PTZ-induced mortality. In some studies, the anticonvulsant effect of the combination of diazepam and ZMEO was also studied. The protective effects of ZMEO against hindlimb tonic extensions (HLTEs) were also examined by maximal electroshock (MES) seizure testing. The γ-aminobutyric acid (GABA)ergic mechanism and nitric oxide (NO) pathway involvement in anticonvulsant activity of ZMEO were assessed by pretreating animals with flumazenil, N�-nitro-L-arginine methyl ester (L-NAME), aminoguanidine, and L-arginine in a PTZ-induced model of seizure. Administration of 20 mg/kg ZMEO significantly increased chronic seizure threshold and latency while reducing frequency of convulsions and mortality in the PTZ-induced model. In the doses studied, ZMEO could not protect mice from HLTE and mortality induced by MES. Pretreatment with L-arginine and diazepam potentiated the anticonvulsant effects of ZMEO, whereas pretreatment with L-NAME, aminoguanidine, and flumazenil reversed anticonvulsant activity. The anticonvulsant activity of ZMEO may be mediated in part through a GABAergic mechanism and the NO signaling pathway. © 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics

Role of the nitric oxide pathway and the endocannabinoid system in neurogenic relaxation of corpus cavernosum from biliary cirrhotic rats

Background and purpose: Relaxation of corpus cavernosum, which is mediated by nitric oxide (NO) released from non-adrenergic non-cholinergic (NANC) neurotransmission, is critical for inducing penile erection and can be affected by many pathophysiological conditions. However, the peripheral effect of liver cirrhosis on erectile function is as yet unknown. The aim of the present study was to investigate the effect of biliary cirrhosis on NANC-mediated relaxation of rat corpus cavernosum and the possible roles of endocannabinoid and nitric oxide systems in this model. Experimental approach: Cirrhosis was induced by bile duct ligation. Controls underwent sham operation. Four weeks later, strips of corpus cavernosum were mounted in a standard organ bath and NANC-mediated relaxations were obtained by applying electrical field stimulation. Key results: The NANC-mediated relaxation was enhanced in corporal strips from cirrhotic animals. Anandamide potentiated the relaxations in both groups. Either AM251 (CB 1 antagonist) or capsazepine (vanilloid VR 1 antagonist), but not AM630 (CB 2 antagonist), prevented the enhanced relaxations of cirrhotic strips. Either the non-selective NOS inhibitor L-NAME or the selective neuronal NOS inhibitor L-NPA inhibited relaxations in both groups, but cirrhotic groups were more resistant to the inhibitory effects of these agents. Relaxations to sodium nitroprusside (NO donor) were similar in tissues from the two groups. Conclusions and implications: Cirrhosis potentiates the neurogenic relaxation of rat corpus cavernosum probably via the NO pathway and involving cannabinoid CB 1 and vanilloid VR 1 receptors. © 2007 Nature Publishing Group All rights reserved

Anticonvulsant activity of Astragalus squarrosus Bunge

Abstract The anticonvulsant activity of Astragalus squarrosus total extract was assessed in pentylenetetrazole (PTZ)-induced convulsion in mice, with diazepam as the standard drug, while mechanistic studies were also conducted using flumazenil, a GABA A-benzodiazepine receptor complex site antagonist. The extract produced protection against convulsion at 400 mg/kg, comparable with protection of benzodiazepine (diazepam). The mean onset and percentage protection against convulsion in extracttreated mice were reduced by flumazenil. The results suggest that A. squarrosus extract possesses biologically active constituent(s) that have anticonvulsant activity which supports the ethnomedical claims of its use in the management of seizure

Anticonvulsant activity of Astragalus squarrosus Bunge

The anticonvulsant activity of Astragalus squarrosus total extract was assessed in pentylenetetrazole (PTZ)-induced convulsion in mice, with diazepam as the standard drug, while mechanistic studies were also conducted using flumazenil, a GABA A-benzodiazepine receptor complex site antagonist. The extract produced protection against convulsion at 400 mg/kg, comparable with protection of benzodiazepine (diazepam). The mean onset and percentage protection against convulsion in extract-treated mice were reduced by flumazenil. The results suggest that A. squarrosus extract possesses biologically active constituent(s) that have anticonvulsant activity which supports the ethnomedical claims of its use in the management of seizure

Aripiprazole prevents from development of vincristine-induced neuropathic nociception by limiting neural NOS overexpression and NF-kB hyperactivation

Purpose: Increased nitric oxide (NO) synthesis and NF-kB activation have been shown as critical players in the pathophysiology of vincristine-induced peripheral neuropathy. Consistently, neural nitric oxide synthase (nNOS) inhibitors alleviated the neuropathic pain. Previous studies demonstrated that aripiprazole is capable of modulating NO synthesis and also has been reported its modulatory effect on NF-kB activity. Methods: Aripiprazole was administered daily to the male Wistar rats at the same time with establishing neuropathic model by I.P. injection of vincristine every 2 days, over 2 weeks. Efficacy of aripiprazole in suppressing the development of neuropathy was evaluated by assessing changes in body weight, mechanical threshold, withdrawal latency, sciatic nerve conduction velocity (SNCV), and compound motor action potential (CMAP) characteristics. Expression of nNOS and NF-kB activation were evaluated by western blotting Results: Rats receiving aripiprazole during neuropathy establishment period demonstrated a normal weight gain pattern, a significantly higher mechanical withdrawal threshold, and SNCV compared to vincristine-treated group. Furthermore, the amplitude and area of CMAP were significantly higher in aripiprazole group. Western blotting demonstrated a significantly reduced expression of nNOS and NF-kB activation in dorsal root ganglia of aripiprazole co-treated rats. Conclusion: In conclusion, aripiprazole effectively prevents from vincristine-induced neuropathy by limiting nNOS overexpression and NF-kB hyperactivation. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature

Challenge of Private Rehabilitation Centers and Welfare Organization (Behzisti)

Studying the situation of providing services for people with disability are very important and in current situation which is dominate on system providing rehabilitation services in Iran, private rehabilitation centers can be the best and the most important focus for this study. This research performed by qualitative method and with phenomenology type, and purposeful sampling did as purposeful and based on similar samples. The samples of this study consisted of 14 managers of private rehabilitation centers who had especial experiences about the theme of research and providing rehabilitation services. The method of executing research was base on deep and open semi-structured interview that use from method focus group discussion which is a type of semi-structure interview for collecting data from samples. Collected data were analyzed by written analyze method and used from suggested Van Manen suggestion method. Managers of private rehabilitation centers meet different problems and confront with different situations in their centers. General problem which appear as a frame of problems related to private politic, especial problems related to private rehabilitation centers activities, and intra/extra communication. The delivery of services to private sector does not mean depriving the responsibility from Welfare Organization and its rehabilitation deputy. The organization should issue establishment license for private rehabilitation centers and administer it

Inhibition of NMDA receptor/NO signaling blocked tolerance to the anticonvulsant effect of morphine on pentylenetetrazole-induced seizures in mice

Although morphine has anticonvulsant effect in several animal models of seizure, its potential clinical application in epilepsy may be hindered by its adverse effects like the phenomenon of opioid tolerance. The present study evaluated the development of tolerance to the anticonvulsant effect of morphine in a model of clonic seizure induced by pentylenetetrazole (PTZ) in male Swiss mice. We also examined whether N-methyl-. d-aspartate (NMDA) receptor/nitrergic system blockage was able to prevent the probable tolerance. Our data demonstrated that anticonvulsant effects of a potent dose of morphine (1. mg/kg) was abolished in chronic morphine-treated mice (with the same dose of morphine twice daily, 4 days, i.p.). Chronic pretreatment with low and non-effective doses of different NMDA antagonists ifenprodil (0.5. mg/kg), MK-801 (0.05. mg/kg) and ketamine (0.5. mg/kg) as well as the non-selective nitric oxide (NO) synthase inhibitor l-NAME (2. mg/kg) inhibited the development of tolerance to the anticonvulsant effect of morphine (1. mg/kg). Moreover, a single acute injection of the above mentioned agents at the same doses reversed the expression of tolerance to the anticonvulsant effects of morphine (1. mg/kg). These results demonstrate that anticonvulsant effect of morphine can be subject to tolerance after repeated administration. Both development and expression of tolerance are inhibited by NMDA receptor/nitrergic system blockage, suggesting a role for NMDA receptor/NO signaling in the development of tolerance to the anticonvulsant effect of morphine. © 2010 Elsevier B.V

Atorvastatin attenuates the antinociceptive tolerance of morphine via nitric oxide dependent pathway in male mice

The development of morphine-induced antinociceptive tolerance limits its therapeutic efficacy in pain management. Atorvastatin, or competitive inhibitor of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase, is mainstay agent in hypercholesterolemia treatment. Beyond the cholesterol-lowering activity, exploration of neuroprotective properties of this statin indicates its potential benefit in central nervous disorders. The aim of the present study was to assess the effects of atorvastatin in development and expression of morphine-induced analgesic tolerance in male mice and probable involvement of nitric oxide. Chronic and acute treatment with atorvastatin 10 and 20 mg/kg, respectively, could alleviate morphine tolerance in development and expression phases. Chronic co-administration of nitric oxide synthase (NOS) inhibitors including L-NAME (non selective NOS inhibitor; 2 mg/kg), aminoguanidine (selective inducible NOS inhibitor; 50 mg/kg) and 7-NI (selective neuronal NOS inhibitor; 15 mg/kg) with atorvastatin blocked the protective effect of atorvastatin in tolerance reversal. Moreover, reversing the atorvastatin effect was also observed in acute simultaneous treatment of L-NAME (5 mg/kg) and aminoguanidine (100 mg/kg) with atorvastatin. Co-treatment of guanylyl cyclase inhibitor, ODQ (chronic dose: 10 mg/kg and acute dose: 20 mg/kg) was associated with prevention of atorvastatin anti-tolerance properties. Our results revealed that the atorvastatin modulating role in morphine antinociceptive tolerance is mediated at least in part via nitric oxide in animal pain models of hot plate and tail flick. © 2016 Elsevier Inc

Voltage-dependent calcium channel and NMDA receptor antagonists augment anticonvulsant effects of lithium chloride on pentylenetetrazole-induced clonic seizures in mice

Although lithium is still a mainstay in the treatment of bipolar disorder, its underlying mechanisms of action have not been completely elucidated. Several studies have shown that lithium can also modulate seizure susceptibility in a variety of models. In the present study, using a model of clonic seizures induced with pentylenetetrazole (PTZ) in male Swiss mice, we investigated whether there is any interaction between lithium and either calcium channel blockers (CCBs: nifedipine, verapamil, and diltiazem) or N-methyl-D-aspartate (NMDA) receptor antagonists (ketamine and MK-801) in modulating seizure threshold. Acute lithium administration (5-100mg/kg, ip) significantly (P<0.01) increased seizure threshold. CCBs and NMDA receptor antagonists also exerted dose-dependent anticonvulsant effects on PTZ-induced seizures. Noneffective doses of CCBs (5mg/kg, ip), when combined with a noneffective dose of lithium (5mg/kg, ip), exerted significant anticonvulsant effects. Moreover, co-administration of a noneffective dose of either MK-801 (0.05mg/kg, ip) or ketamine (5mg/kg, ip) with a noneffective dose of lithium (5mg/kg, ip) significantly increased seizure threshold. Our findings demonstrate that lithium increases the clonic seizure threshold induced by PTZ in mice and interacts with either CCBs or NMDA receptor antagonists in exerting this effect, suggesting a role for Ca2+ signaling in the anticonvulsant effects of lithium in the PTZ model of clonic seizures in mice. © 2010 Elsevier Inc

Synthesis, receptor affinity and effect on pentylenetetrazole-induced seizure threshold of novel benzodiazepine analogues: 3-Substituted 5-(2-phenoxybenzyl)-4H-1,2,4-triazoles and 2-amino-5-(phenoxybenzyl)-1,3,4- oxadiazoles

The new series of 5-(2-phenoxybenzyl)-4H-1,2,4-triazoles, possessing C-3 thio, alkylthio and ethoxy substituents, and 2-amino-5-(2-phenoxybenzyl)-1,3,4- oxadiazoles were designed and synthesized as novel benzodiazepine analogues. Most of them revealed similar to superior binding affinity to the GABA A/benzodiazepine receptor complex, relative to diazepam as the reference drug. Among them, 5-(4-chloro-2-(2-fluorophenoxy)benzyl)-3-benzylthio- 4H-1,2,4-triazole (8l) showed the highest affinity (IC50 = 0.892 nM) relative to diazepam (IC50 = 2.857 nM) and also showed the most increase in pentylenetetrazole-induced seizure threshold relative to diazepam as the reference drug. © 2014 Elsevier Ltd. All rights reserved