Possible Involvement of Endogenous Opioids and Nitric Oxide in the Anticonvulsant Effect of Acute Chloroquine Treatment in Mice

2017 ◽  
Vol 41 (S1) ◽  
pp. S630-S630
Author(s):  
A. Abkhoo
Keyword(s):  
Nitric Oxide ◽  
Effective Dose ◽  
Clonic Seizure ◽  
Endogenous Opioids ◽  
Seizure Threshold ◽  
Anticonvulsant Effect ◽  
Nitric Oxide Signaling ◽  
Nos Inhibitor ◽  
Neuronal Nos ◽  
Anticonvulsant Effects

IntroductionChloroquine, a 4-aminoquinoline derivative, has long been used for the treatment of malaria and rheumatological disorders, including rheumatoid arthritis and systemic lupus erythematosus. Accumulating evidence now suggests potential use of chloroquine as a neuroprotectant. Studies have shown that nitric oxide (NO) pathway is involved in the chloroquine actions. Considering the fact that nitrergic neurotransmission plays a crucial role in the central nervous system functioning, in the present study we evaluated whether nitrergic system is involved in the anticonvulsant effects of chloroquine in a model of clonicseizure in mice.MethodsClonic seizure threshold was determined by infusion of pentylenetetrazole (PTZ, 0.5%) at a constant rate of 1 mL/min into the tail vein of male Swiss mice (23–29 g). Minimal dose of PTZ (mg/kg of mice weight) needed to induce clonicseizure was considered as an index of seizure threshold.ResultsChloroquine (5 mg/kg, acutely 30 min before test, intraperitoneally), i.p significantly increased the seizure threshold. Acute co-administration of a non-effective dose of the non-selective NO synthase (NOS) inhibitor, L-NAME (L-NG-Nitro-L-arginine methyl ester hydrochloride,5 mg/kg, i.p.) or the selective inhibitor of neuronal NOS, 7-NI (7-nitroindazole, 40 mg/kg, i.p.) with an effective dose of chloroquine (5 mg/kg) inhibited its anticonvulsant effects. Co-administration of a non-effective dose the selective inducible NOS inhibitor, aminoguanidine (100 mg/kg, i.p.) with chloroquine 5 mg/kg did not alter its anticonvulsant effects.ConclusionChloroquine increases the PTZ-induced clonic seizure threshold in mice. We demonstrated for the first time that nitric oxide signaling probably through neuronal NOS could be involved in the anticonvulsant effects of chloroquine in this model of seizure in mice.Disclosure of interestThe author has not supplied his/her declaration of competing interest.

Anticonvulsant effect of minocycline on pentylenetetrazole-induced seizure in mice: involvement of nitric oxide and N-methyl-d-aspartate receptor

2018 ◽  
Vol 96 (8) ◽  
pp. 742-750 ◽  
Author(s):  
Hossein Amini-Khoei ◽  
Nastaran Kordjazy ◽  
Arvin Haj-Mirzaian ◽  
Shayan Amiri ◽  
Arya Haj-Mirzaian ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nmda Receptor ◽  
Seizure Threshold ◽  
Anticonvulsant Effect ◽  
Acute Administration ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Nitrite Level ◽  
Nos Inhibitor ◽  
Neuronal Nos

Anticonvulsant effects of minocycline have been explored recently. This study was designed to examine the anticonvulsant effect of acute administration of minocycline on pentylenetetrazole-induced seizures in mouse considering the possible role of the nitric oxide/N-methyl-d-aspartate (NMDA) pathway. We induced seizure using intravenous administration of pentylenetetrazole. Our results showed that acute administration of minocycline increased the seizure threshold. Furthermore, co-administration of subeffective doses of the nonselective nitric oxide synthase (NOS) inhibitor NG-l-arginine methyl ester (10 mg/kg) and the neuronal NOS inhibitor 7-nitroindazole (40 mg/kg) enhanced the anticonvulsant effect of subeffective doses of minocycline (40 mg/kg). We found that inducible NOS inhibitor aminoguanidine (100 mg/kg) had no effect on the antiseizure effect of minocycline. Moreover, l-arginine (60 mg/kg), as a NOS substrate, reduced the anticonvulsant effect of minocycline. We also demonstrated that pretreatment with the NMDA receptor antagonists ketamine (0.5 mg/kg) and MK-801 (0.05 mg/kg) increased the anticonvulsant effect of subeffective doses of minocycline. Results showed that minocycline significantly decreased the hippocampal nitrite level. Furthermore, co-administration of a neuronal NOS inhibitor like NMDA receptor antagonists augmented the effect of minocycline on the hippocampal nitrite level. In conclusion, we revealed that anticonvulsant effect of minocycline might be, at least in part, due to a decline in constitutive hippocampal nitric oxide activity as well as inhibition of NMDA receptors.

Implication of nitrergic system in the anticonvulsant effects of ferulic acid in pentylenetetrazole-induced seizures in male mice

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Hossein Amini-Khoei ◽  
Shakiba Nasiri Boroujeni ◽  
Zahra Lorigooini ◽  
Arash Salehi ◽  
Reihaneh Sadeghian ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ferulic Acid ◽  
Effective Dose ◽  
Onset Time ◽  
Seizure Threshold ◽  
Anticonvulsant Effect ◽  
Male Mice ◽  
Neuroprotective Effects ◽  
Nitric Oxide Synthase Inhibitor ◽  
The Brain

Abstract Objectives Seizures are abnormal discharge of neurons in the brain. Ferulic acid (FA) is a phenolic compound with antioxidant and neuroprotective effects. The present study aimed to investigate the role of the nitrergic system in the anticonvulsant effect of FA in pentylenetetrazol (PTZ)-induced seizures in male mice. Methods 64 male Naval Medical Research Institute (NMRI) mice weighing 25–29 g were randomly divided into eight experimental groups (n=8). FA at doses 5, 10, and 40 mg/kg alone and in combination with L-nitro-arginine methyl ester (L-NAME) (nitric oxide synthase inhibitor) or L-arginine (L-arg) (nitric oxide [NO] precursor) was administrated (intraperitoneal). PTZ was injected (i.v. route) 30 min after drugs administration (1 mL/min). Seizure onset time was recorded and the nitrite levels of prefrontal cortex and serum were determined by the Griess method. Results FA at doses of 10 and 40 mg/kg significantly increased the seizure threshold as well as reduced the serum and brain NO levels in comparison to the saline-received group. Co-administration of the effective dose of FA (10 mg/kg) plus L-arg significantly decreased the seizure threshold in comparison to the effective dose of FA alone. Co-injection of the sub-effective dose of FA (5 mg/kg) with L-NAME significantly increased the seizure threshold as well as significantly decreased the brain NO level in comparison to the sub-effective dose of FA alone. Conclusions We showed that the nitrergic system, partially at least, mediated the anticonvulsant effect of FA in PTZ-induced seizures in mice. We concluded that L-NAME potentiated while L-arg attenuated the anticonvulsant effect of FA.

scholarly journals Implication of Nitrergic System in the Anticonvulsant Effect of Ferulic Acid in Pentylenetetrazole-induced Seizures in Male Mice

2020 ◽  
Author(s):  
Hossein Amini Khoei ◽  
Shakiba Nasiri Boroujeni ◽  
Zahra Lorigooini ◽  
Arash Salehi ◽  
Reihaneh Sadeghian ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ferulic Acid ◽  
Effective Dose ◽  
Onset Time ◽  
Seizure Threshold ◽  
Anticonvulsant Effect ◽  
Male Mice ◽  
Neuroprotective Effects ◽  
Nitric Oxide Synthase Inhibitor ◽  
Brain Nitric Oxide

Abstract Background and Aim: Given the widespread prevalence of seizures worldwide and the low efficacy of synthetic drugs, studies are needed to find new compounds with appropriate efficacy. Ferulic acid (FA) is a phenolic compound with antioxidant and neuroprotective effects. The aim of present study was to investigate the role of nitrergic system in the anticonvulsant effect of FA in pentylenetetrazol-induced seizures in male mice. Material and Methods: 64 male NMRI mice weighing 25-29 g were randomly divided into 8 experimental groups (n=8). FA at doses 5, 10 and 40 mg / kg alone and in combination with L-NAME (nitric oxide synthase inhibitor) or L-arg (nitric oxide precursor) was administrated (i.p.). PTZ was injected (i.v. route) 30 min after drugs administration. Seizure onset time was recorded and the nitrite levels of prefrontal cortex and serum were determined by Griess Method. Results: FA at doses of 10 and 40 mg / kg significantly increased the seizure threshold as well as reduced the serum and brain nitric oxide levels in comparison to the saline- received group. Co-administration of effective dose of FA (10 mg/kg) plus L-arginine significantly decreased the seizure threshold in compared to the effective dose of FA alone. Co-injection of sub-effective dose of FA (5 mg/kg) with L-NAME significantly increased the seizure threshold as well as significantly decreased the brain nitric oxide level in compared to the sub-effective dose of FA alone.Conclusion: FA partially at least, via modulation of nitrergic system possessed anticonvulsant effect in PTZ-induced seizures in mice.

scholarly journals Nitric oxide mediates anomalous tubuloglomerular feedback in rats fed high-NaCl diet after subtotal nephrectomy

2019 ◽  
Vol 316 (2) ◽  
pp. F223-F230 ◽  
Author(s):  
Scott C. Thomson
Keyword(s):  
Nitric Oxide ◽  
Tubuloglomerular Feedback ◽  
Cross Term ◽  
Nitric Oxide Signaling ◽  
Subtotal Nephrectomy ◽  
Single Nephron ◽  
Nos Inhibitor ◽  
Tubular Flow ◽  
Fluid Collections ◽  
Distal Delivery

Tubuloglomerular feedback (TGF) responses become anomalous in rats fed high-NaCl diet after subtotal nephrectomy (STN), such that stimulating TGF causes single nephron GFR (SNGFR) to increase rather than decrease. Micropuncture experiments were performed to determine whether this anomaly results from heightened nitric oxide response to distal delivery, which is a known mechanism for resetting TGF, or from connecting tubule TGF (cTGF), which is a novel amiloride-inhibitable system for offsetting TGF responses. Micropuncture was done in Wistar Froemter rats fed high-NaCl diet (HS) for 8–10 days after STN or sham nephrectomy. TGF was manipulated by orthograde microperfusion of Henle’s loop with artificial tubular fluid with or without NOS inhibitor, LNMMA, or the cell-impermeant amiloride analog, benzamil. SNGFR was measured by inulin clearance in tubular fluid collections from the late proximal tubule. TGF responses were quantified as the increase in SNGFR that occurred when the perfusion rate was reduced from 50 to 8 nl/min in STN or 40 to 8 nl/min in sham animals. The baseline TGF response was anomalous in STN HS (−4 ± 3 vs 14 ± 3 nl/min, P < 0.001). TGF response was normalized by perfusing STN nephron with LNMMA (14 ± 3 nl/min, P < 0.005 for ANOVA cross term) but not with benzamil (−3 ± 4 nl/min, P = 0.4 for ANOVA cross term). Anomalous TGF occurs in STN HS due to heightened effect of tubular flow on nitric oxide signaling, which increases to the point of overriding the normal TGF response. There is no role for cTGF in this phenomenon.

Role of Endothelial Nitric Oxide Synthase as a Trigger and Mediator of Isoflurane-induced Delayed Preconditioning in Rabbit Myocardium

2005 ◽  
Vol 103 (1) ◽  
pp. 74-83 ◽  
Author(s):  
Pascal C. Chiari ◽  
Martin W. Bienengraeber ◽  
Dorothee Weihrauch ◽  
John G. Krolikowski ◽  
Judy R. Kersten ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Methyl Ester ◽  
Nitric Oxide Synthase ◽  
Infarct Size ◽  
Coronary Occlusion ◽  
Nos Inhibitor ◽  
Neuronal Nos ◽  
Oxide Synthase ◽  
Inducible Nos

Background Isoflurane produces delayed preconditioning in vivo. The authors tested the hypothesis that endothelial, inducible, or neuronal nitric oxide synthase (NOS) is a trigger or mediator of this protective effect. Methods In the absence or presence of exposure to isoflurane (1.0 minimum alveolar concentration) 24 h before experimentation, pentobarbital-anesthetized rabbits (n = 128) instrumented for hemodynamic measurement received 0.9% saline (control), the nonselective NOS inhibitor N-nitro-l-arginine methyl ester (10 mg/kg), one of two of the selective inducible NOS antagonists aminoguanidine (300 mg/kg) or 1400W (0.5 mg/kg), or the selective neuronal NOS inhibitor 7-nitroindazole (50 mg/kg) administered before exposure to isoflurane (trigger; day 1) or left anterior descending coronary artery occlusion (mediator; day 2). All rabbits underwent 30 min of coronary occlusion followed by 3 h of reperfusion. Tissue samples for reverse-transcription polymerase chain reaction and immunohistochemistry were also obtained in the presence or absence of N-nitro-l-arginine methyl ester with or without isoflurane pretreatment. Results Isoflurane significantly (P &lt; 0.05) reduced infarct size (23 +/- 5% [mean +/- SD] of the left ventricular area at risk; triphenyltetrazolium chloride staining) as compared with control (42 +/- 7%). N-nitro-l-arginine methyl ester administered before isoflurane or coronary occlusion abolished protection (49 +/- 7 and 43 +/- 10%, respectively). Aminoguanidine, 1400W, and 7-nitroindazole did not alter infarct size or affect isoflurane-induced delayed preconditioning. Isoflurane increased endothelial but not inducible NOS messenger RNA transcription and protein translation immediately and 24 h after administration of the volatile agent. Pretreatment with N-nitro-l-arginine methyl ester attenuated isoflurane-induced increases in endothelial NOS expression. Conclusions The results suggest that endothelial NOS but not inducible or neuronal NOS is a trigger and mediator of delayed preconditioning by isoflurane in vivo.

scholarly journals Inhibition of neuroinflammatory nitric oxide signaling suppresses glycation and prevents neuronal dysfunction in mouse prion disease

2021 ◽  
Vol 118 (10) ◽  
pp. e2009579118
Author(s):  
Julie-Myrtille Bourgognon ◽  
Jereme G. Spiers ◽  
Sue W. Robinson ◽  
Hannah Scheiblich ◽  
Paul Glynn ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Misfolding ◽  
Hippocampal Neurons ◽  
Therapeutic Potential ◽  
Early Disease ◽  
Nitric Oxide Signaling ◽  
Gene And Protein Expression ◽  
No Signaling ◽  
Nos Inhibitor

Several neurodegenerative diseases associated with protein misfolding (Alzheimer’s and Parkinson’s disease) exhibit oxidative and nitrergic stress following initiation of neuroinflammatory pathways. Associated nitric oxide (NO)-mediated posttranslational modifications impact upon protein functions that can exacerbate pathology. Nonenzymatic and irreversible glycation signaling has been implicated as an underlying pathway that promotes protein misfolding, but the direct interactions between both pathways are poorly understood. Here we investigated the therapeutic potential of pharmacologically suppressing neuroinflammatory NO signaling during early disease progression of prion-infected mice. Mice were injected daily with an NO synthase (NOS) inhibitor at early disease stages, hippocampal gene and protein expression levels of oxidative and nitrergic stress markers were analyzed, and electrophysiological characterization of pyramidal CA1 neurons was performed. Increased neuroinflammatory signaling was observed in mice between 6 and 10 wk postinoculation (w.p.i.) with scrapie prion protein. Their hippocampi were characterized by enhanced nitrergic stress associated with a decline in neuronal function by 9 w.p.i. Daily in vivo administration of the NOS inhibitor L-NAME between 6 and 9 w.p.i. at 20 mg/kg prevented the functional degeneration of hippocampal neurons in prion-diseased mice. We further found that this intervention in diseased mice reduced 3-nitrotyrosination of triose-phosphate isomerase, an enzyme involved in the formation of disease-associated glycation. Furthermore, L-NAME application led to a reduced expression of the receptor for advanced glycation end-products and the diminished accumulation of hippocampal prion misfolding. Our data suggest that suppressing neuroinflammatory NO signaling slows functional neurodegeneration and reduces nitrergic and glycation-associated cellular stress.

Altered mesenteric venous capacitance and volume pooling in cirrhotic rats are mediated by nitric oxide

2008 ◽  
Vol 295 (2) ◽  
pp. G252-G259 ◽  
Author(s):  
Yang Li ◽  
Hongqun Liu ◽  
Seyed Ali Gaskari ◽  
John V. Tyberg ◽  
Samuel S. Lee
Keyword(s):  
Nitric Oxide ◽  
Blood Volume ◽  
Portal Pressure ◽  
Venous Capacitance ◽  
Inflatable Cuff ◽  
Duct Ligation ◽  
Nos Inhibitors ◽  
Nos Inhibitor ◽  
Neuronal Nos ◽  
Circulating Volume

In cirrhosis, despite augmented blood volume, effective circulating volume is decreased. This implies abnormal regulation of blood volume, i.e., venous pooling. Because gut veins are the main blood reservoir, we studied mesenteric venous capacitance and compliance in a rat model of cirrhosis. Cirrhosis was induced by bile duct ligation (4 wk). Controls were sham operated. Changes in first-order mesenteric vein diameters induced by drugs, hemorrhage, and stepwise increases in portal pressure (inflatable cuff) were directly observed by intravital microscopy. Effects of nitric oxide on responses to acute graded hemorrhage were studied by use of selective NO synthase (NOS) isoform inhibitors. Pressures were related to diameters to assess capacitance and compliance. Compared with controls, cirrhotic rats demonstrated increased mesenteric venous capacitance and decreased compliance. Norepinephrine induced venoconstriction but did not affect compliance. Prazosin markedly diminished compliance in controls but not cirrhotics. Conversely, the nonspecific NOS inhibitor N-nitro-l-arginine methyl ester (l-NAME) decreased compliance in cirrhotics, but not controls. Tetrodotoxin venodilated controls, venoconstricted cirrhotics, and markedly decreased compliance in both groups. When hemorrhaged, controls rapidly venoconstricted to compensate for initial hypotension, whereas cirrhotic rats remained hypotensive because venoconstriction was severely blunted. Pretreatment with l-NAME or the selective neuronal NOS inhibitors S-methyl-l-thiocitrulline and 7-nitroindazole normalized the homeostatic responses of cirrhotic rats, whereas the selective endothelial-constitutive NOS inhibitor N-iminoethyl-l-ornithine did not affect the response. In conclusion, mesenteric veins of cirrhotic rats showed enhanced capacitance, attenuated compensatory constrictive response to hemorrhage, and decreased compliance. The first two abnormalities were caused by neuronal NOS-derived nitric oxide.

Effects of Modafinil on Clonic Seizure Threshold Induced by Pentylenetetrazole in Mice: Involvement of Glutamate, Nitric oxide, GABA, and Serotonin Pathways

2018 ◽  
Vol 43 (11) ◽  
pp. 2025-2037 ◽  
Author(s):  
Erfan Bahramnjead ◽  
Soheil Kazemi Roodsari ◽  
Nastaran Rahimi ◽  
Payam Etemadi ◽  
Iraj Aghaei ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Clonic Seizure ◽  
Seizure Threshold

scholarly journals Involvement of N-Methyl-D-Aspartate Receptors in the Anticonvulsive Effects of Licofelone on Pentylenetetrazole-Induced Clonic Seizure in Mice

2021 ◽  
Vol 11 (1) ◽  
pp. 14-21
Author(s):  
Ramtin Gholizadeh ◽  
Zohreh Abdolmaleki ◽  
Taraneh Bahremand ◽  
Mehdi Ghasemi ◽  
Mehdi Gharghabi ◽  
...  
Keyword(s):  
Combined Treatment ◽  
Clonic Seizure ◽  
In Vivo Model ◽  
Anticonvulsant Effect ◽  
No Production ◽  
Acute Administration ◽  
Seizure Models ◽  
Clonic Seizures ◽  
Anticonvulsant Effects

Background and Purpose: Licofelone is a dual 5-lipoxygenase/cyclooxygenase inhibitor, with well-documented anti-inflammatory and analgesic effects, which is used for treatment of osteoarthritis. Recent preclinical studies have also suggested neuroprotective and anti-oxidative properties of this drug in some neurological conditions such as seizure and epilepsy. We have recently demonstrated a role for nitric oxide (NO) signaling in the anti-epileptic activity of licofelone in two seizure models in rodents. Given the important role of N-methyl-D-aspartate receptors (NMDARs) activation in the NO production and its function in the nervous system, in the present study, we further investigated the involvement of NMDAR in the effects of licofelone (1, 3, 5, 10, and 20 mg/kg, intraperitoneal [i.p.]) in an in vivo model of seizure in mice.Methods: Clonic seizures were induced in male NMRI mice by intravenous administration of pentylenetetrazol (PTZ).Results: Acute administration of licofelone exerted anticonvulsant effects at 10 (p<0.01) and 20 mg/kg (p<0.001). A combined treatment with sub-effective doses of the selective NMDAR antagonist MK-801 (0.05 mg/kg, i.p.) and licofelone (5 mg/kg, i.p.) significantly (p<0.001) exerted an anticonvulsant effect on the PTZ-induced clonic seizures in mice. Notably, pre-treatment with the NMDAR co-agonist D-serine (30 mg/kg, i.p.) partially hindered the anticonvulsant effects of licofelone (20 mg/kg).Conclusions: Our data suggest a possible role for the NMDAR in the anticonvulsant effects of licofelone on the clonic seizures induced by PTZ in mice.

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