Anticonvulsant effects of Paeonia daurica subsp. macrophylla root extracts in pentylenetetrazol-induced seizure models in mice

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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Connexin36 Gap Junction Blockade Is Ineffective at Reducing Seizure-Like Event Activity in Neocortical Mouse Slices

Epilepsy Research and Treatment ◽

10.1155/2010/310753 ◽

2010 ◽

Vol 2010 ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Logan J. Voss ◽

Noortje Mutsaerts ◽

James W. Sleigh

Keyword(s):

Gap Junctions ◽

Gap Junction ◽

Population Activity ◽

Low Magnesium ◽

Artificial Cerebrospinal Fluid ◽

Seizure Models ◽

Neocortical Slice ◽

Neocortical Seizures ◽

Anticonvulsant Effects

Despite much research, there remains controversy over the role of gap junctions in seizure processes. Many studies report anticonvulsant effects of gap junction blockade, but contradictory results have also been reported. The aim of this study was to clarify the role of connexin36 (Cx36) gap junctions in neocortical seizures. We used the mouse neocortical slice preparation to investigate the effect of pharmacological (mefloquine) and genetic (Cx36 knockout mice (Cx36KO)) manipulation of Cx36 gap junctions on two seizure models: low-magnesium artificial cerebrospinal fluid (ACSF) and aconitine perfusion in low-magnesium ACSF. Low-magnesium- (nominally zero) and aconitine- (230 nM) induced seizure-like event (SLE) population activity was recorded extracellularly. The results were consistent in showing that neither mefloquine (25 μM) nor genetic knockdown of Cx36 expression had anticonvulsant effects on SLE activity generated by either method. These findings call into question the widely held idea that open Cx36 gap junctions promote seizure activity.

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Studies on Anticonvulsant Effects of Novel Histamine H3R Antagonists in Electrically and Chemically Induced Seizures in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms19113386 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3386 ◽

Cited By ~ 10

Author(s):

Alaa Alachkar ◽

Dorota Łażewska ◽

Gniewomir Latacz ◽

Annika Frank ◽

Agata Siwek ◽

...

Keyword(s):

Clonic Seizure ◽

Maximal Electroshock ◽

Protective Effects ◽

Chemically Induced ◽

Seizure Models ◽

Dose Dependent Fashion ◽

Full Protection ◽

Anticonvulsant Effects

A newly developed series of non-imidazole histamine H3 receptor (H3R) antagonists (1–16) was evaluated in vivo for anticonvulsant effects in three different seizure models in Wistar rats. Among the novel H3R antagonists examined, H3R antagonist 4 shortened the duration of tonic hind limb extension (THLE) in a dose-dependent fashion in the maximal electroshock (MES)-induced seizure and offered full protection against pentylenetetrazole (PTZ)-induced generalized tonic-clonic seizure (GTCS), following acute systemic administration (2.5, 5, 10, and 15 mg/kg, i.p.). However, only H3R antagonist 13, without appreciable protective effects in MES- and PTZ-induced seizure, fully protected animals in the strychnine (STR)-induced GTCS following acute systemic pretreatment (10 mg/kg, i.p.). Moreover, the protective effect observed with H3R antagonist 4 in MES-induced seizure was completely abolished when animals were co-administered with the H3R agonist (R)-α-methylhistamine (RAMH, 10 mg/kg, i.p.). However, RAMH failed to abolish the full protection provided by the H3R antagonist 4 in PTZ-induced seizure and H3R antagonist 13 in STR-induced seizure. Furthermore, in vitro antiproliferative effects or possible metabolic interactions could not be observed for compound 4. Additionally, the predictive in silico, as well as in vitro, metabolic stability for the most promising H3R antagonist 4 was assessed. The obtained results show prospective effects of non-imidazole H3R antagonists as innovative antiepileptic drugs (AEDs) for potential single use against epilepsy.

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