Anticonvulsant and acute adverse effect profiles of picolinic acid 2-fluoro-benzylamide in various experimental seizure models and chimney test in mice

The objective of this study was to evaluate the anticonvulsant properties of picolinic acid 2-fluoro-benzylamide (Pic-2F-BZA) in numerous experimental seizure models [maximal electroshock (MES), bicuculline (BIC), pentylenetetrazole (PTZ), pilocarpine (PILO), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainic acid (KA) and N-methyl-D-aspartic acid (NMDA)-induced seizures]. Moreover, the acute adverse-effect profile of the agent with respect to impairment of motor performance was assessed in animals subjected to the chimney test. Results indicate that Pic-2F-BZA in time- and dose-dependent manners produced both the anti-electroshock action and acute adverse effects in the MES and chimney tests in mice respectively. The experimentally derived median effective dose (ED(50) value) in the MES test was 24.2 mg/kg (at 5 min after i.p. administration), whereas the median toxic dose (TD(50) value) in the chimney test was 71.7 mg/kg. Furthermore, Pic-2F-BZA produced clear-cut antiseizure effects in all chemically induced seizure models and its ED(50) values amounted to 19.9 mg/kg for KA-, 39.5 mg/kg for AMPA-, 56.2 mg/kg for PTZ-, 76.4 mg/kg for BIC-, 160.1 mg/kg for PILO- and 165.2 mg/kg for NMDA-induced seizures. Based on this study, one can conclude that Pic-2F-BZA, because of its broad spectrum of anticonvulsant action and the short time to peak of its maximum anticonvulsant effects (5 min after its i.p. administration), deserves more attention as a potential antiepileptic drug for status epilepticus patients.     

Comparison of behavioral,neuroprotective, and proinflammatory cytokine modulating effects exercised by (+)‐cis‐EC and (−)‐cis‐EC stereoisomers in a PTZ‐induced kindling test in mice

Epoxy‐carvone (EC) has chiral centers that allow generation of stereoisomers, including (+)‐cis‐EC and (?)‐cis‐EC, whose effects in the kindling tests have never been studied. Accordingly, this study aims to comparatively investigate the effect of stereoisomers (+)‐cis‐epoxy‐carvone and (?)‐cis‐epoxy‐carvone on behavioral changes measured in scores, in the levels of cytokines (IL‐1β, IL‐6, and TNFα) and neuronal protection in the face of continuous treatment with pentylenetetrazol. Swiss mice were divided into five groups (n = 10), receiving vehicle, (+) – cis‐EC, (?) – cis‐EC (both at the dose of 30 mg/kg), and diazepam (4 mg/kg). Thirty minutes after the respective treatment was administered to the animals one subconvulsive dose of PTZ (35 mg/kg). Seven subconvulsives treatments were made on alternate days, in which each treatment several parameters were recorded. In the eighth treatment, the animals receiving the highest dose of PTZ (75 mg/kg) and were sacrificed for quantification of cytokines and histopathologic analysis. All drugs were administered by intraperitoneal route. In the kindling test, (+)‐cis‐EC and (?)‐cis‐EC reduced the average scores. The stereoisomer (+)‐cis‐EC decreased levels of proinflammatory cytokines IL‐1β, IL‐6, and TNFα, whereas comparatively (?)‐cis‐EC did not reduce IL‐1β levels. Histopathological analysis of the mice hippocampi undergoing this methodology showed neural protection for treated with (+)‐cis‐EC. The results suggest that the anticonvulsant effect of (+)‐cis‐EC possibly takes place due to reduction of proinflammatory cytokines involved in the epileptogenic process, besides neuronal protection, yet further investigation of the mechanisms involved is required.     

Involvement of α2‐adrenoceptors,imidazoline, and endothelin‐A receptors in the effect of agmatine on morphine and oxycodone‐induced hypothermia in mice

Potentiation of opioid analgesia by endothelin‐A (ET_A) receptor antagonist, BMS182874, and imidazoline receptor/α₂‐adrenoceptor agonists such as clonidine and agmatine are well known. It is also known that agmatine blocks morphine hyperthermia in rats. However, the effect of agmatine on morphine or oxycodone hypothermia in mice is unknown. The present study was carried out to study the role of α₂‐adrenoceptors, imidazoline, and ET_A receptors in morphine and oxycodone hypothermia in mice. Body temperature was determined over 6 h in male Swiss Webster mice treated with morphine, oxycodone, agmatine, and combination of agmatine with morphine or oxycodone. Yohimbine, idazoxan, and BMS182874 were used to determine involvement of α₂‐adrenoceptors, imidazoline, and ET_A receptors, respectively. Morphine and oxycodone produced significant hypothermia that was not affected by α₂‐adrenoceptor antagonist yohimbine, imidazoline receptor/α₂ adrenoceptor antagonist idazoxan, or ET_A receptor antagonist, BMS182874. Agmatine did not produce hypothermia; however, it blocked oxycodone but not morphine‐induced hypothermia. Agmatine‐induced blockade of oxycodone hypothermia was inhibited by idazoxan and yohimbine. The blockade by idazoxan was more pronounced compared with yohimbine. Combined administration of BMS182874 and agmatine did not produce changes in body temperature in mice. However, when BMS182874 was administered along with agmatine and oxycodone, it blocked agmatine‐induced reversal of oxycodone hypothermia. This is the first report demonstrating that agmatine does not affect morphine hypothermia in mice, but reverses oxycodone hypothermia. Imidazoline receptors and α₂‐adrenoceptors are involved in agmatine‐induced reversal of oxycodone hypothermia. Our findings also suggest that ET_A receptors may be involved in blockade of oxycodone hypothermia by agmatine.