New insights on relaxant effects of (—)‐borneol monoterpene in rat aortic rings

The monoterpene alcohol (?)‐borneol has many biological effects such as sedative, anti‐inflammatory, analgesic, anti‐nociceptive, antithrombotic and vasorelaxant effects. Our objective in this study was to investigate the mechanism of action of (?)‐borneol and determine its vasorelaxant effect. (?)‐Borneol was tested on isolated aortic rings contracted with PE (10^?6 m ). This study was performed in the absence or in the presence of endothelium, L‐NAME (100 μm ), indomethacin (10 μm ), TEA (1 and 10 mm ), 4‐AP (1 mm ) or glibenclamide (1 mm ) to assess the participation of EDRF, nitric oxide, prostanoids and potassium channels on the relaxing effect of (?)‐borneol. In this work, (?)‐borneol induced a relaxant effect in aortic rings, with and without endothelium, in a concentration‐dependent manner. The pharmacological characterization obtained using L‐NAME, indomethacin, TEA, 4‐AP and glibenclamide demonstrates that the effect of (?)‐borneol was modified in the presence of L‐NAME, indomethacin and glibenclamide showing that these signal transduction pathways are involved in the relaxing effect of the monoterpene. (?)‐Borneol has a vasorelaxant effect that depends on the presence of vascular endothelium, with the participation of nitric oxide and prostanoids. Also, (?)‐borneol displayed a direct action on the vascular smooth muscle, greatly dependent on K_ATP channels.     

Comparative study of alpha‐ and beta‐pinene effect on PTZ‐induced convulsions in mice

Convulsions occur in response to a loss of balance between excitatory and inhibitory neurotransmitters, and the treatment for this condition consists in restore such lost balance. Many anticonvulsant drugs present side effects which may limit their use. This fact has stimulated the search for new sources of treatment from aromatic plants. Many monoterpenes commonly present in essential oils are known because of their anticonvulsant properties. The anticonvulsant effect of α‐ and β‐pinene, two structural isomers, is still little studied. Thus, the present work evaluated the anticonvulsant effect of α‐ and β‐pinene in pentylenetetrazole‐induced convulsions model. Initially, the oral LD₅₀ for α‐ and β‐pinene was estimated. Following the oral administration, a mild sedation was observed and no deaths were recorded; the LD₅₀ estimated for both monoterpenes was greater than 2 000 mg/kg, p.o. Further, animals were orally treated with α‐pinene (100, 200 and 400 mg/kg), β‐pinene (100, 200 and 400 mg/kg) and the equimolar mixture of α‐ and β‐pinene (400 mg/kg) and subjected to the pentylenetetrazole‐induced convulsions model. In this model, only the dose of 400 mg/kg of the compounds was able to significantly decrease the seizure intensity. The latency of first convulsion was significantly increased by the mixture of α‐ and β‐pinene (400 mg/kg). In addition, β‐pinene and the mixture of the two monoterpenes, both at a dose of 400 mg/kg, significantly increased the time of death of animals. The treatment with β‐pinene and the equimolar mixture of the two monoterpenes significantly reduced hippocampal nitrite level and striatal content of dopamine (DA) and norepinephrine (NE). Taken together, the results suggest that α‐pinene appears to be devoid of anticonvulsant action. This fact, however, seems to be dependent on the chemical structure of the compound, since pretreatment with the β‐pinene increased the time of death pf PTZ‐treated mice, which seems to depend on the ability of the compound to reduce nitrite concentration and NE and DA content, during the pentylenetetrazole‐induced seizure.     

Protective effect of (−)-epigallocatechin-gallate (EGCG) on lipid peroxide metabolism in isoproterenol induced myocardial infarction in male Wistar rats: A histopathological study

This study aims to evaluate the preventive effect of (−)-epigallocatechin-gallate (EGCG) on lipid peroxides, enzymatic and non-enzymatic antioxidants and histopathological findings in isoproterenol (ISO)-induced rats. Myocardial infarction (MI) is induced in rats by subcutaneous injection of ISO (100 mg/kg body weight) at an interval of 24 h for 2 days. ISO-treated rats show a significant increase in the levels of thiobarbituric acid reactive substances, lipid hydroperoxides in plasma and heart and plasma uric acid and a significant decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase in heart and the levels of reduced glutathione, vitamin C and vitamin E in plasma and the heart and ceruloplasmin in plasma. Oral pretreatment with EGCG (10, 20 and 30 mg/kg body weight) daily for a period of 21 days show significant decrease in the levels of lipid peroxidation products and uric acid and improved the antioxidant status by increasing the activities of antioxidant enzymes and non-enzymic antioxidants. Histopathological findings of the myocardial tissue show the protective effect of EGCG in ISO-induced rats. The effect at a dose of 30 mg/kg of EGCG was more pronounced than that of the other two doses (10 and 20 mg/kg body weight). Thus, the present study reveals that EGCG exerts cardioprotective effect against ISO-induced MI due to its free radical scavenging and antioxidant effects, which maintains the tissue defense system against myocardial damage.     

Influence of arachidonyl‐2′‐chloroethylamide,a selective cannabinoid CB1 receptor agonist,on the anticonvulsant and acute side‐effect potentials of clobazam,lacosamide, and pregabalin in the maximal electroshock‐induced seizure model and chimney test in mice

The influence of arachidonyl‐2′‐chloroethylamide (ACEA – a selective cannabinoid CB₁ receptor agonist) on the anticonvulsant potency and acute adverse‐effect potentials of clobazam, lacosamide, and pregabalin was determined in the maximal electroshock‐induced seizure model and chimney test in mice. ACEA (2.5 mg/kg, i.p.) significantly enhanced the anticonvulsant potency of pregabalin in the mouse maximal electroshock‐induced seizure model by decreasing the median effective dose (ED₅₀) of pregabalin from 125.39 to 78.06 mg/kg (P < 0.05). In contrast, ACEA (2.5 mg/kg) had no significant impact on the anticonvulsant potency of clobazam and lacosamide in the mouse maximal electroshock‐induced seizure model. On the other hand, ACEA (2.5 mg/kg) did not affect acute adverse effects of clobazam, lacosamide or pregabalin, and the median toxic doses (TD₅₀) for the studied anti‐epileptic drugs in combination with ACEA did not differ from the TD₅₀ values as determined for the drugs administered alone in the chimney test. In conclusion, ACEA ameliorates the pharmacological profile of pregabalin, when considering both the anticonvulsant and the acute adverse effects of the drug in preclinical study on animals. The combination of pregabalin with ACEA can be of pivotal importance for patients with epilepsy as a potentially advantageous combination if the results from this study translate into clinical settings.     

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.     

Neuropharmacological effects of lipoic acid and ubiquinone on δ‐aminolevulinic dehydratase,Na+, K+‐ATPase,and Mg2+‐ATPase activities in rat hippocampus after pilocarpine‐induced seizures

In this study, we investigated the effects of lipoic acid (LA) in the hippocampus oxidative stress caused by pilocarpine‐induced seizures in adult rats. Wistar rats were treated with 0.9% saline (i.p., control group), LA (10 mg/kg, i.p., LA group), ubiquinone [20 mg/kg, i.p., ubiquinone (UQ) group], pilocarpine (400 mg/kg, i.p., P400 group), and the association of LA (10 mg/kg, i.p.) plus pilocarpine (400 mg/kg, i.p.) or UQ (20 mg/kg, i.p.) plus pilocarpine (400 mg/kg, i.p.), 30 min before of administration of P400 (LA plus P400 group and UQ plus P400 group, respectively). After the treatments, all groups were observed for 1 h. The enzyme activities (δ‐aminolevulinic dehydratase (δ‐ALA‐D), Mg²⁺‐ATPase, and Na⁺, K⁺‐ATPase) were measured using spectrophotometric methods, and the results compared to values obtained from saline and pilocarpine‐treated animals. Protective effects of LA and UQ were also evaluated on the same parameters. We reported here for the first time that Na⁺, K⁺‐ATPase and δ‐ALA‐D activities inhibition and Mg²⁺‐ATPase stimulation in the pilocarpine model are probably attributed to the oxidative stress caused by seizures in the rat hippocampus. The addition of the antioxidants LA and UQ may reverses the previously mentioned Na⁺, K⁺‐ATPase and δ‐ALA‐D inhibitions and Mg²⁺‐ATPase stimulation. Conclusions: The oxidative stress plays an important signaling role in pilocarpine‐induced seizures, and antioxidant drugs might be considered as therapeutical tools in this pathology.     

Sumatriptan reduces severity of status epilepticus induced by lithium–pilocarpine through nitrergic transmission and 5‐HT1B/D receptors in rats: A pharmacological‐based evidence

Status epilepticus (SE) is a life‐threatening neurologic disorder that can be as both cause and consequence of neuroinflammation. In addition to previous reports on anti‐inflammatory property of the anti‐migraine medication sumatriptan, we have recently shown its anticonvulsive effects on pentylenetetrazole‐induced seizure in mice. In the present study, we investigated further (i) the effects of sumatriptan in the lithium–pilocarpine SE model in rats, and (ii) the possible involvement of nitric oxide (NO), 5‐hydroxytryptamin 1B/1D (5‐HT_1B/1D) receptor, and inflammatory pathways in such effects of sumatriptan. Status epilepticus was induced by lithium chloride (127 mg/kg, i.p) and pilocarpine (60 mg/kg, i.p.) in Wistar rats. While SE induction increased SE scores and mortality rate, sumatriptan (0.001‐1 mg/kg, i.p.) improved it (P < 0.001). Administration of the selective 5‐HT_1B/1D antagonist GR‐127935 (0.01 mg/kg, i.p.) reversed the anticonvulsive effects of sumatriptan (0.01 mg/kg, i.p.). Although both tumor necrosis factor‐α (TNF‐α) and NO levels were markedly elevated in the rats' brain tissues post‐SE induction, pre‐treatment with sumatriptan significantly reduced both TNF‐α (P < 0.05) and NO (P < 0.001) levels. Combined GR‐127935 and sumatriptan treatment inhibited these anti‐inflammatory effects of sumatriptan, whereas combined non‐specific NOS (L‐NAME) or selective neuronal NOS (7‐nitroindazole) inhibitors and sumatriptan further reduced NO levels. In conclusion, sumatriptan exerted a protective effect against the clinical manifestations and mortality rate of SE in rats which is possibly through targeting 5‐HT_1B/1D receptors, neuroinflammation, and nitrergic transmission.