Payandemehr Borna, Khoshneviszadeh Mahsima, Varastehmoradi Bardia, Gholizadeh Ramtin, Bahremand Taraneh, Attar Hossein, Bahremand Arash, Dehpour Ahmad Reza
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box: 13145-784, Tehran, Iran.
Neurochem Res. 2015 Sep;40(9):1819-28. doi: 10.1007/s11064-015-1669-z. Epub 2015 Jul 28.
Licofelone is a COX/5-LOX inhibitor, which recently was approved as an effective treatment for osteoarthritis. Beside its analgesic and anti-inflammatory effects, some reports show neuro-protective properties for this agent in central nervous system. Several lines of evidence declare the involvement of COX or LOX isoenzymes in epileptic disorders. To set the foundation for future research into the neurobiology of licofelone as a potential therapeutic agent, we studied the effect of licofelone in an animal model of epilepsy. Although different neurotransmitters and neuro-modulators like nitric oxide were introduced as suggested targets of licofelone, the underlying mechanisms of central effects of this drug are not still fully understood. We have utilized pentylenetetrazole-induced clonic seizure model to investigate the behavioral consequences of licofelone administration and its possible mechanisms in seizure susceptibility. Licofelone revealed anticonvulsant properties at the dose of 10 mg/kg (i.p) or higher in mice. Pre-treatment with NO (nitric oxide) donor, L-arginine, reversed this anticonvulsant effects dose dependently. L-NAME, as a non-selective nitric oxide synthase (NOS) inhibitor, potentiated the anticonvulsant effects of licofelone. A neuronal NOS inhibitor, 7-NI did not affect seizure threshold alone or in combination with licofelone. Using non-effective doses of selective inhibitors of inducible NOS, aminoguanidine or 1400W, significantly increased the seizure threshold when were accompanied by licofelone in low doses. These data support the involvement of NO as an important role player in the central neuro-protective properties of licofelone. Furthermore, it implies that down regulation of iNOS seems crucial for anticonvulsant properties of this COX/5-LOX inhibitor in seizure susceptibility.
利考非隆是一种环氧化酶/5-脂氧合酶抑制剂，最近被批准作为骨关节炎的有效治疗药物。除了其镇痛和抗炎作用外，一些报告显示该药物在中枢神经系统中具有神经保护特性。有几条证据表明环氧化酶或脂氧合酶同工酶参与癫痫疾病。为了为未来将利考非隆作为潜在治疗药物进行神经生物学研究奠定基础，我们研究了利考非隆在癫痫动物模型中的作用。尽管不同的神经递质和神经调节剂如一氧化氮被认为是利考非隆的潜在靶点，但该药物中枢作用的潜在机制仍未完全清楚。我们利用戊四氮诱导的阵挛性癫痫模型来研究利考非隆给药的行为后果及其在癫痫易感性中的可能机制。利考非隆在小鼠腹腔注射剂量为10mg/kg或更高时显示出抗惊厥特性。用一氧化氮供体L-精氨酸预处理可剂量依赖性地逆转这种抗惊厥作用。L-NAME作为一种非选择性一氧化氮合酶抑制剂，增强了利考非隆的抗惊厥作用。神经元型一氧化氮合酶抑制剂7-NI单独或与利考非隆联合使用时均不影响癫痫阈值。使用无效剂量的诱导型一氧化氮合酶选择性抑制剂氨基胍或1400W，当与低剂量利考非隆联合使用时，可显著提高癫痫阈值。这些数据支持一氧化氮在利考非隆的中枢神经保护特性中起重要作用。此外，这意味着诱导型一氧化氮合酶的下调似乎对这种环氧化酶/5-脂氧合酶抑制剂在癫痫易感性中的抗惊厥特性至关重要。
