Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Department of Neurology, University of Massachusetts Medical School, Worcester, MA, United States.
Epilepsy Res. 2020 Aug;164:106362. doi: 10.1016/j.eplepsyres.2020.106362. Epub 2020 May 11.
Although accumulating evidence indicates that the immunomodulatory medication thalidomide exerts anticonvulsant properties, the mechanisms underlying such effects of thalidomide are still unknown. Our previous preclinical study suggested that nitric oxide (NO) signaling may be involved in the anticonvulsant effects of thalidomide in a mouse model of clonic seizure. Additionally, several studies have shown a modulatory interaction between thalidomide and opioids in opioids intolerance, nociception and neuropathic pain. However, it is unclear whether opioidergic transmission or its interaction with NO signaling is involved in the anticonvulsant effects of thalidomide. Given the fact that both opioidergic and nitrergic transmissions have bimodal modulatory effects on seizure thresholds, in the present study we explored the involvement of these signaling pathways in the possible anticonvulsant effects of thalidomide on the pentylenetetrazole (PTZ)-induced clonic seizure in mice. Our data showed that acute administration of thalidomide (5-50 mg/kg, i.p., 30 min prior PTZ injection) dose-dependently elevated PTZ-induced clonic seizure thresholds. Acute administration of low doses (0.5-3 mg/kg, i.p., 60 min prior PTZ) of morphine exerted anticonvulsant effects (P < 0.001), whereas higher doses (15-60 mg/kg, 60 min prior PTZ) had proconvulsant effects (P < 0.01). Acute administration of a non-effective anticonvulsant dose of morphine (0.25 mg/kg) prior non-effective dose of thalidomide (5 mg/kg) exerted a robust (P < 0.01) anticonvulsant effect. Administration of a non-effective proconvulsant dose of morphine (7.5 mg/kg) prior thalidomide (5 mg/kg) didn't affect clonic seizure thresholds. Acute administration of a non-effective dose of the opioid receptor antagonist naltrexone (1 mg/kg, i.p.) significantly prevented anticonvulsant effects of thalidomide (10 mg/kg, i.p.). Pretreatment with non-effective dose of the NO precursor L-arginine (60 mg/kg, i.p.) significantly (P < 0.01) reduced the anticonvulsant effects of combined low doses of morphine (0.25 mg/kg) and thalidomide (5 mg/kg). Conversely, pretreatment with non-effective doses of either non-selective (L-NAME, 5 mg/kg, i.p.) or selective neuronal (7-nitroindazole, 30 mg/kg, i.p.) NO synthase (NOS) inhibitors significantly augmented the anticonvulsant effects of combined low doses of thalidomide and morphine, whereas the inducible NOS inhibitor aminoguanidine (100 mg/kg, i.p.) did not exert such effect. Our results indicate that opioidergic transmission and its interaction with neuronal NO signaling may contribute to the anti-seizure activity of thalidomide in the mice PTZ model of clonic seizure.
尽管越来越多的证据表明免疫调节药物沙利度胺具有抗惊厥作用，但沙利度胺产生这种作用的机制仍不清楚。我们之前的临床前研究表明，一氧化氮（NO）信号可能参与了沙利度胺在氯胺酮惊厥小鼠模型中的抗惊厥作用。此外，几项研究表明，沙利度胺和阿片类药物在阿片类药物不耐受、疼痛和神经病理性疼痛之间存在调节相互作用。然而，阿片能传递及其与 NO 信号的相互作用是否参与沙利度胺的抗惊厥作用尚不清楚。鉴于阿片能和氮能传递对惊厥阈值都有双相调节作用，在本研究中，我们探讨了这些信号通路是否参与沙利度胺对小鼠戊四氮（PTZ）诱导的阵挛性惊厥可能产生的抗惊厥作用。我们的数据显示，沙利度胺（5-50mg/kg，腹腔注射，PTZ 注射前 30 分钟）急性给药呈剂量依赖性地提高 PTZ 诱导的阵挛性惊厥阈值。阿片类药物的急性低剂量（0.5-3mg/kg，腹腔注射，PTZ 注射前 60 分钟）表现出抗惊厥作用（P<0.001），而较高剂量（15-60mg/kg，PTZ 注射前 60 分钟）则具有促惊厥作用（P<0.01）。急性给予非有效抗惊厥剂量的吗啡（0.25mg/kg），然后给予非有效剂量的沙利度胺（5mg/kg），则产生强大的（P<0.01）抗惊厥作用。预先给予非有效促惊厥剂量的吗啡（7.5mg/kg），然后给予沙利度胺（5mg/kg），则不影响阵挛性惊厥阈值。急性给予非有效剂量的阿片受体拮抗剂纳曲酮（1mg/kg，腹腔注射）可显著阻止沙利度胺（10mg/kg，腹腔注射）的抗惊厥作用。预先给予非有效剂量的一氧化氮前体 L-精氨酸（60mg/kg，腹腔注射）可显著（P<0.01）降低低剂量吗啡（0.25mg/kg）和沙利度胺（5mg/kg）联合用药的抗惊厥作用。相反，预先给予非选择性（L-NAME，5mg/kg，腹腔注射）或选择性神经元（7-硝基吲唑，30mg/kg，腹腔注射）一氧化氮合酶（NOS）抑制剂的非有效剂量显著增强了低剂量沙利度胺和吗啡联合用药的抗惊厥作用，而诱导型 NOS 抑制剂氨基胍（100mg/kg，腹腔注射）则没有这种作用。我们的结果表明，阿片能传递及其与神经元 NO 信号的相互作用可能有助于沙利度胺在小鼠 PTZ 阵挛性惊厥模型中的抗惊厥作用。
