Keshavarzi Mohammad, Ghasemi Moein, Manavi Mohammad Amin, Dehpour Ahmad Reza, Shafaroodi Hamed
Department of Pharmacology & Toxicology, Faculty of Pharmacy and Pharmaceutical Sciences, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
Pharmacology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
IBRO Neurosci Rep. 2024 Nov 26;17:485-492. doi: 10.1016/j.ibneur.2024.11.013. eCollection 2024 Dec.
Epilepsy remains a challenge, with one-third of patients experiencing refractory seizures despite current anti-seizure medications. The nitrergic system, which involves nitric oxide (NO) and NO synthase (NOS) enzymes, plays a complex role in seizure pathophysiology. Pentoxifylline (PTPh), an FDA-approved phosphodiesterase inhibitor, has anticonvulsant effects; however, its relationship with the pathway is unclear. This study focused at how the nitrergic system could be involved in PTPh's anticonvulsant effects.
Seizures were induced in male mice by intravenous pentylenetetrazole (PTZ) infusion (absence-like seizures), intraperitoneal PTZ injection, and maximal electroshock (generalized tonic-clonic seizures). PTPh was administered at various doses, alone or in combination with the NO precursor L-arginine, as well as non-selective (L-NAME) and selective NOS inhibitors (nNOS inhibitor 7-NI and iNOS inhibitor aminoguanidine). Seizure thresholds, latencies, incidence, and mortality were assessed. Moreover, in the next paradigm, using maximal electroshock model, we evaluate possible protective effects of PTPh against generalized tonic-clonic seizures and subsequent mortality.
In the intravenous PTZ model, PTPh (≥150 mg/kg) increased the seizure threshold, potentiated by L-arginine but reduced by L-NAME and 7-nitroindazole. In the intraperitoneal PTZ model, 150 mg/kg PTPh decreased tonic seizure frequency, which was mitigated by aminoguanidine. However, PTPh failed to prolong clonic seizure latency. In the maximal electroshock test, 100 mg/kg PTPh protected against tonic seizure incidence (reduced by aminoguanidine). Although PTPh could not reduce mortality, its combination with L-NAME or 7-nitroindazole increased mortality compared with the vehicle-treated group.
PTPh exerted anticonvulsant effects against absence-like and generalized tonic-clonic seizures, likely through modulation of the nitrergic system involving neuronal, endothelial, and inducible NOS isoform. These findings provide novel insights into the complex interplay between NO signaling and the anticonvulsant actions of PTPh, highlighting the potential therapeutic implications of targeting the NO pathway in epilepsy management.
癫痫仍然是一个挑战，尽管目前有抗癫痫药物，但仍有三分之一的患者经历难治性癫痫发作。涉及一氧化氮（NO）和一氧化氮合酶（NOS）酶的氮能系统在癫痫病理生理学中发挥着复杂的作用。己酮可可碱（PTPh）是一种经美国食品药品监督管理局（FDA）批准的磷酸二酯酶抑制剂，具有抗惊厥作用；然而，其与该途径的关系尚不清楚。本研究聚焦于氮能系统如何参与PTPh的抗惊厥作用。
通过静脉注射戊四氮（PTZ）（失神样发作）、腹腔注射PTZ和最大电休克（全身强直阵挛性发作）诱导雄性小鼠癫痫发作。PTPh以不同剂量单独给药或与NO前体L-精氨酸联合给药，以及与非选择性（L-NAME）和选择性NOS抑制剂（nNOS抑制剂7-NI和iNOS抑制剂氨基胍）联合给药。评估癫痫发作阈值、潜伏期、发生率和死亡率。此外，在下一个范式中，使用最大电休克模型，我们评估PTPh对全身强直阵挛性发作和随后死亡率的可能保护作用。
在静脉注射PTZ模型中，PTPh（≥150mg/kg）提高了癫痫发作阈值，L-精氨酸使其增强，但L-NAME和7-硝基吲唑使其降低。在腹腔注射PTZ模型中，150mg/kg PTPh降低了强直性癫痫发作频率，氨基胍可减轻这种作用。然而，PTPh未能延长阵挛性癫痫发作潜伏期。在最大电休克试验中，100mg/kg PTPh预防了强直性癫痫发作的发生（氨基胍可降低其发生率）。虽然PTPh不能降低死亡率，但其与L-NAME或7-硝基吲唑联合使用时，与溶剂处理组相比死亡率增加。
PTPh对失神样发作和全身强直阵挛性发作具有抗惊厥作用，可能是通过调节涉及神经元、内皮和诱导型NOS亚型的氮能系统。这些发现为NO信号与PTPh抗惊厥作用之间的复杂相互作用提供了新的见解，突出了靶向NO途径在癫痫管理中的潜在治疗意义。
