Department of Neuroscience, Psychology, Drug Research and Child Health, NEUROFARBA-Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Int J Mol Sci. 2022 Jun 2;23(11):6229. doi: 10.3390/ijms23116229.
Neuropathy development is a major dose-limiting side effect of anticancer treatments that significantly reduces patient's quality of life. The inadequate pharmacological approaches for neuropathic pain management warrant the identification of novel therapeutic targets. Mitochondrial dysfunctions that lead to reactive oxygen species (ROS) increase, cytosolic Ca imbalance, and lactate acidosis are implicated in neuropathic pain pathogenesis. It has been observed that in these deregulations, a pivotal role is played by the mitochondrial carbonic anhydrases (CA) VA and VB isoforms. Hence, preclinical studies should be conducted to assess the efficacy of two novel selenides bearing benzenesulfonamide moieties, named and , and able to inhibit CA VA and VB against paclitaxel-induced neurotoxicity in mice. Acute treatment with and (30-100 mg/kg, per os - p.o.) determined a dose-dependent and long-lasting anti-hyperalgesic effect in the Cold plate test. Further, repeated daily treatment for 15 days with 100 mg/kg of both compounds (starting the first day of paclitaxel injection) significantly prevented neuropathic pain development without the onset of tolerance to the anti-hyperalgesic effect. In both experiments, acetazolamide (AAZ, 100 mg/kg, p.o.) used as the reference drug was partially active. Moreover, ex vivo analysis demonstrated the efficacy of and repeated treatments in reducing the maladaptive plasticity that occurs to glia cells in the lumbar portion of the spinal cord and in improving mitochondrial functions in the brain and spinal cord that were strongly impaired by paclitaxel-repeated treatment. In this regard, and ameliorated the metabolic activity, as observed by the increase in citrate synthase activity, and preserved an optimal mitochondrial membrane potential (ΔΨ) value, which appeared depolarized in brains from paclitaxel-treated animals. In conclusion, and have therapeutic and protective effects against paclitaxel-induced neuropathy without tolerance development. Moreover, and reduced glial cell activation and mitochondrial dysfunction in the central nervous system, being a promising candidate for the management of neuropathic pain and neurotoxicity evoked by chemotherapeutic drugs.
神经病变的发展是癌症治疗的一个主要剂量限制的副作用，它显著降低了患者的生活质量。对于神经性疼痛管理的药理学方法不足，需要确定新的治疗靶点。导致活性氧（ROS）增加、细胞溶质 Ca 失衡和乳酸酸中毒的线粒体功能障碍与神经性疼痛的发病机制有关。已经观察到，在这些失调中，线粒体碳酸酐酶（CA）VA 和 VB 同工型起着关键作用。因此，应该进行临床前研究来评估两种新型含苯磺酰胺基硒化物的疗效，它们分别命名为和，并能够抑制 CA VA 和 VB，以对抗紫杉醇诱导的小鼠神经毒性。急性用（30-100mg/kg，口服 - p.o.）治疗确定了在冷板测试中的剂量依赖性和持久的抗痛觉过敏作用。此外，用两种化合物（从紫杉醇注射的第一天开始）每天重复治疗 15 天，剂量为 100mg/kg，可显著预防神经性疼痛的发展，而不会对抗痛觉过敏作用产生耐受。在这两种实验中，乙酰唑胺（AAZ，100mg/kg，口服）作为参考药物部分有效。此外，离体分析表明，重复用和治疗可有效降低脊髓腰部胶质细胞发生的适应性可塑性，并改善因紫杉醇重复治疗而严重受损的大脑和脊髓中的线粒体功能。在这方面，和改善了代谢活性，如柠檬酸合酶活性的增加所观察到的，并且保持了最佳的线粒体膜电位（ΔΨ）值，该值在紫杉醇处理动物的大脑中显得去极化。总之，和对紫杉醇诱导的周围神经病变具有治疗和保护作用，而无耐药性发展。此外，和减少了中枢神经系统中的神经胶质细胞激活和线粒体功能障碍，是管理化疗药物引起的神经性疼痛和神经毒性的有希望的候选药物。
