日前,在线出版的《自然—医学》期刊上发表的一项研究表明,研究人员发现,阻止胱氨酸—谷氨酸脂输送器能减少神经胶质瘤所诱导的小鼠癫痫发作。
因为肿瘤细胞分泌出刺激性的神经递质谷氨酸酯,神经胶质瘤患者常常会发生癫痫。神经胶质瘤的生存需要有氨基酸胱氨酸的存在,在肿瘤上的胱氨酸—谷氨酸酯输送器将胱氨酸送往肿瘤细胞中之时,肿瘤也在附近的脑组织周围分泌出大量的谷氨酸酯,导致肿瘤附近的神经细胞过度活跃,癫痫发作。
柳氮磺胺吡啶是食品和药物管理署(FDA)批准使用的胱氨酸—谷氨酸酯输送器抑止剂,用于治疗肠道炎症患者。Harald Sontheimer和同事给患肿瘤的小鼠使用柳氮磺胺吡啶,发现这种药物能阻止导致肿瘤的大脑谷氨酸酯水平的升高,也能减少神经胶质瘤所引发的小鼠癫痫发作。这些新发现表明,有望开发新的治疗方法以减少人类因脑肿瘤引发的癫痫发作。(生物谷 Bioon.com)
doi:10.1038/nm.2453
PMC:
PMID:
Glutamate release by primary brain tumors induces epileptic activity
Susan C Buckingham, Susan L Campbell, Brian R Haas, Vedrana Montana, Stefanie Robel, Toyin Ogunrinu & Harald Sontheimer
Epileptic seizures are a common and poorly understood comorbidity for individuals with primary brain tumors. To investigate peritumoral seizure etiology, we implanted human-derived glioma cells into severe combined immunodeficient mice. Within 14–18 d, glioma-bearing mice developed spontaneous and recurring abnormal electroencephalogram events consistent with progressive epileptic activity. Acute brain slices from these mice showed marked glutamate release from the tumor mediated by the system xc− cystine-glutamate transporter (encoded by Slc7a11). Biophysical and optical recordings showed glutamatergic epileptiform hyperexcitability that spread into adjacent brain tissue. We inhibited glutamate release from the tumor and the ensuing hyperexcitability by sulfasalazine (SAS), a US Food and Drug Administration–approved drug that blocks system xc−. We found that acute administration of SAS at concentrations equivalent to those used to treat Crohn's disease in humans reduced epileptic event frequency in tumor-bearing mice compared with untreated controls. SAS should be considered as an adjuvant treatment to ameliorate peritumoral seizures associated with glioma in humans.