Department of Pharmaceutical Sciences, Temple University Health Sciences Center, Philadelphia, PA 19140, USA.
Neuroscience. 2010 Sep 15;169(4):1800-4. doi: 10.1016/j.neuroscience.2010.06.041. Epub 2010 Jun 23.
Antibiotics containing a beta-lactam ring (e.g. ceftriaxone) display anti-glutamate effects that underlie their efficacy in animal models of central nervous system (CNS) diseases [Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB (2005) Nature 433:73-77]. We hypothesized that the structurally related beta-lactamase inhibitors (clavulanic acid, tazobactam)--which also contain a beta-lactam ring--will mimic ceftriaxone efficacy in an invertebrate (planarian) assay designed to screen for anti-seizure activity [Rawls SM, Thomas T, Adeola M, Patil T, Raymondi N, Poles A, Loo M, Raffa RB (2009) Pharmacol Biochem Behav 93:363-367]. Glutamate or cocaine administration produced planarian seizure-like activity (pSLA). Glutamate- or cocaine-induced pSLA was inhibited by ceftriaxone, clavulanic acid, or tazobactam, but not by the non-beta-lactam antibiotic vancomyocin. The present findings indicate beta-lactamase inhibitors display efficacy, and mimic ceftriaxone activity, in an invertebrate anti-seizure screen. These results suggest beta-lactamase inhibitors--particularly ones such as clavulanic acid that display enhanced brain penetrability, oral bioavailability, and negligible anti-bacterial activity--might offer an attractive alternative to direct antibiotic therapy for managing CNS diseases caused by increased glutamate transmission and provide a solution to the growing concern that ceftriaxone will be of only limited utility as a CNS-active therapeutic because of its intolerable side effects.
含β-内酰胺环的抗生素（如头孢曲松）具有抗谷氨酸作用，这是它们在中枢神经系统（CNS）疾病动物模型中有效的基础[Rothstein JD、Patel S、Regan MR、Haenggeli C、Huang YH、Bergles DE、Jin L、Dykes Hoberg M、Vidensky S、Chung DS、Toan SV、Bruijn LI、Su ZZ、Gupta P、Fisher PB（2005）自然 433:73-77]。我们假设，结构上相关的β-内酰胺酶抑制剂（克拉维酸、他唑巴坦）——它们也含有β-内酰胺环——将在一种用于筛选抗惊厥活性的无脊椎动物（扁形虫）测定中模拟头孢曲松的疗效[Rawls SM、Thomas T、Adeola M、Patil T、Raymondi N、Poles A、Loo M、Raffa RB（2009）药理学与生物化学行为 93:363-367]。谷氨酸或可卡因给药产生扁形虫惊厥样活动（pSLA）。头孢曲松、克拉维酸或他唑巴坦抑制谷氨酸或可卡因诱导的 pSLA，但非β-内酰胺抗生素万古霉素则不能。本研究结果表明，β-内酰胺酶抑制剂在无脊椎动物抗惊厥筛选中具有疗效，并模拟头孢曲松的活性。这些结果表明，β-内酰胺酶抑制剂——特别是那些具有增强的脑穿透性、口服生物利用度和可忽略的抗细菌活性的抑制剂，如克拉维酸——可能为管理由谷氨酸传递增加引起的 CNS 疾病提供一种有吸引力的替代直接抗生素治疗方法，并为人们日益关注的头孢曲松由于其不可耐受的副作用，将只能有限地用于治疗 CNS 疾病这一问题提供解决方案。
