β-lactamase inhibitors display anti-seizure properties in an invertebrate assay.
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.
Rawls
S M
SM
Department of Pharmaceutical Sciences, Temple University Health Sciences Center, Philadelphia, PA 19140, USA. scott.rawls@temple.edu
Karaca
F
F
Madhani
I
I
Bhojani
V
V
Martinez
R L
RL
Abou-Gharbia
M
M
Raffa
R B
RB
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010932:Planarians / Q000187:drug effects* / Q000201:enzymology; D012640:Seizures / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000502:physiology
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases