Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1993 Feb;37(2):199–202. doi: 10.1128/aac.37.2.199

Low neurotoxicity of LJC 10,627, a novel 1 beta-methyl carbapenem antibiotic: inhibition of gamma-aminobutyric acidA, benzodiazepine, and glycine receptor binding in relation to lack of central nervous system toxicity in rats.

M Hikida 1, Y Masukawa 1, K Nishiki 1, N Inomata 1
PMCID: PMC187638  PMID: 8383938

Abstract

The toxicity of LJC 10,627 to the central nervous system of rats was evaluated by examining the effects of the compound on gamma-aminobutyric acidA, benzodiazepine, and glycine receptor binding in rat synaptic membranes and on the induction of behavioral convulsions by intraventricular administration to rats. The concentrations of this compound needed to inhibit specific [3H]muscimol binding, specific [3H]diazepam binding, and specific [3H]strychnine binding were greater than those of imipenem, as demonstrated by the 50% inhibitory concentrations (IC50S of LJC 10,627, greater than 10 mM for each; IC50S of imipenem, 0.6, 1.9, and 0.2 mM, respectively). These results reflect the fact that LJC 10,627 does not evoke severe convulsions or cause death, even when it is administered intraventricularly at a high dose (300 micrograms per rat), and suggest that the low neurotoxic potential of LJC 10,627 may be attributed to the chemical structure of this compound, which has a methyl radical at the 1 beta site and a triazolium radical at the side chain of the second site.

Full text

PDF
199

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akahane K., Sekiguchi M., Une T., Osada Y. Structure-epileptogenicity relationship of quinolones with special reference to their interaction with gamma-aminobutyric acid receptor sites. Antimicrob Agents Chemother. 1989 Oct;33(10):1704–1708. doi: 10.1128/aac.33.10.1704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Antoniadis A., Müller W. E., Wollert U. Inhibition of GABA and benzodiazepine receptor binding by penicillins. Neurosci Lett. 1980 Jul;18(3):309–312. doi: 10.1016/0304-3940(80)90302-x. [DOI] [PubMed] [Google Scholar]
  3. Bechtel T. P., Slaughter R. L., Moore T. D. Seizures associated with high cerebrospinal fluid concentrations of cefazolin. Am J Hosp Pharm. 1980 Feb;37(2):271–273. [PubMed] [Google Scholar]
  4. Calandra G. B., Brown K. R., Grad L. C., Ahonkhai V. I., Wang C., Aziz M. A. Review of adverse experiences and tolerability in the first 2,516 patients treated with imipenem/cilastatin. Am J Med. 1985 Jun 7;78(6A):73–78. doi: 10.1016/0002-9343(85)90104-4. [DOI] [PubMed] [Google Scholar]
  5. Christ W. Central nervous system toxicity of quinolones: human and animal findings. J Antimicrob Chemother. 1990 Oct;26 (Suppl B):219–225. doi: 10.1093/jac/26.suppl_b.219. [DOI] [PubMed] [Google Scholar]
  6. Conway N., Beck E., Somerville J. Penicillin encephalopathy. Postgrad Med J. 1968 Dec;44(518):891–897. doi: 10.1136/pgmj.44.518.891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hikida M., Kawashima K., Nishiki K., Furukawa Y., Nishizawa K., Saito I., Kuwao S. Renal dehydropeptidase-I stability of LJC 10,627, a new carbapenem antibiotic. Antimicrob Agents Chemother. 1992 Feb;36(2):481–483. doi: 10.1128/aac.36.2.481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hodgman T., Dasta J. F., Armstrong D. K., Visconti J. A., Reilley T. E. Ampicillin-associated seizures. South Med J. 1984 Oct;77(10):1323–1325. doi: 10.1097/00007611-198410000-00031. [DOI] [PubMed] [Google Scholar]
  9. Hori S., Kurioka S., Matsuda M., Shimada J. Inhibitory effect of cephalosporins on gamma-aminobutyric acid receptor binding in rat synaptic membranes. Antimicrob Agents Chemother. 1985 Apr;27(4):650–651. doi: 10.1128/aac.27.4.650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kamei C., Sunami A., Tasaka K. Epileptogenic activity of cephalosporins in rats and their structure-activity relationship. Epilepsia. 1983 Aug;24(4):431–439. doi: 10.1111/j.1528-1157.1983.tb04913.x. [DOI] [PubMed] [Google Scholar]
  11. Lipman B., Neu H. C. Imipenem: a new carbapenem antibiotic. Med Clin North Am. 1988 May;72(3):567–579. doi: 10.1016/s0025-7125(16)30759-3. [DOI] [PubMed] [Google Scholar]
  12. Möhler H., Okada T. Benzodiazepine receptor: demonstration in the central nervous system. Science. 1977 Nov 25;198(4319):849–851. doi: 10.1126/science.918669. [DOI] [PubMed] [Google Scholar]
  13. Nicoll R. A. The coupling of neurotransmitter receptors to ion channels in the brain. Science. 1988 Jul 29;241(4865):545–551. doi: 10.1126/science.2456612. [DOI] [PubMed] [Google Scholar]
  14. Sigel E., Stephenson F. A., Mamalaki C., Barnard E. A. A gamma-aminobutyric acid/benzodiazepine receptor complex of bovine cerebral cortex. J Biol Chem. 1983 Jun 10;258(11):6965–6971. [PubMed] [Google Scholar]
  15. Tse C. S., Hernandez Vera F., Desai D. V. Seizure-like activity associated with imipenem-cilastatin. Drug Intell Clin Pharm. 1987 Jul-Aug;21(7-8):659–660. doi: 10.1177/1060028087021007-820. [DOI] [PubMed] [Google Scholar]
  16. Tsuji A., Sato H., Okezaki E., Nagata O., Kato H. Effect of the anti-inflammatory agent fenbufen on the quinolone-induced inhibition of gamma-aminobutyric acid binding to rat brain membranes in vitro. Biochem Pharmacol. 1988 Nov 15;37(22):4408–4411. doi: 10.1016/0006-2952(88)90625-9. [DOI] [PubMed] [Google Scholar]
  17. Ubukata K., Hikida M., Yoshida M., Nishiki K., Furukawa Y., Tashiro K., Konno M., Mitsuhashi S. In vitro activity of LJC10,627, a new carbapenem antibiotic with high stability to dehydropeptidase I. Antimicrob Agents Chemother. 1990 Jun;34(6):994–1000. doi: 10.1128/aac.34.6.994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. WEINSTEIN L., LERNER P. I., CHEW W. H. CLINICAL AND BACTERIOLOGIC STUDIES OF THE EFFECT OF "MASSIVE" DOSES OF PENICILLIN G ON INFECTIONS CAUSED BY GRAM-NEGATIVE BACILLI. N Engl J Med. 1964 Sep 10;271:525–533. doi: 10.1056/NEJM196409102711101. [DOI] [PubMed] [Google Scholar]
  19. Williams P. D., Bennett D. B., Comereski C. R. Animal model for evaluating the convulsive liability of beta-lactam antibiotics. Antimicrob Agents Chemother. 1988 May;32(5):758–760. doi: 10.1128/aac.32.5.758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Yoshioka H., Nambu H., Fujita M., Uehara H. Convulsion following intrathecal cephaloridine. Infection. 1975;3(2):123–124. doi: 10.1007/BF01641056. [DOI] [PubMed] [Google Scholar]
  21. Young A. B., Snyder S. H. Strychnine binding associated with glycine receptors of the central nervous system. Proc Natl Acad Sci U S A. 1973 Oct;70(10):2832–2836. doi: 10.1073/pnas.70.10.2832. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES