title: Efficacy of GM6001 as an adjuvant to ceftriaxone in a neonatal rat model of Streptococcus pneumoniae meningitis.
abstract: Evidence has demonstrated that matrix metalloproteinases (MMPs) contribute to the pathophysiology of bacterial meningitis; therefore, MMP inhibitors may be a neuroprotective treatment for brain injury caused by meningitis because of their antiinflammatory effects. The objective of this study was to evaluate the effect of the MMP inhibitor GM6001 in a rat model of S. pneumoniae meningitis. For these experiments, 7-day-old Sprague-Dawley rats were randomly divided into an uninfected group, meningitis group, antibiotic group and GM6001+antibiotic group. Uninfected animals were sham infected with sterile saline. Rats in the other three groups were inoculated with S. pneumoniae and left untreated, treated with ceftriaxone, or treated with ceftriaxone combined with GM6001. Rats in the meningitis group were severely ill, and MMP-9 was significantly up-regulated. The change in brain water content was consistent with the MMP-9 level. A significant loss of neurons and impaired learning function were observed in the meningitis group. Treatment with the antibiotic and GM6001 significantly down-regulated the level of MMP-9, decreased the brain water content, attenuated neuronal injury and improved learning. Conclusions: GM6001 protected the brain from damage caused by S. pneumoniae, and this effect may occur via downregulating MMP-9 and decreasing brain water content.
authors.affiliation: Department of Pediatrics, Qilu Hospital, Shandong University, and Brain Science Research Institute, Shandong University, Jinan, P.R. China, liuxinjie@sdu.edu.cn.
authors.forename: Xinjie
authors.initials: X
authors.lastname: Liu
authors.forename: Qizheng
authors.initials: Q
authors.lastname: Han
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001929:Brain Edema / Q000188:drug therapy; D002443:Ceftriaxone / Q000627:therapeutic use*; D004151:Dipeptides / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018093:Gelatinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D020781:Matrix Metalloproteinase 1 / Q000134:cerebrospinal fluid; D020780:Matrix Metalloproteinase 9 / Q000134:cerebrospinal fluid; D018782:Maze Learning / Q000187:drug effects; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D065853:Spatial Learning / Q000187:drug effects; D065852:Spatial Memory / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D002443:Ceftriaxone; D018093:Gelatinases; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1