Current therapeutic strategies for bacterial meningitis (BM) are insufficient and new approaches to the adjunctive therapy of BM are needed. Understanding the processes that lead to brain damage in BM is crucial for the development of more effective new drugs that can preserve neuronal function.
To study these mechanisms and to evaluate new therapeutic strategies, we have developed an infant rat model of BM due to Streptococcus pneumoniae. Preliminary results generated with regard to the proposed grant show that two specific classes of molecules are important mediators of neuronal injury and promising targets of therapeutic intervention in BM:
- Reactive oxygen species (ROS), and
- Matrix metalloproteinases (MMPs).
Reactive oxygen species are potent cytotoxic oxidants. Our preliminary results indicate that ROS play a major role in the development of neuronal injury in BM. Recent studies suggest that the pathogenic effects of ROS are, at least in part, mediated by their capability to induce gene transcription, and on the protein level, to activate latent forms of MMPs.
MMPs are a family of Zn2+-dependent endopeptidases that can degrade virtually all components of extracellular matrix. MMPs are effector molecules of neutrophil extravasation and blood brain barrier breakdown in BM. We have shown that MMPs are present in high concentration in CSF of patients with BM, and their inhibition in the rat model of BM significantly decrease neuronal injury.
We hypothesise: 1) That in BM, ROS generation leads to induction and activation of MMPs, 2) That this pathway is instrumental for the development of neuronal injury, 3) That inhibition of this pathway will reduce the severity of the disease and protect from neurological sequelae more effectively than currently used corticosteroids.
This project addresses an eminent clinical question with an animal model that is meaningful for the human disease of BM, where current therapeutic tools are insufficient. The results of this project are expected to produce the scientific basis for the use of novel adjunctive therapy in human BM.
Results from this study have been published in scientific journals as follows:
Christen S, Schaper M, Lykkesfeldt J, Siegenthaler C, Bifrare YD, Banic S, Leib SL, Tauber MG.
Oxidative stress in brain during experimental bacterial meningitis: differential effects of alpha-phenyl-tert-butyl nitrone and N-acetylcysteine treatment.
Free Radic Biol Med 2001 Sep 15;31(6):754-62.
Leib SL, Clements JM, Lindberg RL, Heimgartner C, Loeffler JM, Pfister LA, Tauber MG, Leppert D.
Inhibition of matrix metalloproteinases and tumour necrosis factor alpha converting enzyme as adjuvant therapy in pneumococcal meningitis.
Brain 2001 Sep;124(Pt 9):1734-42.
Leppert D, Lindberg RL, Kappos L, Leib SL.
Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis.
Brain Res Brain Res Rev 2001 Oct;36(2-3):249-57.
Bifrare YD, Gianinazzi C, Imboden H, Leib SL, Tauber MG.
Bacterial meningitis causes two distinct forms of cellular damage in the hippocampal dentate gyrus in infant rats.
Gianinazzi C, Grandgirard D, Imboden H, Egger L, Meli DN, Bifrare YD, Joss PC, Tauber MG, Borner C, Leib SL.
Caspase-3 mediates hippocampal apoptosis in pneumococcal meningitis.
Acta Neuropathol (Berl) 2003 May;105(5):499-507. Epub 2003 Feb 12.
Meli DN, Christen S, Leib SL.
Matrix metalloproteinase-9 in pneumococcal meningitis: activation via an oxidative pathway.
J Infect Dis 2003 May 1;187(9):1411-5. Epub 2003 Apr 15. http://www.journals.uchicago.edu/JID/journal/issues/v187n9/30088/30088.web.pdf
Schaper M, Leib SL, Meli DN, Brandes RP, Tauber MG, Christen S.
Differential effect of p47phox and gp91phox deficiency on the course of Pneumococcal Meningitis.
Infect Immun 2003 Jul;71(7):4087-92.
Leib SL, Heimgartner C, Bifrare YD, Loeffler JM, Taauber MG.
Dexamethasone aggravates hippocampal apoptosis and learning deficiency in pneumococcal meningitis in infant rats. Pediatr Res 2003 Sep;54(3):353-7. Epub 2003 Jun 4.
Meli DN, Loeffler JM, Baumann P, Neumann U, Buhl T, Leppert D, Leib SL.
In pneumococcal meningitis a novel water-soluble inhibitor of matrix metalloproteinases and TNF-alpha converting enzyme attenuates seizures and injury of the cerebral cortex.
J Neuroimmunol 2004 Jun;151(1-2):6-11.
Schaper M, Gergely S, Lykkesfeldt J, Zbaren J, Lieb SL, Tauber MG, Christen S.
Cerebral vasculature is the major target of oxidative protein alterations in bacterial meningitis.
J Neuropathol Exp Neurol 2002 Jul;61(7):605-13.
Williams PL, Leib SL, Kamberi P, Leppert D, Sobel RA, Bifrare YD, Clemons KV, Stevens DA.
Levels of matrix metalloproteinase-9 within cerebrospinal fluid in a rabbit model of coccidioidal meningitis and vasculitis.
J Infect Dis 2002 Dec 1;186(11):1692-5. Epub 2002 Nov 1. http://www.journals.uchicago.edu/JID/journal/issues/v186n11/020320/020320.web.pdf
Ghielmetti M, Ren H, Leib SL, Tauber MG, Christen S.
Impaired cortical energy metabolism but not major antioxidant defenses in experimental bacterial meningitis.
Brain Res 2003 Jun 27;976(2):139-48.
Gianinazzi C, Grandgirard D, Simon F, Imboden H, Joss P, Tauber MG, Leib SL.
Apoptosis of hippocampal neurons in organotypic slice culture models: direct effect of bacteria revisited
J Neuropathol Exp Neurol 2004 Jun;63(6):610-7.