A study of brain-cell damage in bacterial meningitis to find new treatment strategies
Research archive
- University of Bern, Bern, Switzerland
- Project Number: 0014.0
- Category: Treatment
- Duration: 2001-2004
- Start Date: 01 January 2001
- Type: Lay summary
- View scientific version
Despite powerful antibiotics that can kill meningitis bacteria, treatment cannot always cure meningitis, because toxins the bacteria produce continue causing brain damage even after antibiotics have taken effect. We need to develop new drugs to prevent brain damage. In order to do this we must understand the processes that lead to brain damage in meningitis.
This study investigates these processes and evaluates experimental treatments in rats with pneumococcal meningitis, which, of all forms of acute bacterial meningitis, is the most likely to cause brain damage.
Two of the body's natural chemicals are key to brain cell injury, and could be targets for new therapies against meningitis. One of these chemicals destroys parts of brain cells, including membranes and DNA. It also activates a second type of chemical, which belongs to a family of enzymes that break down links between cells, increasing the inflammation and brain swelling that happen in meningitis. These enzymes are highly concentrated in the fluid surrounding the brain of patients with meningitis. Blocking these enzymes reduces brain-cell injury in experimental meningitis in rats. This project will attempt to block the damage these chemicals cause by using new experimental drugs. This could prevent brain damage and improve prospects of recovery in patients with bacterial meningitis.
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.
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6T38-43XNWJP-7-7&_cdi=4940&_user=10&_orig=search&_coverDate=09%2F15%2F2001&_qd=1&_sk=999689993&view=c&wchp=dGLbVlz-zSkzk&md5=667949a5e3183382459f7fde364dfe78&ie=/sdarticle.pdf
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.
http://brain.oxfordjournals.org/cgi/reprint/124/9/1734.pdf
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.
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6SYS-443K21B-C-5&_cdi=4842&_user=10&_orig=search&_coverDate=10%2F31%2F2001&_qd=1&_sk=999639997&view=c&wchp=dGLbVtz-zSkWz&md5=4ebdf8deb35608da30fbf09534bd8cb6&ie=/sdarticle.pdf
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.
Hippocampus 2003;13(4):481-8.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12836917&query_hl=31&itool=pubmed_docsum
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.
http://www.springerlink.com/(53btcm55shv1wfqa4hz5brz0)/app/home/contribution.asp?referrer=parent&backto=issue,12,15;journal,41,515;linkingpublicationresults,1:100394,1
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.
http://iai.asm.org/cgi/reprint/71/7/4087.pdf
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.
http://www.pedresearch.org/cgi/reprint/54/3/353.pdf
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.
http://linkinghub.elsevier.com/retrieve/pii/S0165572804000517
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.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?orig_db=PubMed&db=PubMed&cmd=Search&term=%22Journal+of+neuropathology+and+experimental+neurology%22%5BJour%5D+AND+61%5Bvolume%5D+AND+7%5Bissue%5D+AND+605%5Bpage%5D+AND+2002%5Bpdat%5D
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.
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6SYR-48KVGYR-6&_user=10&_coverDate=06%2F27%2F2003&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=29beba886f14e25aa4f406d968ede1f6
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.
http://www.jneuropath.com/pt/re/jnen/abstract.00005072-200406000-00005.htm;jsessionid=Fh9VHYQsTrpgLMF6z1x7QQvQxFv1gFWPvwjG1PLLDJs7SsGxwkQJ!2089961419!-949856144!8091!-1