A putative role for homocysteine in the pathophysiology of acute bacterial meningitis in children.

Roney Santos Coimbra,Vânia D’Almeida,Bruno Frederico Aguilar Calegare,Talitah Michel Sanchez Candiani

doi:10.1186/1472-6890-14-43

Abstract

BackgroundAcute bacterial meningitis frequently causes cortical and hippocampal neuron loss leading to permanent neurological sequelae. Neuron death in acute bacterial meningitis involves the excessive activation of NMDA receptors and p53-mediated apoptosis, and the latter is triggered by the depletion of NAD + and ATP cellular stores by the DNA repair enzyme poly(ADP-ribose) polymerase. This enzyme is activated during acute bacterial meningitis in response to DNA damage induced, on its turn, by reactive oxygen and nitrogen species. An excess of homocysteine can also induce this cascade of events in hippocampal neurons.The present work aimed at investigating the possible involvement of homocysteine in the pathophysiology of meningitis by comparing its concentrations in cerebrospinal fluid (CSF) samples from children with viral or acute bacterial meningitis, and control individuals.MethodsHomocysteine and cysteine concentrations were assessed by high-performance liquid chromatography in CSF samples from nine patients with acute bacterial meningitis, 13 patients with viral meningitis and 18 controls (median age: 4 years-old; range: <1 to 13) collected by lumbar puncture at admission at the Children's Hospital Joao Paulo II - FHEMIG, from January 2010 to November 2011.ResultsWe found that homocysteine accumulates up to neurotoxic levels within the central nervous system of patients with acute bacterial meningitis, but not in those with viral meningitis or control individuals. No correlation was found between homocysteine and cysteine concentrations and the cerebrospinal fluid standard cytochemical parameters.ConclusionsOur results suggest that HCY is produced intrathecally in response to acute bacterial meningitis and accumulates within the central nervous system reaching potentially neurotoxic levels. This is the first work to propose a role for HCY in the pathophysiology of brain damage associated with acute bacterial meningitis.

Highlights

Acute bacterial meningitis frequently causes cortical and hippocampal neuron loss leading to permanent neurological sequelae
poly(ADP-ribose) polymerase (PARP) may provide a linkage between oxidative DNA damage and apoptosis or necrosis during Bacterial meningitis (BM) depending upon the severity of the ATP and NAD + withdrawal
The cohort comprised: a) nine patients with acute BM confirmed by cerebrospinal fluid (CSF) culture and/or latex agglutination test, being six infected with pneumococci and three with meningococci; b) 13 patients with Viral meningitis (VM), who had clinical signs of meningitis but presented normal or slightly altered cytochemical parameters in CSF, and negative CSF and blood latex and culture for bacterial pathogens [1]; c) 18 controls subjects attending the hospital because of a suspect of meningitis, but who had no infection of the central nervous system (CNS) or neurodegenerative diseases at the definitive diagnostic

Summary

Introduction

Acute bacterial meningitis frequently causes cortical and hippocampal neuron loss leading to permanent neurological sequelae. Neuron death in acute bacterial meningitis involves the excessive activation of NMDA receptors and p53-mediated apoptosis, and the latter is triggered by the depletion of NAD + and ATP cellular stores by the DNA repair enzyme poly(ADP-ribose) polymerase. This enzyme is activated during acute bacterial meningitis in response to DNA damage induced, on its turn, by reactive oxygen and nitrogen species. The cascade of events that triggers neuronal apoptosis during BM involves the excessive activation of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) which synthesizes ADP-ribose polymers in response to DNA damage [6] This process comes at a very high-energy cost depleting NAD + and ATP and thereby causing cell death. Consistent with this hypothesis, Kruman et al [16] have shown a major role for PARP activation in HCY-induced neuronal apoptosis and increased neuronal vulnerability to excitotoxicity

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