Elsevier

Pediatric Neurology

Volume 36, Issue 5, May 2007, Pages 324-329
Pediatric Neurology

Original article
Brain-Derived Neurotrophic Factor Rescues Neurons From Bacterial Meningitis

https://doi.org/10.1016/j.pediatrneurol.2007.01.007Get rights and content

Mortality and neurologic deficits still occurs frequently following bacterial meningitis in children, despite antibiotic treatment. We investigated the neuroprotective effects of brain-derived neurotrophic factor (BDNF) on brain neurons in bacterial meningitis. The rat model of bacterial meningitis and a normal rat model were developed. Either BDNF or albumin was injected into the cerebral ventricle 24 hours after and before inoculation for 7 days, respectively. Three of the rats treated with albumin died during the course of treatment, but none of those treated with BDNF. The neuronal population in both cerebral cortex and hippocampus of the rats treated with BDNF markedly increased, compared with the rats treated with albumin, but there was no significant difference between the rats treated with BDNF after and before inoculation, nor between the normal rats treated with BDNF and albumin. The present findings indicate that BDNF could protect a large number of neurons in cerebral cortex and hippocampus from inflammatory brain injury in bacterial meningitis. The administration of exogenous BDNF may be a new and effective way to decrease mortality and improve sequelae following bacterial meningitis.

Introduction

Bacterial meningitis is a serious infection most commonly occurring in the central nervous system. This disease is fatal in 5-40% of patients, and transient or permanent neurological sequelae including deafness, epilepsy, mental retardation, and the impairment of sensorimotor function, among others, arise in up to a third of survivors [1], [2]. Advanced antimicrobial agents have had a profound effect on the clinical course and prognosis of bacterial meningitis, and outcomes have been modestly improved by advanced medical intensive care technology and the availability of new, effective antibiotics. Further improvements in treatment can only result from a better understanding of the pathophysiological events that occur after activation of the host’s inflammatory responses by either the bacteria or their products, and of the molecular mechanisms that take part in the genesis of brain damage during bacterial meningitis and after initiation of antibiotic treatment [2], [3], [4], [5].

In previous work [6], [7], we found that the expression of brain-derived neurotrophic factor (BDNF) mRNA and its production in the brain, and its receptor, tyrosine kinase receptor B (TrkB), is downregulated after administration of antibiotics in bacterial meningitis, and that there is a dose-dependent downregulation of BDNF by antibiotics, but there is no effect on the expression of BDNF in normal animals treated with antibiotics. That is, the intrinsic neuroprotective role of BDNF was reduced in bacterial meningitis after treatment with antibiotics [6], [7]. The present work uses a rat model of experimental pneumococcal meningitis to study the neuroprotective effects of BDNF on brain injury.

Section snippets

Animals and Cannula Implantation

Forty-four Sprague-Dawley rats were selected, aged 3 weeks. The rats were anesthetized with 0.15-0.3 mL/100 g 10% chloral hydrate injected intraperitoneally. Two stainless steel cannulas were implanted, into the left and right lateral cerebral ventricles, and were located 3.8 mm rostral to the lambdoid suture of the skull, 2 mm lateral on both sides from the midline of the skull, and 2.5 mm from the skull surface [8]. The rats were fostered in their cages for three days.

Experimental Design and BDNF Injection

The 44 rats were

Mortality Rate

During the course of treatment, one rat in group 2 (the control group after infection) and two rats in group 4 (the control group before infection) died of serious meningitis. The mortality was thus 12.5% and 25%, respectively, but there was no significance difference between the two kinds of mortality (P > 0.05). No rats died in groups 1 or 3 (the group treated after or before infection), nor in groups 5 or 6 (the groups treated or control group after injection of normal saline).

Population of Survival Neurons in Cerebral Cortex

Nissl staining

Discussion

Our experiments have confirmed that neurons of the brain were damaged following bacterial meningitis, that the exogenous BDNF could protect a large number of neurons in cortex and hippocampus from inflammatory brain damage in bacterial meningitis, and that the neuroprotective effect did not show significant difference between the treatment of BDNF before and after infection, nor between the normal group treated with BDNF and the normal control group not so treated. The findings suggest that the

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