Neurotoxic effects of polymorphonuclear granulocytes on hippocampal primary cultures

Klaus Dinkel, Firdaus S. Dhabhar, Robert M. Sapolsky

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Abstract

Many neurological insults and neurodegenerative disorders are accompanied by an acute inflammatory reaction that can contribute to neuronal damage. This inflammation involves infiltration of bloodborne polymorphonuclear leukocytes (PMNs) into the injured brain area. The role of inflammation in brain injury, however, is controversial, because recent studies suggest that inflammation may actually be beneficial in the recovery from brain damage. Therefore, we investigated the effects of pathophysiologically relevant concentrations of PMNs in vitro on mixed hippocampal primary cultures. Rat PMNs and peripheral blood lymphocytes were isolated by density centrifugation and cocultured with hippocampal cells for 24-72 h plus or minus an excitotoxic insult (50 μM kainic acid) or 6-h oxygen glucose deprivation. Cell death was analyzed by immunocytochemistry, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and neuron-specific [2,2′ -azino-bis(ethylbenzothiazoline-6-sulfonic acid)] assay. After 3 days of coculture in the absence of insult, PMNs caused massive neuron loss and dramatic morphological changes in glial cells (astrocyte detachment, aggregation). Furthermore PMNs exacerbated kainic acid- and oxygen glucose deprivation-induced neuron death by 20-30%. The cytotoxic effect of PMNs required heterocellular contact and were ameliorated by protease inhibitors. Lymphocytes, on the other hand, were not neurotoxic, but, instead, increased astrocyte proliferation. These findings suggest that PMN might represent a harmful part of inflammation after brain injury that can contribute to secondary damage.

Original languageEnglish (US)
Pages (from-to)331-336
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number1
DOIs
StatePublished - Jan 2004

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