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Neuroprotective effects of the anti-inflammatory compound triflusal on ischemia-like neurodegeneration in mouse hippocampal slice cultures occur independent of microglia

2009; Elsevier BV; Volume: 218; Issue: 1 Linguagem: Inglês

10.1016/j.expneurol.2009.03.023

1090-2430

Maria Montero Domínguez, Berta González, Jens Zimmer,

Neurological Disease Mechanisms and Treatments

Microglial cells, known to play key roles in neuroinflammation, can be immunotoxically eliminated from hippocampal slice cultures by treatment with saporin coupled to the microglial receptor Mac1. Considering microglial cells as a target for anti-inflammatory treatment we studied the effects of microglial depletion on anti-inflammatory treatment of mouse hippocampal slice cultures subjected to ischemia-like neurodegeneration, induced by oxygen-glucose deprivation (OGD). Hippocampal slice cultures, derived from 7-day-old mice and grown for 2 weeks, were divided into 8 groups: (1) control cultures; (2) sham-OGD cultures; (3) OGD cultures; (4) OGD cultures treated with triflusal during OGD; (5) microglia-depleted control cultures; (6) microglia-depleted sham-OGD cultures; (7) microglia-depleted OGD cultures; and (8) microglia-depleted OGD cultures treated with triflusal during OGD. The resulting neurodegeneration was quantified by densitometric measurements of cellular uptake of propidium iodide (PI), with focus on the hippocampal CA1 subfield. Subjection of regular cultures to OGD for 30 min induced a significant increase in PI uptake in the CA1 pyramidal cell layer, compared to control cultures. The presence of 100 microM triflusal during OGD protected against OGD-induced neurodegeneration, and reduced the number of OGD-induced NFkB positive-cells correspondingly. Cultures treated with the Mac1-saporin complex for 7 days displayed an almost total loss of microglial cells. When subjected to OGD after microglial depletion, these cultures displayed a significant increase in OGD-induced PI uptake compared to non-depleted cultures. The presence of triflusal during OGD of these cultures reduced neurodegeneration of the irrespective absence of microglia. In accordance with that, the presence of triflusal during OGD significantly inhibited the increase in the number of reactive microglia and proliferative cells in the CA1 pyramidal and dentate granule cell layers. We conclude that immunotoxic microglia depletion significantly increases the susceptibility of CA1 pyramidal cells to neurodegeneration and that the anti-inflammatory drug triflusal still can exert its neuroprotective role following depletion of microglia.