Increase inω 3 (peripheral type benzodiazepine) binding sites in the rat cortex and striatum after local injection of interleukin-1, tumour necrosis factor-α and lipopolysaccharide

Abstract

The possible involvement of lymphokines in the glial reaction/proliferation that follows brain injury has been investigated by measuring the density ofω 3 (peripheral type benzodiazepine) binding sites associated to glial cells and macrophages after local injection of lymphokines in the rat cerebral cortex and striatum.ω 3 Site densities were measured either by quantitative autoradiography in brain sections or by conventional binding in membrane using [ 3H]PK 14105 or [ 3H]PK 11195 as ligands. Intracortical or intrastriatal infusion of interleukin-1 (10 and 20 units) caused a marked increase in the density ofω 3 sites (+83% and +80%, respectively, when compared to saline-infused animals) around the injection site at 7 days postinjection. There was a good spatial correspondence between the autoradiographic distribution ofω 3 sites and the distribution of reactive astrocytes (as assessed by GFAP immunostaining) or acid phosphatase rich cells (phagocytes). Significant increases inω 3 site densities were also observed in striatal homogenates 1 week after local administration of tumor necrosis factor-α (TNF-α). The maximal increase (+80%) was observed after the administration of 3 units, higher and lower doses resulting in smaller increases. Intrastriatal injection of E. coli lipopolysaccharide (LPS), a bacterial endotoxin known to stimulate interleukin-1 and TNF-α production by microglial cells in culture, also resulted in significant increases inω 3 site densities in striatal homogenates (maximal increase, +170% 1 week after the injection of 200 ng). In contrast, no change in the density of two binding sites associated with neurons ([ 3H]TCP which indexes NMDA receptor density and [ 3H]Ro15 1788 which binds to centralω 1–2 (benzodiazepine) receptors) was observed after intrastriatal injection of interleukin-1, TNF-α or LPS. The intrastriatal injection of interleukin-2 (5–20 units) or of the chemotactic peptideN-formyl-methionyl-leucyl-phenylalanine (FMLP) failed to alterω 3 site or NMDA receptor densities in striatal homogenates. Based on the present results, we suggest that the increase inω 3 site densities observed in experimental lesions and in human neuropathological states may be mediated by a sequential mechanism involving the activation of microglia or monocytes, the release of interleukin-1 and/or TNF-α and the promotion, by these cytokines, of the astroglial reaction.