Early steps of microglial activation are directly affected by neuroprotectant FK506 in both in vitro inflammation and in rat model of stroke

FK506 (Tacrolimus) is a drug that is widely used after allergenic organ transplant because it blocks the activation of immune system..FK506, similarly as other immunosuppressants such as cyclosporin A, rapamycin and minocycline display neuroprotective effects in animal models of neurological disorders and many potential mechanisms of their action have been proposed but none fully explain the observed effects.
We presented a novel hypothesis that suggests the inhibitory effect of FK506 on initiation of the inflammatory responses in microglia – brain resident immune cells that guard brain from injury and infections, but under pathological conditions produce uncontrolled, deleterious inflammation. We performed a comprehensive study that evaluates the effect of FK506 and CsA on the inflammatory activation of microglial cultures determined by changes in cell morphology, proliferation, motility and inflammation mediator production. We provided a compelling evidence that a majority of these events are directly triggered by FK506 that interferes with MAPK and NFB signaling pathways and blocks both initiation and progression of the inflammatory response.
Moreover, we compared gene expression profiles in rat brains after ischemic damage (a animal model of stroke) and in inflammatory microglial cultures that revealed similarities in gene profiles and signaling pathways. We found that a single injection of FK506 that is neuroprotective blocks globally the induction of genes related to inflammation and neuronal cell death. We propose that FK506 in a complex manner inhibits the initiatory events underlying microglia activation that could explains the protective effects of FK506 in animal models. Taking into account that microglia-mediated inflammation is considered as one of the most important components of brain injury after trauma or stroke, we postulate that effective and multifaceted blockade of microglial activation by FK506 has clinical relevance and potential therapeutic implications.

28 January 2013