Abstract
Under physiological conditions, microglia are unique immune cells resident in the brain that is isolated from the systemic immune system by brain-blood barrier. Following status epilepticus (SE, a prolonged seizure activity), microglia are rapidly activated and blood-derived monocytes that infiltrate the brain; therefore, the regulations of microglia activation and monocyte infiltration are one of the primary therapeutic strategies for inhibition of undesirable consequences from SE. Roscovitine, a potent (but not selective) cyclin-dependent kinase 5 (CDK5) inhibitor, has been found to exert anti-inflammatory and microglia-inhibiting actions in several in vivo models, although the underlying mechanisms have not been clarified. In the present study, roscovitine attenuated SE-induces monocyte infiltration without vasogenic edema formation in the frontoparietal cortex (FPC), accompanied by reducing expressions of monocyte chemotactic protein-1 (MCP-1) and lysosome-associated membrane protein 1 (LAMP1) in resident microglia, while it did not affect microglia transformation to amoeboid form. Furthermore, roscovitine ameliorated the up-regulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, but not nuclear factor-κB-S276 phosphorylation. Similar to roscovitine, SB202190, a p38 MAPK inhibitor, mitigated monocyte infiltration and microglial expressions of MCP-1 and LAMP1 in the FPC following SE. Therefore, these findings suggest for the first time that roscovitine may inhibit SE-induced neuroinflammation via regulating p38 MAPK-mediated microglial responses.
Highlights
Under physiological conditions, microglia are unique immune cells resident in the brain that is isolated from the systemic immune system by a brain-blood barrier
We demonstrate for the first time that roscovitine effectively ameliorated Status epilepticus (SE)-induced microglia activation and monocyte infiltration by inhibiting monocyte chemotactic protein-1 (MCP-1) induction in activated microglia, which was mediated by p38 mitogen-activated protein kinase (p38 MAPK) activation independent of nuclear factor-κB (NFκB)-S276 phosphorylation
Since CD68 and ionizing calcium-binding adaptor molecule 1 (Iba-1) are commonly used markers for peripheral monocytes/activated microglia and resident microglia/activated microglia, respectively [7,21], these findings suggest that roscovitine may mitigate monocyte infiltration into the brain parenchyma, but not morphogenesis of activated microglia, independent of vasogenic edema formation following SE
Summary
Microglia are unique immune cells resident in the brain that is isolated from the systemic immune system by a brain-blood barrier. Microglia are rapidly activated, and increase synthesis and release of various cytokines and chemokines in the brain [1,2,3,4,5]. Microglia activation is one of the common and early hallmarks of neurological diseases. SE results in specific patterns of neuron loss and astroglial/microglial responses in various brain regions. SE-induced microglia activation accelerates vasogenic edema and neuronal death [7,8]. SE leads to blood-derived leukocyte infiltration in brain parenchyma. Neutrophils transiently invade brain parenchyma during the acute phase of SE, disappearing thereafter
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