Abstract
Reactive astrogliosis is a prominent and ubiquitous reaction of astrocytes to many types of brain injury. Up-regulation of glial fibrillary acidic protein (GFAP) expression and astroglial proliferation are hallmarks of reactive astrogliosis. However, the mechanisms that regulate reactive astrogliosis remain elusive. In the present study, status epilepticus (SE, a prolonged seizure activity) led to reactive astrogliosis showing the increases in GFAP expression and the number of proliferating astrocytes with prolonged extracellular signal receptor-activated kinases 1/2 (ERK1/2) activation and reduced nuclear p27Kip1 level. U0126, an ERK1/2 inhibitor, showed opposite effects. Leptomycin B (LMB), an inhibitor of chromosomal maintenance 1 (CRM1), attenuated nucleocytoplasmic p27Kip1 export and astroglial proliferation, although it up-regulated ERK1/2 phosphorylation and GFAP expression. Roscovitine ameliorated the reduced nuclear p27Kip1 level and astroglial proliferation without changing GFAP expression and ERK1/2 phosphorylation. U0126 aggravated SE-induced astroglial apoptosis in the molecular layer of the dentate gyrus that was unaffected by LMB and roscovitine. In addition, U0126 exacerbated SE-induced neuronal death, while LMB mitigated it. Roscovitine did not affect SE-induced neuronal death. The present data elucidate for the first time the roles of nucleocytoplasmic p27Kip1 transport in ERK1/2-mediated reactive astrogliosis independent of SE-induced neuronal death and astroglial apoptosis. Therefore, our findings suggest that nucleocytoplasmic p27Kip1 export may be required for ERK1/2-mediated astroglial proliferation during reactive astrogliosis, and that nuclear p27Kip1 entrapment may be a potential therapeutic strategy for anti-proliferation in reactive astrocytes.
Highlights
Astrocytes are the most numerous non-neuronal cell types in the brain, which participate in the maintenance of extracellular glutamate level (Anderson and Swanson, 2000; Mazzanti et al, 2001), ionic/pH environment (Amiry-Moghaddam and Ottersen, 2003; Simard and Nedergaard, 2004), metabolic substrates (Kasischke et al, 2004), and brain-blood barrier integrity (Takano et al, 2006)
U0126 ameliorated the up-regulated glial fibrillary acidic protein (GFAP) expression and extracellular signal receptor-activated kinases 1/2 (ERK1/2) phosphorylation induced by SE, while Leptomycin B (LMB) showed opposite effects (p < 0.05 vs. vehicle, respectively; Figures 1B,C and Supplementary Figure S1)
The major findings in the present study are that the release of nuclear p27Kip1 entrapment may be required for ERK1/2-mediated astroglial proliferation during reactive astrogliosis, ERK1/2 activation may play an important role in up-regulation of GFAP expression in reactive astrocytes
Summary
Astrocytes are the most numerous non-neuronal cell types in the brain, which participate in the maintenance of extracellular glutamate level (Anderson and Swanson, 2000; Mazzanti et al, 2001), ionic/pH environment (Amiry-Moghaddam and Ottersen, 2003; Simard and Nedergaard, 2004), metabolic substrates (Kasischke et al, 2004), and brain-blood barrier integrity (Takano et al, 2006). Astrocytes are acutely degenerated in the molecular layer of the dentate gyrus, but not in the CA1 region (Kang et al, 2006; Kim et al, 2010, 2011, 2014a, 2017). These regional specific astroglial death patterns reflect functional heterogeneity of astrocytes. Reactive astrocytes release many growth factors and trophic factors, which promote neuronal survival, synaptogenesis, neurogenesis, and angiogenesis after brain injury (Horner and Gage, 2000; Panickar and Norenberg, 2005; Shibuya, 2009). The mechanisms that regulate reactive astrogliosis are complex and remain elusive
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