Inhibition of complement C3/C3aR alleviates hydrocephalus following germinal matrix hemorrhage in neonatal rats

Abstract

Objective To investigate the effect of astrocyte-microglia crosstalk mediated by complement C3/C3aR signaling on hydrocephalus after germinal matrix hemorrhage (GMH) in newborn rats. Methods GMH was induced in post-natal day 7 SD rats by collagenase Ⅶ-S injection into the ganglionic eminence. We detected the changes in the expression of periventricular C3 and C3aR over time after GMH, and observed the effect of intraperitoneal injection of C3aRA (a selective C3aR antagonist) on hydrocephalus using magnetic resonance imaging (MRI). The learning and memory functions of the rats were tested after the treatment using Morris water maze test, and the expression of interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) and aquaporin 4 in the brain tissues were detected using Western blotting at different time points after GMH. Results The neonatal rats with GMH showed significantly up-regulated expression of C3 and C3aR around the cerebral ventricles and increased expression of IL-1β, IL-6, TNF-α and TGF-β1 in the brain, presenting also with obvious lateral ventricle dilation, compression of the cortex and hippocampus, and impairment of the learning and memory functions. Treatment of the rats with C3aRA obviously decreased C3 and C3aR expression, alleviated hydrocephalus, improved the neurological deficits, and reduced the expression of the inflammatory factors in the brain. GMH caused obvious ectopic expression of aquaporins 4 and increased its expression level on the astrocytes, and C3aRA treatment significantly improved the abnormal expression of aquaporins 4. Conclusion GMH causes the astrocytes to up-regulate and release C3, which binds to C3aR on the microglia to promote inflammation and aggravate hydrocephalus. The ectopic expression of aquaporin 4 in astrocytes may play an important role in the occurrence of hydrocephalus following GMH. rats newborn

Keywords

• germinal matrix hemorrhage
• hydrocephalus
• c3/c3ar
• astrocytes
• microglias
• aquaporin 4
• rats newborn