Progesterone exerts neuroprotective effects and improves long-term neurologic outcome after intracerebral hemorrhage in middle-aged mice

Abstract

In this study, we examined the effect of progesterone on histopathologic and functional outcomes of intracerebral hemorrhage (ICH) in 10–12-month-old mice. Progesterone or vehicle was administered by intraperitoneal injection 1 hour after collagenase-induced ICH and then by subcutaneous injections at 6, 24, and 48 hours. Oxidative and nitrosative stress were assayed at 12 hours post-ICH. Injury markers were examined on day 1, and lesion was examined on day 3. Neurologic deficits were examined for 28 days. Progesterone posttreatment reduced lesion volume, brain swelling, edema, and cell degeneration and improved long-term neurologic function. These protective effects were associated with reductions in protein carbonyl formation, protein nitrosylation, and MMP-9 activity and attenuated cellular and molecular inflammatory responses. Progesterone also reduced VEGF expression, increased neuronal-specific Na+/K+ ATPase α3 subunit expression, and reduced PKC-dependent Na+/K+ ATPase phosphorylation. Furthermore, progesterone reduced glial scar thickness, myelin loss, brain atrophy, and residual injury volume on day 28 after ICH. With multiple brain targets, progesterone warrants further investigation for its potential use in ICH therapy.

Multimodality MRI assessment of grey and white matter injury and blood-brain barrier disruption after intracerebral haemorrhage in mice

“…Brain tissue loss is common in ICH models15171928293031. Most previous MRI studies have focused only on hemispheric brain tissue loss1928293031 rather than atrophy in different brain regions.…”

“…Most previous MRI studies have focused only on hemispheric brain tissue loss1928293031 rather than atrophy in different brain regions. However, histology results show that brain atrophy occurs in several brain regions, including cortex1532 and striatum19, and results in ventricular enlargement28.…”

“…Hippocampus did not exhibit this change in ratio. Iron overload333435, perihaematomal oedema, and inflammation-mediated cell death192829 may contribute to brain atrophy because blocking these processes was shown to attenuate brain atrophy after ICH3334.…”

(−)-Epicatechin, a Natural Flavonoid Compound, Protects Astrocytes Against Hemoglobin Toxicity via Nrf2 and AP-1 Signaling Pathways

“…In fibroblasts from Nrf2 KO mice, HO1 expression is increased by arsenite treatment, probably via AP-1 activation [57]. In astrocytes, high glucose-induced HO1 expression is regulated by AP-1 activation and contributes to neuronal apoptosis [58]. AP-1 is also involved in the regulation of matrix metalloproteinase-9 [59], which contributes to early ICH injury [60, 61].…”

Modulators of microglial activation and polarization after intracerebral haemorrhage

“…Suitable markers include keratan sulfate (targeted by 5D4 antibody) 35,36 , cell surface glycoprotein F4/80 (targeted by F4/80 antibody) 35,36 , CD11b 37,38 , Iba1 (REFS 39,40) and CD68 (REFS 41,42). However, anti-CD11b antibody cannot distinguish microglia from neutrophils and monocytes in the ICH brain: although in the intact brain CD11b is expressed only by microglia, this marker is also expressed by neutrophils and monocytes in the ICH brain 39,43 .…”