PPARγ Agonists Accelerate MRI Signal Resolution Mediated by Resting-State Astroglia in Acute Intracerebral Hemorrhage

Abstract

Background: In the aftermath of intracerebral hemorrhage (ICH), the clearance of harmful substances from the hematoma helps to mitigate brain edema and reduce the risk of subsequent neurological damage. This study aimed to investigate the mechanism underlying early hematoma processing following ICH and to explore the potential of modulating this process via astrocyte regulation.

Methods: ICH was induced by intrastriatal injection of bacterial collagenase. A calcium channel blocker, pyr3 (ethyl 1-[4-(2,3,3-trichloroprop-2-enoylamino)phenyl]-5-(trifluoromethyl)pyrazole-4-carboxylate), was used to suppress astrocyte activity, or combined with PPARγ (peroxisome proliferator-activated receptor gamma) agonists (rosiglitazone and pioglitazone) as the intervention approach. The rats were randomly assigned to the following groups: ICH with vehicle treatment, ICH with pyr3 treatment, ICH with rosiglitazone treatment, ICH with pioglitazone treatment, ICH with pyr3 and rosiglitazone treatment, and ICH with pyr3 and pioglitazone treatment. Drugs were administered via the intraventricular route into the contralateral ventricle 10 minutes after ICH induction. The evolution of hematoma within the first 21 hours was meticulously examined using T2-weighted magnetic resonance imaging. Motor behavioral testing and diffusion-weighted imaging were used to assess longer-lasting functional outcomes and edema. To assess astrocyte-specific responses, an astrocyte cell line was incubated with hemin followed by different drug treatments. An intracellular hemin assay was used to quantify the hemin uptake capacity of astrocytes.

Results: Delayed signaling transitions of the hematoma were observed in the ICH with pyr3 treatment group in T2-weighted images, manifesting in different ICH models (ANOVA; P<0.001). The additional treatment of rosiglitazone rescued the delayed signaling transition (ANOVA; P<0.01) with a slight reduction in hematoma volume (ANOVA; P<0.001). ICH with pyr3 and pioglitazone treatment group exhibited improved motor behavior (ANOVA; P<0.001), gait (ANOVA; P<0.001), and reduced brain water content (ANOVA; P<0.01) than ICH with the vehicle treatment group. In cultured astrocytes, the combined treatment group showed increased HCP-1 (heme carrier protein-1) expression and hemin uptake within a few hours (P<0.001).

Conclusions: Combined treatment with the calcium channel blocker, pyr3, and the PPARγ agonist accelerated the early absorption of heme iron by resting-state astrocytes, leading to improved functional performance and reduced edema in later stages.

Keywords: astrocytes; blood-brain barrier; cerebral hemorrhage; ischemic stroke; peroxisome proliferator-activated receptors.