Abstract

Highlights What are the main findings? Histone demethylase JMJD3 is highly upregulated in murine astrocytes after intracerebral hemorrhage (ICH) in vitro and in vivo and correlates with neuroinflammation. JMJD3 inhibition by GSK-J4 attenuates astrocytic neuroinflammation and preserves blood–brain barrier integrity in acute mouse ICH model, likely via MMP-9 suppression. What are the implications of the main findings? Astrocytic JMJD3 is a key regulator of neuroinflammation after ICH and represents a potential therapeutic target in the acute phase. GSK-J4 confers histological and functional neuroprotection in acute ICH mice, highlighting its therapeutic potential. Abstract Background: Intracerebral hemorrhage (ICH) is a devastating subtype of stroke, in which neuroinflammation and blood–brain barrier (BBB) disruption are secondary pathophysiological events that drive progressive brain injury. Histone lysine demethylase JMJD3 (Jumonji C domain-containing protein 3) is a master epigenetic switch governing inflammatory signaling; however, its participation in ICH-induced vascular disruption and its possible mechanism remain elusive. Objective: To examine the expression patterns of JMJD3 in the context of ICH and to evaluate the therapeutic potential of its specific inhibitor, GSK-J4, in attenuating neuroinflammation and BBB disruption in a murine ICH model. Methods: Hemin treatment of a mouse C8-D1A astrocytic cell line was used to develop an in vitro ICH model. The transcript level of the Jmjd3 gene and its correlation with pro-inflammatory signaling were analyzed with or without GSK-J4 pretreatment. ICH in vivo was created experimentally in adult male C57BL/6 mice through stereotactic striatal injection of collagenase IV, and the mice were randomly assigned to sham, ICH + vehicle, and ICH + GSK-J4 (30 mg/kg intraperitoneally (i.p.), every other day starting three days before ICH) groups.