Xanthotoxol alleviates secondary brain injury after intracerebral hemorrhage by inhibiting microglia-mediated neuroinflammation and oxidative stress

Intracerebral hemorrhage (ICH) refers to the spontaneous rupture of blood vessels in the brain and leads to high morbidity, disability, and mortality. In 2019, ICH constitutes 27.9% of all new strokes and affects approximately 3.41 million individuals worldwide [1]. The mortality for patients with ICH is around 40–50% in the first month, half of which occurs during the first 48–72 h [2]. Primary and secondary brain injuries are two pathological changes post-ICH. The tissue injury and enlarged hematoma are major characteristics of the primary injury [2]. Hemolytic products surrounding the hematoma trigger secondary brain injury (SBI), leading to severe neurological defects. Neuroinflammation, oxidative stress and neuronal death are three crucial pathophysiological processes related with SBI development [3]. Despite great advancements in ICH mechanisms and therapeutic options, this neurologic emergency remains a challenge for physicians [4]. Thus, it is of great significance to develop novel effective candidates to prevent neurological deterioration after ICH.

The fruit of Fructus Cnidii is a traditional Chinese herb containing coumarins characterized by anticoagulant, antimicrobial, vasodilator, sedative and hypnotic activities [5]. Xanthotoxol, a biologically active linear furocoumarin, is mainly extracted from the fruit of Fructus Cnidii and shows strong pharmacological activities as anti-inflammatory, antioxidant, neuroprotective and sedative properties [6], [7], [8]. A previous study has demonstrated the anti-inflammatory effect of xanthotoxol in an animal model of cerebral ischemia/reperfusion injury [9]. However, the biological functions of xanthotoxol in ICH remain uncertain.

Microglia, the resident immune cells of the central nervous system (CNS), exert critical functions in maintaining cerebral homeostasis. ICH is found to induce the activation of microglia, and activated microglia produces pro-inflammatory cytokines and stimulates the excessive generation of radical oxygen species [10]. Additionally, activated microglia are identified by high capacity for phagocytic removal of apoptotic cells and debris [11]. Moreover, microglia have two different polarized states, the classical M1 phenotype and the alternative M2 phenotype [12]. The classical M1 phenotype secretes pro-inflammatory chemokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and CD86, while the M2 phenotype exhibits anti-inflammatory cytokines, including CD206 and transforming growth factor β (TGF-β) [13]. Therefore, reduction in microglial M1 polarization protects hemorrhagic brain following ICH.

Collectively, this study investigates the biological functions of xanthotoxol involving inflammation and oxidative stress, and its related mechanisms in cellular and animal models of ICH. An ICH animal model was established by injecting mice with collagenase VII according to a previous study [14]. Hemin was used to simulate ICH in cell culture [15]. Nuclear factor-κB (NF-κB) is a fundamental player in neuroinflammation post-ICH [16]. The production of TNF-α, IL-1β and IL-6 following ICH activates NF-κB [17]. The peak of NF-κB activation occurs within 48 h following ICH through NF-κB subunit p65 induction [18]. A previous study suggests that the anti-inflammatory effects of xanthotoxol are mediated by the NF-κB signaling [19]. Hence, we hypothesized that the NF-κB signaling is involved in the regulation of xanthotoxol roles in ICH. We believe that insights gained from this study would be beneficial for advancing future clinical studies targeting ICH treatment.

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