Neuroinflammation Involving Endothelin-1 and Platelet-Activating Factor Receptors Contributes To Self-Injurious Behaviors Induced by Bay k-8644 in Adolescent Mice

초록

Bay k-8644, an activator of L-type voltage-gated calcium channels, induces self-injurious behaviors in mice. Although previous studies using animal models have suggested the possible implications of neuroinflammation in self-injurious behaviors, this has not yet been elucidated in the context of Bay k-8644-induced self-injurious behaviors. In this study, Bay k-8644 (50 µg, i.c.v.)-induced self-injurious behaviors were accompanied by increased expression of endothelin (ET)-1, platelet-activating factor (PAF) receptors, and Iba-1 in the striatum. Pretreatment with the ET receptor antagonist bosentan (10 mg/kg, i.p.), the PAF receptor antagonist ginkgolide B (10 mg/kg, i.p.), or the microglial activation inhibitor minocycline (40 mg/kg/day for 5 days, i.p.) significantly inhibited Bay k-8644-induced self-injurious behaviors and microglial activation in the striatum. Interestingly, bosentan also suppressed Bay k-8644-induced PAF receptor expression, indicating that ET-1 may act as an upstream modulator of the PAF signaling under these experimental conditions. Bay k-8644-induced ET-1 expression and consequent pro-inflammatory changes were reversed by the protein kinase C (PKC) inhibitor NPC-15,437 and the Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor KN-93. Moreover, Bay k-8644-induced self-injurious behaviors and microglial activation were significantly potentiated by exogenous ET-1 administration (10 pmol, i.c.v.) or by weak neuroinflammation in the striatum induced by systemic injection of low-dose lipopolysaccharide (LPS; 1 mg/kg, i.p.). Our results suggest that neuroinflammatory changes associated with ET-1/PAF signaling in the striatum contribute to Bay k-8644-induced self-injurious behaviors. © 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

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