Attenuation of zinc-enhanced inflammatory M1 phenotype of microglia by peridinin protects against short-term spatial-memory impairment following cerebral ischemia in mice

• Published in: Biochemical and biophysical research communications 2018-12, Vol.507 (1-4), p.476-483
• Main Authors: Ueba, Yusuke, Aratake, Takaaki, Onodera, Ken-ichi, Higashi, Youichirou, Hamada, Tomoya, Shimizu, Takahiro, Shimizu, Shogo, Yawata, Toshio, Nakamura, Rina, Akizawa, Toshifumi, Ueba, Tetsuya, Saito, Motoaki
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Anti-inflammatory effect; BRAIN; CAROTENOIDS; DINOFLAGELLATE; INFLAMMATION; ISCHEMIA; LIPOPOLYSACCHARIDES; LYMPHOKINES; M1 inflammatory phenotype; MICE; Microglia; NERVE CELLS; Peridinin; Spatial memory; Zinc
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2018.11.067

Activated microglia exhibit two opposite activation states, the inflammatory M1 and the anti-inflammatory M2 activation states. In the mammalian brain, ischemia elicits a massive release of zinc from hippocampal neurons, and the extracellular zinc primes M1 microglia—by inducing reactive oxygen species (ROS) generation—to enhance their production of proinflammatory cytokines, which ultimately results in short-term spatial memory impairment. Here, we examined how peridinin, a carotenoid in dinoflagellates, affects the zinc-enhanced inflammatory M1 phenotype of microglia. Treatment of microglia with 30–300 ng/mL peridinin caused a dose-dependent attenuation of zinc-enhanced interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNFα) secretion when M1 activation was induced by lipopolysaccharide exposure. Moreover, peridinin inhibited the increase in ROS levels in zinc-treated microglia without directly interacting with zinc. Notably, when mice were administrated peridinin (20–200 ng/animal) intracerebroventricularly 5 min before cerebral ischemia-reperfusion, the peridinin treatment not only suppressed the increase in expression of IL-1β, IL-6, TNFα, and the microglial M1 surface marker CD16/32, but also protected the mice against ischemia-induced short-term spatial-memory impairment. Our findings suggest that peridinin prevents extracellular zinc-enhanced proinflammatory cytokine secretion from M1 microglia by inhibiting the increase in microglial ROS levels, and that this anti-inflammatory effect of peridinin might result in protection against deficits in short-term spatial memory. •Peridinin suppressed zinc-enhanced inflammatory M1 phenotype of microglia.•Zinc-increased microglial ROS level was abolished by peridinin.•Peridinin protected mice from ischemia-induced deficits in short-term spatial memory.