Maprotiline ameliorates isoflurane-induced microglial activation via regulating triggering receptor expressed in myeloid cells 2 (TREM2)

Abstract

Isoflurane-induced neurotoxicity has attracted much interest. Recent studies suggest that isoflurane causes microglial activation, resulting in an inflammatory response and microglial insult. Maprotiline is a novel drug that has been licensed as an antidepressant with considerable anti-inflammatory activity. However, it is still unknown whether maprotiline possesses a protective effect against isoflurane-induced microglial insult. Here, we found that maprotiline ameliorated isoflurane-caused reduction in BV2 microglial cell viability and lactate dehydrogenase (LDH) release. Maprotiline mitigated isoflurane-induced oxidative stress by inhibiting reactive oxygen species (ROS) production and increasing superoxide dismutase (SOD) activity. Isoflurane-induced expression and production of inflammatory markers including tumor necrosis factor (TNF-α), interleukin (IL)-1β, cyclooxygenase‐2 (COX-2), and prostaglandin E2 (PGE 2 ) were decreased in maprotiline-treated cells. Maprotiline inhibited the mRNA and protein levels of Iba1, a marker of microglial activation, in isoflurane-induced BV2 cells. Maprotiline treatment restored isoflurane-induced reduction of TREM2 in BV2 microglial cells. In addition, the knockdown of TREM2 abolished the beneficial effects of maprotiline against isoflurane. Collectively, maprotiline exerted protective effects against isoflurane-caused oxidative stress, inflammatory response, and cell injury via regulating TREM2. These findings show that maprotiline prevented the isoflurane-induced microglial activation, indicating that maprotiline might be used as an optimal therapeutic agent for preventing the isoflurane-caused neurotoxicity.

Apolipoprotein E mimetic peptide COG1410 alleviates blood‑brain barrier injury in a rat model of ischemic stroke

“…By contrast, silencing TREM2 expression was previously found to enhance lipopolysaccharide-induced proinflammatory cytokine production in microglia (53). In another study, knockdown of TREM2 increased PGE2 production by BV2 cells, where the overexpression of TREM2 was found to reduce LPS-induced inflammation by inhibiting the PI3K/NF-κB signaling pathway (28,54). According to previous researches, the ApoE-TREM2 binding interface was found in amino acids 130-149 of ApoE (26,27,(55)(56)(57), while the amino acids of COG1410 are exactly in this area.…”