Neonatal Inhibition of Connexin 36 Ameliorates Fetal Brain Injury Induced by Maternal Noninfectious Fever in Mice

Abstract

Prenatal fever could result in brain function impairments in the offspring. The present study investigated the effect of interleukin-6 (IL-6)-induced maternal fever on the offspring and the involvement of connexin 36 in this process. Pregnant C57BL/6J mice were injected with IL-6 on gestational day 15. The levels of iNOS and COX-2 were measured as an index of neuroinflammation in the brain of newborn pups. Offspring were treated with the connexin 36 (Cx36) inhibitor mefloquine at postnatal day (P)1–P3 or at P40–P42. Rotarod, grip traction, and foot fault tests were carried out to evaluate the motor behavior of adult offspring. Injection of IL-6 led to an elevation of the core temperature in the pregnant dams. Offspring of these dams showed significantly increased COX-2 and iNOS mRNA expression and protein levels in the whole-brain samples and significantly increased Cx36 in the cerebellum. Moreover, offspring of these dams showed motor deficits at an adult age. Neonatal administration of the Cx36 inhibitor mefloquine could prevent these motor deficits. Maternal fever during pregnancy induced by IL-6 injection could lead to neuroinflammation and motor deficits in the offspring. Neonatal inhibition of Cx36 could ameliorate the motor deficits in the offspring, indicating an involvement of Cx36 in the IL-6-induced maternal fever.

Inhibition of Connexin 36 attenuates HMGB1‐mediated depressive‐like behaviors induced by chronic unpredictable mild stress

“…Evidence indicated that Cx36 took part in several pathophysiological activities, like injury and inflammation (Wang et al., 2019 ), which was closely related to depressive disorder. Therefore, we first sought to see how Cx36 changed in depressive model induced by CUMS.…”

Mefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer

“…Among them, MFQ, an FDA-approved antimalarial compound, is used for the prevention or treatment of mild and moderate malaria 20 , with neuropsychiatric side effects 14,18,21 . Later, it was discovered that MFQ specifically blocks Cx36 GJC, contributing to these side effects, such as spreading depression, NMDAR-mediated neuronal death, tremor, motor deficits, convulsant, stage IV seizures, cell death upon oxygenglucose deprivation, and hypersensitivity to pain [22][23][24][25][26][27][28][29] . Additionally, it is noteworthy that MFQ exhibits 10-to 100-fold higher sensitivity to Cx36 (IC50 value of 310 nM) and Cx50 (IC50 value of 1.1 μM) compared to other connexins.…”