Metformin attenuates susceptibility to inflammation-induced preterm birth in mice with higher endocannabinoid levels.

Premature decidual senescence is a contributing factor to preterm birth. Fatty acid amide hydrolase mutant females (Faah-/-) with higher endocannabinoid levels are also more susceptible to preterm birth upon lipopolysaccharide (LPS) challenge due to enhanced decidual senescence; this is associated with mitogen-activated protein kinase p38 activation. Previous studies have shown that mechanistic target of rapamycin complex 1 (mTORC1) contributes to decidual senescence and promotes the incidence of preterm birth. In this study, we sought to attenuate premature decidual aging in Faah-/- females by targeting mTORC1 and p38 signaling pathways. Because metformin is known to inhibit mTOR and p38 signaling pathways, Faah-/- females were treated with metformin. These mice had a significantly lower preterm birth incidence with a higher rate of live birth after an LPS challenge on day 16 of pregnancy; metformin treatment did not affect placentation or neonatal birth weight. These results were associated with decreased levels of p38, as well as pS6, a downstream mediator of mTORC1 activity, in day 16 Faah-/-decidual tissues. Since metformin treatment attenuates premature decidual senescence with limited side effects during pregnancy, careful use of this drug may be effective in ameliorating specific adverse pregnancy events.

Cannabinoid receptor 1/2 double-knockout mice develop epilepsy.

The endocannabinoid system has gained attention as an important modulator of activity in the central nervous system. Initial studies focused on cannabinoid receptor 1 (CB1), which is widely expressed in the brain, but recent work also implicates cannabinoid receptor 2 (CB2) in modulating neuronal activity. Both receptors are capable of reducing neuronal activity, generating interest in cannabinoid receptor agonists as potential anticonvulsants. CB1 (Cnr1) and CB2 (Cnr2) single-knockout mice have been generated, with the former showing heightened seizure sensitivity, but not overt seizures. Given overlapping and complementary functions of CB1 and CB2 receptors, we queried whether double-knockout mice would show an exacerbated neurological phenotype. Strikingly, 30% of double-knockout mice exhibited provoked behavioral seizures, and 80% were found to be epileptic following 24/7 video-electroencephalographic monitoring. Single-knockout animals did not exhibit seizures. These findings highlight the importance of the endocannabinoid system for maintaining network stability.