The neuroprotective action of 3,3′-diindolylmethane against ischemia involves an inhibition of apoptosis and autophagy that depends on HDAC and AhR/CYP1A1 but not ERα/CYP19A1 signaling

Abstract

There are no studies examining the effects of 3,3′-diindolylmethane (DIM) in neuronal cells subjected to ischemia. Little is also known about the roles of apoptosis and autophagy as well as AhR and ERα signaling and HDACs in DIM action. We demonstrated for the first time the strong neuroprotective capacity of DIM in mouse primary hippocampal cell cultures exposed to ischemia at early and later stages of neuronal development. The protective effects of DIM were mediated via inhibition of ischemia-induced apoptosis and autophagy that was accompanied by a decrease in AhR/CYP1A1 signaling and an increase in HDAC activity. DIM decreased the levels of pro-apoptotic factors, i.e., Fas, Caspase-3, and p38 mitogen-activated protein kinase (MAPK). DIM also reduced the protein levels of autophagy-related Beclin-1 (BECN1) and microtubule-associated proteins 1A/1B light chain (LC3), partially reversed the ischemia-induced decrease in Nucleoporin 62 (NUP62) and inhibited autophagosome formation. In addition, DIM completely reversed the ischemia-induced decrease in histone deacetylase (HDAC) activity in hippocampal neurons. Although DIM inhibited AhR/CYP1A1 signaling, it did not influence the protein expression levels of ERα and ERα-regulated CYP19A1 which are known to be controlled by AhR. This study demonstrated for the first time, that the neuroprotective action of 3,3′-diindolylmethane against ischemia involves an inhibition of apoptosis and autophagy and depends on AhR/CYP1A1 signaling and HDAC activity, thus creating the possibility of developing new therapeutic strategies that target neuronal degeneration at specific molecular levels.

Neuroprotective effect of 3,3’-Diindolylmethane against perinatal asphyxia involves inhibition of the AhR and NMDA signaling and hypermethylation of specific genes

“…To our knowledge, there is no relevant in vivo study to compare our data with. According to our previous results, DIM protects hippocampal neurons against hypoxia and ischemia in vitro through the inhibition of proteins in the AhR signaling pathway, including AhR, ARNT and CYP1A1 [6,7] which is in line with our present in vivo results i.e., the downregulation of AhR signaling in DIMtreated rats subjected to birth asphyxia. DIM was found to cause widespread changes in promoter methylation patterns in prostate cells and to act as HDAC inhibitor in cancer cells [48,49].…”

“…DIM was found to cause widespread changes in promoter methylation patterns in prostate cells and to act as HDAC inhibitor in cancer cells [48,49]. Previously, we showed that DIM has ability to reverse the ischemia-induced decrease in HDAC activity in mouse brain neurons [7]. Based on these data, one may assume that DIM changes the epigenetic status of ischemic brain not only via DNA hypermethylation as evidenced in the present study, but also by affecting histone acetylation.…”

“…In experimental studies, DIM administered orally to mice at a dose of 250 mg/kg reached a concentration of 5-36.5 µM in the brain within 6 h of its administration [5]. Furthermore, our previous study demonstrated that DIM strongly protected mouse primary hippocampal cells against hypoxia/ischemia [6,7] that inspired us to test the neuroprotective capacity of the compound in an in vivo model of rat perinatal asphyxia.…”

“…We recently showed that DIM protects neurons against hypoxia/ischemia via inhibition of apoptosis [6,7]. However, there are no data on the effects of DIM on the apoptosis-signaling pathway in a model of perinatal asphyxia.…”

Reoxygenation induces reactive oxygen species production and ferroptosis in renal tubular epithelial cells by activating aryl hydrocarbon receptor

“…Some data support a detrimental role of AhR during the anoxic phase of I-R injury. Inhibition of AhR/CYP1A1 protects murine hippocampal cells from anoxia-induced apoptosis (44). However, no data are available concerning the role of AhR during the subsequent reoxygenation.…”