Is Aryl Hydrocarbon Receptor Antagonism After Ischemia Effective in Alleviating Hepatic Ischemia-Reperfusion Injury in Rats?

Aryl hydrocarbon receptors (AhRs) have been reported to be important mediators of ischemic injury in the brain. Furthermore, the pharmacological inhibition of AhR activation after ischemia has been shown to attenuate cerebral ischemia-reperfusion (IR) injury. Here, we investigated whether AhR antagonist administration after ischemia was also effective in ameliorating hepatic IR injury. A 70% partial hepatic IR (45-minute ischemia and 24-hour reperfusion) injury was induced in rats. We administered 6,2',4'-trimethoxyflavone (TMF, 5 mg/kg) intraperitoneally 10 minutes after ischemia. Hepatic IR injury was observed using serum, magnetic resonance imaging-based liver function indices, and liver samples. TMF-treated rats showed significantly lower relative enhancement (RE) values and serum alanine aminotransferase (ALT) and aspartate aminotransferase levels than did untreated rats at three hours after reperfusion. After 24 hours of reperfusion, TMF-treated rats had significantly lower RE values, ΔT1 values, serum ALT levels, and necrotic area percentage than did untreated rats. The expression of the apoptosis-related proteins, Bax and cleaved caspase-3, was significantly lower in TMF-treated rats than in untreated rats. This study demonstrated that inhibition of AhR activation after ischemia was effective in ameliorating IR-induced liver injury in rats.

Aryl Hydrocarbon Receptors in Indole Derivative Treated Mice: Neuropharmacological Perspectives

Aim/objective. When applied in pharmacological doses, the indole derivative melatonin exhibits neuroactive and neuroprotective effects. Indoles and their metabolites, such as kynurenine, are ligands of aryl hydrocarbon receptors (AhR). This study aimed to evaluate the antiepileptic and analgesic activity of melatonin and two synthetic melatonin derivatives. The possible involvement of AhR and kynurenine in their neuropharmacological effects were also tested. Methods. The tested substances were: melatonin, two melatonin derivatives bearing aryl hydrocarbon moiety with either furyl or thienyl substitute (3e and 3f), and alpha naphthoflavone (ANF), an antagonist of AhR. After intraperitoneal injection of 30, 100, or 300 mg/kg of the tested agents for seven days, male mice ICR (25-30 g) were subjected to a corneal kindling seizure model. Two tests for analgesia, i.e., the hot plate test and the formalin test, were also applied. AhR and kynurenine concentrations were evaluated in brain homogenates. Results. Substances 3e and 3f demonstrated an antiepileptic activity comparable to that of melatonin. Some analgesic activity was also shown, albeit lower than that of melatonin in equivalent doses. For melatonin and 3f treated mice, dose-dependent increases in AhR and kynurenine levels in brain homogenates were recorded. The antagonist ANF neither blocks the antiseizure activity of the tested indoles, nor demonstrated analgesic activity. Conclusion. Melatonin and the two tested melatonin-aroylhydrazone derivatives bearing either furyl or thienyl substitute exhibit antiepileptic and analgesic activity. Our results did not support the involvement of AhR in the demonstrated neurobiological activity. Further studies are needed to elucidate their exact molecular mechanisms.

Aryl hydrocarbon receptors as potential therapeutic targets

Aryl hydrocarbon receptors (AhR) are regulators of the expression of cytochrome P-450 isoforms, mediating a wide variety of the effects of substances from the endogenous or exogenous origin, including those produced from the microbiome. An exciting new aspect of their activity is their localization in the brain and their potential to modulate the action of the immune system. AhR is emerging as an essential toxicological and therapeutic target for neuromodulation. Further studies are needed for elucidating their utility as drug-targets.

A Review of the Functional Roles of the Zebrafish Aryl Hydrocarbon Receptors

Over the last 2 decades, the zebrafish (Danio rerio) has emerged as a stellar model for unraveling molecular signaling events mediated by the aryl hydrocarbon receptor (AHR), an important ligand-activated receptor found in all eumetazoan animals. Zebrafish have 3 AHRs—AHR1a, AHR1b, and AHR2, and studies have demonstrated the diversity of both the endogenous and toxicological functions of the zebrafish AHRs. In this contemporary review, we first highlight the evolution of the zebrafish ahr genes, and the characteristics of the receptors including developmental and adult expression, their endogenous and inducible roles, and the predicted ligands from homology modeling studies. We then review the toxicity of a broad spectrum of AHR ligands across multiple life stages (early stage, and adult), discuss their transcriptomic and epigenetic mechanisms of action, and report on any known interactions between the AHRs and other signaling pathways. Through this article, we summarize the promising research that furthers our understanding of the complex AHR pathway through the extensive use of zebrafish as a model, coupled with a large array of molecular techniques. As much of the research has focused on the functions of AHR2 during development and the mechanism of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) toxicity, we illustrate the need to address the considerable knowledge gap in our understanding of both the mechanistic roles of AHR1a and AHR1b, and the diverse modes of toxicity of the various AHR ligands.