Abstract
IMA-08401 (C2) is a novel aryl hydrocarbon receptor (AHR) agonist and selective AHR modulator (SAHRM) that is structurally similar to laquinimod (LAQ). Both compounds are converted to the AHR-active metabolite DELAQ (IMA-06201) in vivo. SAHRMs have been proposed as therapeutic options for various autoimmune disorders. Clinical trials on LAQ have not reported any significant toxic outcomes and C2 has shown low toxicity in rats; however, their functional resemblance to the highly toxic AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) raises questions. Here, we characterize the hepatic transcriptomic changes induced by acute (single-dose) and subacute exposure (repeated dosing for 5 days followed by a 5-day recovery period) to C2 in Sprague-Dawley rats. Exposure to C2 leads to activation of the AHR, as shown by altered transcription of Cyp1a1. We identify a heightened response early after exposure that drops off by day 10. Acute exposure to C2 leads to changes to transcription of genes involved in antiviral and antibacterial responses, which highlights the immunomodulator effects of this AHR agonist. Subacute exposure causes an oxidative stress response in the liver, the consequences of which require further study on target tissues such as the CNS and immune system, both of which may be compromised in this patient population.
Highlights
Laquinimod (LAQ) is a derivative of linomide
LAQ demonstrates reduced toxicity, but has proven effective in mouse models of autoimmune disorders, functioning as an immunoregulatory drug without general immunosuppressive properties [5]. Since these models share considerable clinical and immunological characteristics with human autoimmune disorders, LAQ has been proposed for treatment of multiple sclerosis (MS) [6,7], Crohn’s disease [8], and Huntington’s disease [9]
The most consistent sign of high TCDD exposure is chloracne; numerous studies have linked exposure to cancer incidence and mortality [31,32,33,34] and other morbidities, such as diabetes [35,36,37]. These outcomes can be directly linked to TCDD-activation of aryl hydrocarbon receptor (AHR)—numerous studies have demonstrated differences in TCDD-induced toxicity between and within species resulting from genetic differences affecting AHR structure
Summary
Laquinimod (LAQ) is a derivative of linomide ( known as roquinimex). Linomide has immunomodulatory, antiangiogenic, and antineoplastic activity, and was once proposed as a therapy for cancer and autoimmune diseases because it can both enhance and curb immune responses [1,2,3]. The most consistent sign of high TCDD exposure is chloracne; numerous studies have linked exposure to cancer incidence and mortality [31,32,33,34] and other morbidities, such as diabetes [35,36,37] These outcomes can be directly linked to TCDD-activation of AHR—numerous studies have demonstrated differences in TCDD-induced toxicity between and within species resulting from genetic differences affecting AHR structure. Exposed animals did not exhibit most of the major signs of toxicity typically observed with TCDD exposure, despite repeated daily administration of high C2 doses (highest achievable given the solubility characteristics of the compound) Perhaps most strikingly, these rats did not experience the dramatic body weight loss associated with TCDD-induced wasting syndrome [42,43]. The transcriptomic profiles from acute and subacute exposures have been compared, hanavderbeseuenltscocmonptararesdte,danwditrhestuhlotssecofrnotmrasstiemdiwlairthsttuhdoisees forfomTCsDimDileaxrpsotusduirees. oTfhTisCsDtuDdeyxwpoilsluprero. vTihdies svtaulduyabwleililnpsirgohvtidinetovathlueambleecihnasnigishmt ianntod tshaefemtyeochf aCn2isamndanpdrovsaidfeetya obfasCis2oafncdomprpoavriidsoenafobrasoitshoerf cpormoppoasreidsotnheforarpoetuhteirc pArHopRoasegdonthisetrsa. peutic AHR agonists
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