Journal Article

Regulation of cannabinoid CB2 receptor constitutive activity in vivo: repeated treatments with inverse agonists reverse the acute activation of JNK and associated apoptotic signaling in mouse brain

Salort, Glòria, García-Sevilla, Jesús A., Álvaro-Bartolomé, María

2017

Overview

Rationale CB 2 receptors express constitutive activity and inverse agonists regulate receptor basal activity , which might be involved in death mechanisms. This study assessed the effects of a selective CB 2 agonist (JWH133) and different CB 2 inverse agonists (AM630, JTE907, raloxifene) on death pathways in brain. Objectives The acute (JWH13) and the acute/chronic effects (AM630, JTE907, raloxifene) of CB 2 ligands regulating pro-apoptotic c-Jun NH 2 -terminal kinase (p-JNK/JNK ratio) and associated signaling of extrinsic (Fas receptor, Fas-Associated death domain protein, FADD) and intrinsic (Bax, cytochrome c) death pathways (nuclear poly (ADP-ribose) polymerase PARP) were investigated in mouse brain. Methods Mice were treated with CB 2 drugs and target protein contents were assessed by western blot analysis. Results JWH133 reduced cortical JNK (−27–45%) whereas AM630 acutely increased JNK in cortex (+61–148%), cerebellum (+34–40%), and striatum (+33–42%). JTE907 and raloxifene also increased cortical JNK (+31%–57%). Acute AM630, but not JWH133, increased cortical FADD, Bax, cytochrome c, and PARP cleavage. Repeated treatments with the three CB 2 inverse agonists were associated with a reversal of the acute effects resulting in decreases in cortical JNK (AM630: −36%; JTE907: −25%; raloxifene: −11%). Chronic treatments also induced a reversal with down-regulation (AM630) or only tolerance (JTE907 and raloxifene) on other apoptotic markers (FADD, Bax, cytochrome c, PARP). Conclusions AM630 and JTE907 are CB 2 protean ligands. Thus, chronic inverse agonists abolished CB 2 constitutive activity and then the ligands behaved as agonists reducing (like JWH133) JNK activity. Acute and chronic treatments with CB 2 inverse agonists regulate in opposite directions brain death markers.

• Publisher: Springer Berlin Heidelberg
• Subject: Biomedical and Life Sciences / Biomedicine / Neurosciences / Original Investigation / Pharmacology/Toxicology / Psychiatry