3,4-Methylenedioxymethamphetamine causes cytotoxicity on 661W cells through inducing macrophage polarization

The abuse of 3,4-methylenedioxymethamphetamine (MDMA), a psychedelic drug, can lead to a variety of disorders in neural system, including the death of retinal neural cells. MDMA at lower doses does not cause obvious cytotoxicity to photoreceptor cells, indicating potential indirect mechanisms which have not yet been elucidated. This study investigated the effect of MDMA at nontoxic concentration on macrophage activation state and its resultant toxicity to photoreceptor cells. Using a co-culture system, cytotoxicity was caused by MDMA on 661W cells after co-culturing with RAW264.7 macrophage. Results showed that MDMA induced the macrophages to M1 polarization, releasing more pro-inflammatory cytokines, upregulating the M1-related gene and protein expression. The phenotype, secretion pattern, and cytotoxicity of the macrophages treated by MDMA are comparable to those of the ones stimulated by IFNγ and LPS. Our study demonstrated that MDMA promoted macrophage polarization to M1 and induced inflammatory response, providing the scientific rationale for the photoreceptor cell damage caused by the MDMA abuse.