Changes in interleukin-1 signal modulators induced by 3,4-methylenedioxymethamphetamine (MDMA): Regulation by CB2 receptors and implications for neurotoxicity

Background: 3,4-methylenedioxymethamphetamine (mdma) produces a neuroinflammatory reaction in rat brain characterized by an increase in interleukin-1 beta (il-1β) and microglial activation. the cb2 receptor agonist jwh-015 reduces both these changes and partially protects against mdma-induced neurotoxicity. we have examined mdma-induced changes in il-1 receptor antagonist (il-1ra) levels and il-1 receptor type i (il-1ri) expression and the effects of jwh-015. the cellular location of il-1β and il-1ri was also examined. mdma-treated animals were given the soluble form of il-1ri (sil-1ri) and neurotoxic effects examined.methods: dark agouti rats received mdma (12.5 mg/kg,i.p.) and levels of il-1ra and expression of il-1ri measured 1 h,3 h or 6 h later. jwh-015 (2.4 mg/kg,i.p.) was injected 48 h,24 h and 0.5 h before mdma and il-1ra and il-1ri measured. for localization studies,animals were sacrificed 1 h or 3 h following mdma and stained for il-1β or il-1ri in combination with neuronal and microglial markers. sil-1ri (3 μg/animal; i.c.v.) was administered 5 min before mdma and 3 h later. 5-ht transporter density was determined 7 days after mdma injection.results: mdma produced an increase in il-ra levels and a decrease in il-1ri expression in hypothalamus which was prevented by cb2 receptor activation. il-1ri expression was localized on neuronal cell bodies while il-1β expression was observed in microglial cells following mdma. sil-1ri potentiated mdma-induced neurotoxicity. mdma also increased igg immunostaining indicating that blood brain-barrier permeability was compromised.conclusions: in summary,mdma produces changes in il-1 signal modulators which are modified by cb2 receptor activation. these results indicate that il-1β may play a partial role in mdma-induced neurotoxicity. © 2011 torres et al; licensee biomed central ltd.