Effects of 3,4-methylenedioxymethamphetamine (MDMA) on BDNF pathway, HDAC epigenetic enzymes and neurofilament proteins

3,4-methylenedioxymethamphetamine (MDMA) is a psychoactive substance used for recreational purposes. Possible clinical use of MDMA, in combination with psychotherapy, has been considered for the treatment of PTSD. However, MDMA causes neurotoxic effects and its use was associated with psychiatric symptoms, memory and cognitive deficits. To elucidate these aspects, the first aim of this study was to investigate the effects of acute and repeated MDMA treatment on BDNF/TrkB and HDACs in animal models. According to recent evidence about HDAC inhibitors, we used sodium butyrate to investigate its ability to affect MDMA-induced molecular and behavioral alterations. Moreover, considering that an alteration of BDNF has been reported in the brain of animals treated with psychoactive substances and in the blood of substance abusers, possible alterations of this neurotrophin levels were investigated in blood samples of MDMA users. Since different BDNF pools exist in plasma and serum, distinct determination of the neurotrophin were evaluated in both matrices. Furthermore, recent evidence has shown that neurofilaments can represent valid biomarkers of neural damage. Given the neurotoxic effects of ecstasy, we investigated neurofilaments in serotonergic neuronal cells. Particularly, we assessed MDMA effects on neurofilament proteins in differentiated serotonergic cells and we investigated if BDNF could protect serotonergic neurons from MDMA effects. Data showed that MDMA alters different crucial genes as well as the proteins involved in both substance use disorders and psychiatric conditions. Animal studies showed alterations both in BDNF pathways and in HDACs. Moreover, investigation in humans brought into view that peripheral BDNF could not reflect central BDNF and serum and plasma BDNF can express different types of this neurotrophin. Furthermore, data obtained in the differentiated serotonergic cell line highlight the useful role of NF-L as a biomarker of neuronal damage induced by MDMA, confirming the importance of studying NFs in the field of neuropsychiatric disorders.