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ENDOCANNABINOID TOXICITY IN A CELL CULTURE MODEL OF PARKINSON'S DISEASE
  1. E Salter*,
  2. ML Zeissler,
  3. SPH Alexander,
  4. CO Hanemann,
  5. JP Zajicek,
  6. CB Carroll
  1. Peninsula College of Medicine and Dentistry; University of Nottingham Medical School

    Abstract

    Background Endocannabinoids (EC) are up-regulated in Parkinson's disease (PD) which may be part of an auto protective mechanism or add to the pathogenesis of the disease. 2-arachidonylglycerol (2AG) is the most abundant EC, synthesised by diacylglycerol lipase α (DAGLa) and hydrolysed by monoacylglycerol lipase (MAGL) into arachidonic acid (AA) and glycerol. AA is converted to PGE2 prostaglandins by cyclooxygenase 2 (COX2). In this study we employed a cell culture model of PD to study the effects of 2AG. We hypothesise that 2AG potentiates MPP+ induced cell death. We investigated whether the levels of enzymes involved in 2AG metabolism were altered in the PD model.

    Method Human SH-SY5Y neuroblastoma cells were differentiated with retinoic acid and exposed to the PD relevant neurotoxin MPP+. 2AG was co-applied with MPP+ and incubated for 48 h. Cell death was analysed using the LDH assay. Enzyme levels were measured using Western blotting. MAGL activity was determined by [3H]2-AG hydrolysis.

    Results 2AG alone was not toxic. However, when co-applied with MPP+ cell death was significantly potentiated. This effect was dependent on the concentration of MPP+. The MAGL inhibitor JZL 184 had a similar effect. 7 mM MPP+ resulted in increased COX2 expression after 6 h and led to a non-significant increase in MAGL activity after 24 h. There was no change in MAGL or DAGLa enzyme levels.

    Conclusion We propose the toxic effect of 2AG is mediated by higher levels of COX2 and PGE2 induction.

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