Neuroprotective effects of fatty acid amide hydrolase inhibitor (URB597) and low-frequency EMF against paraquat-induced neurotoxicity: relevance to neurodegenerative disease
Date
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Paraquat is an herbicide and neurotoxin that elicits many of the pathological features seen in Parkinson’s Disease (PD). There are currently limited therapeutics available to prevent neurodegeneration or repair neuronal damage, therefore the demand for novel research in neuroprotection is imperative. Emerging evidence suggests that the endocannabinoid system (ECS) may be a useful treatment strategy for PD as it is acts as a neuromodulator within the central nervous system (CNS). In this study, the fatty acid amide hydrolase (FAAH) inhibitor URB597 was implemented to obstruct the breakdown of anandamide, one of the two main cannabinoids in the ECS; this leads to the accumulation of anandamide and activation of the cannabinoid receptor type 1 (CB1R). Additionally, the effects of a low-frequency electromagnetic field patterned to mimic the activity of the CB1 receptor were explored. The results from this study revealed that 500 µM paraquat reduced differentiation [F(4,57 = 6.659, p=<0.001, η2= 0.334] and cell viability [F(4,26 = 5.579, p= 0.004, η2= 0.48] in PC12 cells in comparison to controls. Similarly, 500µM paraquat significantly reduced locomotor behaviours in planaria after 24 hours of exposure [F(2,41 = 28.965, p= <0.001, η2= 0.586] but showed the most significant decrease after 72 hours in comparison to controls [t(59)=7.647, p=<0.00]. The reduction in differentiation, cell viability, and planarian locomotor activity elicited by paraquat confirms its efficiency as a neurotoxic agent in PC12 cells, causing symptoms of neurodegeneration. When PC12 cells were exposed to URB597 in conjunction with paraquat, levels of cell differentiation were significantly higher than those seen in paraquat alone [t(20)= -4.032, p=<0.001]. Correspondingly, planaria that were exposed to URB597 in conjunction with paraquat showed significantly higher levels of locomotor activity compared to paraquat alone after 72 hours of exposure [F(3,126 = 26.008, p= <0.001, η2= 0.382]. Finally, treatment using low-frequency EMF patterned after CB1 activity demonstrated an increase in planarian locomotor velocity when exposed to paraquat in comparison to controls [U=1409.5, z=-2.110, p=0.035]. These results support the idea that CB1 receptor activation modulates the activity of other neurotransmitter levels. Overall, I found that (1) paraquat produced neurotoxic damage in PC12 cells and planaria, (2) URB597 provided neuroprotective effects against paraquatinduced decreases to differentiation and planarian locomotor behaviours, and (3) an EMF patterned after CB1R activation provided neuroprotective effects against a paraquat-induced decrease in planarian locomotor behaviours. Both URB597 and the CB1R EMF demonstrated neuroprotective effects against paraquat-induced neurotoxicity. The results of this research provide evidence that manipulation of the ECS could be a beneficial target involving neuroprotection against neurodegenerative diseases.