The cannabinoid CP55,940 prolongs survival and improves locomotor activity in Drosophila melanogaster against paraquat: Implications in Parkinson’s disease M. Jimenez-Del-Rio * , A. Daza-Restrepo, C. Velez-Pardo School of Medicine, Department of Internal Medicine, Neurosciences Research Program, University of Antioquia, Calle 62 # 52-59, Building 1, Room 412, SIU Medellin, Colombia Received 27 February 2008; accepted 25 April 2008 Available online 2 May 2008 Abstract Cannabinoids have been shown to function as protective agents via receptor-independent and/or receptor-dependent mechanisms against stressful conditions. However, the neuroprotective mechanism of cannabinoids is far from conclusive. Therefore, the genuine antioxidant impact of cannabinoids in vivo is still uncertain. In this study, we demonstrate for the first time that CP55,940, a nonselective CB 1 /CB 2 cannabinoid receptor agonist, significantly protects and rescues Drosophila melanogaster against paraquat (PQ) toxicity via a receptor-independent mechanism. Interestingly, CP55,940 restores the negative geotaxis activity (i.e., climbing capability) of the fly exposed to PQ. Moreover, Drosophila fed with (1–200 mM) SP600125, a specific inhibitor of the stress responsive Jun-N-terminal kinase (JNK) signaling, and 20 mM PQ increased survival percentage and movement function (i.e., climbing capability) when compared to flies only treated with PQ. Taken together our results suggest that exogenous antioxidant cannabinoids can protect against and rescue from locomotor dysfunction in wild type (Canton-S) Drosophila exposed to stress stimuli. Therefore, cannabinoids may offer promising avenues for the design of molecules to prevent, delay, or ameliorate the treatment of population at high risk of suffering Parkinson disease. # 2008 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved. Keywords: Drosophila melanogaster; Paraquat; Cannabinoids; Oxidative stress; Neuroprotection; Rescue 1. Introduction Parkinson’s disease (PD) is a common progressive neurode- generative disorder with classical symptoms such as bradyki- nesia, rigidity, resting tremor, and postural instability. The most prominent neuropathological feature of the disorder is progres- sive loss of 50–70% of dopaminergic neurons located in the substantia nigra (Esposito et al., 2007). Although genetic research has identified several genes involved in familial forms of PD (Tan and Skipper, 2007), the cause of >90% of PD cases is unknown. Substantial evidence suggests environmental risk factors as causative of PD (Elbaz and Tranchant, 2007). Exposure of humans to the environmental toxins such as 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP) and paraquat (PQ, 1,1 0 -dimethyl-4 0 ,4 0 -bipyridilium dimethylsulphate) induce acute and irreversible Parkinsonism (Ballard et al., 1985; Hertzman et al., 1990; Liou et al., 1997). One potential mechanism by which those xenobiotic compounds may cause dopaminergic loss is through inhibition of the NADH dehydrogenase complex (also known as complex I) of the mitochondrial electron transport chain. This inhibition leads to reactive oxygen species (ROS) production such as superoxide radicals (O 2  ) and hydrogen peroxide (H 2 O 2 ), oxidative stress (defined as an intracellular overload production of ROS, which are not balanced by an adequate antioxidant system), and cell death (Bove et al., 2005; Dinis-Oliveira et al., 2006). Unfortunately, neuroprotection is still an elusive goal for the treatment of PD patients (Biglan and Ravina, 2007). Therefore, it is crucial to investigate innovative therapeutic approaches aimed to alleviate, retard or reduce the dopaminergic neural deterioration in PD. Cannabinoids are a group of terpenophenolic compounds present in cannabis (Cannabis sativa L.). Currently, there are www.elsevier.com/locate/neures Available online at www.sciencedirect.com Neuroscience Research 61 (2008) 404–411 * Corresponding author. Tel.: +57 4 219 64 57; fax: +57 4 219 64 44. E-mail address: mdelrio@quimbaya.udea.edu.co (M. Jimenez-Del-Rio). 0168-0102/$ – see front matter # 2008 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved. doi:10.1016/j.neures.2008.04.011