Δ 9 -tetrahydrocannabinol (Δ 9 -THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson's disease

Department of Clinical Neurobiology, Peninsula College of Medicine and Dentistry, University of Plymouth, Plymouth, UK.
Neuropathology and Applied Neurobiology (Impact Factor: 3.93). 01/2012; 38(6):535-47. DOI: 10.1111/j.1365-2990.2011.01248.x
Source: PubMed


C. B. Carroll, M.-L. Zeissler, C. O. Hanemann and J. P. Zajicek (2012) Neuropathology and Applied Neurobiology38, 535–547
Δ9-tetrahydrocannabinol (Δ9-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson's disease
Aims:Δ9-tetrahydrocannabinol (Δ9-THC) is neuroprotective in models of Parkinson's disease (PD). Although CB1 receptors are increased within the basal ganglia of PD patients and animal models, current evidence suggests a role for CB1 receptor-independent mechanisms. Here, we utilized a human neuronal cell culture PD model to further investigate the protective properties of Δ9-THC. Methods: Differentiated SH-SY5Y neuroblastoma cells were exposed to PD-relevant toxins: 1-methyl-4-phenylpyridinium (MPP+), lactacystin and paraquat. Changes in CB1 receptor level were determined by quantitative polymerase chain reaction and Western blotting. Cannabinoids and modulatory compounds were co-administered with toxins for 48 h and the effects on cell death, viability, apoptosis and oxidative stress assessed. Results: We found CB1 receptor up-regulation in response to MPP+, lactacystin and paraquat and a protective effect of Δ9-THC against all three toxins. This neuroprotective effect was not reproduced by the CB1 receptor agonist WIN55,212-2 or blocked by the CB1 antagonist AM251. Furthermore, the antioxidants α-tocopherol and butylhydroxytoluene as well as the antioxidant cannabinoids, nabilone and cannabidiol were unable to elicit the same neuroprotection as Δ9-THC. However, the peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist T0070907 dose-dependently blocked the neuroprotective, antioxidant and anti-apoptotic effects of Δ9-THC, while the PPARγ agonist pioglitazone resulted in protection from MPP+-induced neurotoxicity. Furthermore, Δ9-THC increased PPARγ expression in MPP+-treated SH-SY5Y cells, another indicator of PPARγ activation. Conclusions: We have demonstrated up-regulation of the CB1 receptor in direct response to neuronal injury in a human PD cell culture model, and a direct neuronal protective effect of Δ9-THC that may be mediated through PPARγ activation.

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    • "These PPAR-mediated anti-inflammatory effects are also elicited by other CBs, although with some differences. For example, the activation of PPAR-γ receptors by Δ 9 -THC protected differentiated SH-SY5Y neuroblastoma cells exposed to relevant parkinsonian toxins (e.g., MPPþ, lactacystin, paraquat), whereas other antioxidant CBs did not (e.g., CBD, nabilone:Carroll et al. 2012). "
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    ABSTRACT: This review focuses on the role of the endocannabinoid signaling system in controlling neuronal survival, an extremely important issue to be considered when developing new therapies for neurodegenerative disorders. First, we will describe the cellular and molecular mechanisms, and the signaling pathways, underlying these neuroprotective properties, including the control of glutamate homeostasis, calcium influx, the toxicity of reactive oxygen species, glial activation and other inflammatory events; and the induction of autophagy. We will then concentrate on the preclinical studies and the few clinical trials that have been carried out targeting endocannabinoid signaling in three important chronic progressive neurodegenerative disorders (Parkinson's disease, Huntington's chorea, and Alzheimer's disease), as well as in other less well-studied disorders. We will end by offering some ideas and proposals for future research that should be carried out to optimize endocannabinoid-based treatments for these disorders. Such studies will strengthen the possibility that these therapies will be investigated in the clinical scenario and licensed for their use in specific disorders.
    No preview · Article · Sep 2015 · Handbook of experimental pharmacology
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    • "The benefit of cannabinoids in PD is not limited to the symptomatic amelioration. Lately, several reports have revealed interesting neuroprotective and anti-inflammatory effects of these drugs in cell cultures and animal models of PD (Lastres-Becker et al., 2005; Garcia-Arencibia et al., 2007; Fernandez-Ruiz et al., 2011; Jeon et al., 2011; Carroll et al., 2012). Although CB1 receptor-mediated effects cannot be excluded, some authors argue that CB1 receptors may have a minimal implication in neuroprotection (Lastres-Becker et al., 2005; Fernandez-Ruiz et al., 2007; Price et al., 2009; Chung et al., 2011). "
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    ABSTRACT: There is substantial evidence supporting a role for the endocannabinoid system as a modulator of the dopaminergic activity in the basal ganglia, a forebrain system that integrates cortical information to coordinate motor activity regulating signals. In fact, the administration of plant-derived, synthetic or endogenous cannabinoids produces several effects on motor function. These effects are mediated primarily through the CB(1) receptors that are densely located in the dopamine-enriched basal ganglia networks, suggesting that the motor effects of endocannabinoids are due, at least in part, to modulation of dopaminergic transmission. On the other hand, there are profound changes in CB(1) receptor cannabinoid signaling in the basal ganglia circuits after dopamine depletion (as happens in Parkinson's disease) and following l-DOPA replacement therapy. Therefore, it has been suggested that endocannabinoid system modulation may constitute an important component in new therapeutic approaches to the treatment of motor disturbances. In this article we will review studies supporting the endocannabinoid modulation of dopaminergic motor circuits.
    Full-text · Article · Jun 2012 · Frontiers in Pharmacology
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    ABSTRACT: We have demonstrated that R(+)WIN55,212-2, a synthetic cannabinoid that possesses cannabimimetic properties, acts as a novel regulator of Toll-like receptor 3 (TLR3) signaling to interferon (IFN) regulatory factor 3 (IRF3) activation and IFN-β expression, and this is critical for manifesting its protective effects in a murine multiple sclerosis model. Here we investigated the role of peroxisome proliferator-activated receptor-α (PPARα) in mediating the effects of R(+)WIN55,212-2 on this pathway. Data herein demonstrate that the TLR3 agonist poly(I:C) promotes IFN-β expression and R(+)WIN55,212-2 enhances TLR3-induced IFN-β expression in a stereoselective manner via PPARα. R(+)WIN55,212-2 promotes increased transactivation and expression of PPARα. Using the PPARα antagonist GW6471, we demonstrate that R(+)WIN55,212-2 acts via PPARα to activate JNK, activator protein-1, and positive regulatory domain IV to transcriptionally regulate the IFN-β promoter. Furthermore, GW6471 ameliorated the protective effects of R(+)WIN55,212-2 during the initial phase of experimental autoimmune encephalomyelitis. Overall, these findings define PPARα as an important mediator in manifesting the effects of R(+)WIN55,212-2 on the signaling cascade regulating IFN-β expression. The study adds to our molecular appreciation of potential therapeutic effects of R(+)WIN55,212-2 in multiple sclerosis.
    Preview · Article · May 2012 · Journal of Biological Chemistry
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