Abstract
Phytocannabinoids protect neurons against stressful conditions, possibly via the heme oxygenase (HO) system. In cultures of primary mesencephalic neurons and neuroblastoma cells, we determined the capability of cannabidiol (CBD) and tetrahydrocannabinol (THC) to counteract effects elicited by complex I-inhibitor rotenone by analyzing neuron viability, morphology, gene expression of IL6, CHOP, XBP1, HO-1 (stress response), and HO-2, and in vitro HO activity. Incubation with rotenone led to a moderate stress response but massive degeneration of dopaminergic neurons (DN) in primary mesencephalic cultures. Both phytocannabinoids inhibited in-vitro HO activity, with CBD being more potent. Inhibition of the enzyme reaction was not restricted to neuronal cells and occurred in a non-competitive manner. Although CBD itself decreased viability of the DNs (from 100 to 78%), in combination with rotenone, it moderately increased survival from 28.6 to 42.4%. When the heme degradation product bilirubin (BR) was added together with CBD, rotenone-mediated degeneration of DN was completely abolished, resulting in approximately the number of DN determined with CBD alone (77.5%). Using N18TG2 neuroblastoma cells, we explored the neuroprotective mechanism underlying the combined action of CBD and BR. CBD triggered the expression of HO-1 and other cell stress markers. Co-treatment with rotenone resulted in the super-induction of HO-1 and an increased in-vitro HO-activity. Co-application of BR completely mitigated the rotenone-induced stress response. Our findings indicate that CBD induces HO-1 and increases the cellular capacity to convert heme when stressful conditions are met. Our data further suggest that CBD via HO may confer full protection against (oxidative) stress when endogenous levels of BR are sufficiently high.
Highlights
We investigated the protective potential of CBs against cell stress and neuronal cell death induced by the well-known complex I
In order to find out whether CBs modulate the activity of heme oxygenase (HO), we analyzed the capability to convert heme in homogenates of primary mesencephalic cells subjected to a 48-h treatment with the stressor rotenone, the CBs CBD and THC as well as the HO product BR and the HO substrate heme (Figure 1)
We found that cells treated with CBD for 48 h displayed only 44% of the heme degrading capacity compared to control cells
Summary
Phytocannabinoids (CBs) from Cannabis sativa are discussed to provide neuroprotection against chronic neurodegenerative disorders like multiple sclerosis, Huntington’s disease, Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis [1,2]. Impairment of mitochondrial function resulting in enhanced oxidative stress has been. In several in-vitro models of mitochondrial dysfunction, especially oxidative stress models relevant to PD, neuroprotective effects of CBs have been demonstrated. Tetrahydrocannabinol (THC) and cannabidiol (CBD) are protective for dopaminergic neurons damaged by oxidative stress induced by the inhibition of complex I of the electron transport chain and cell degeneration produced by glutamate [7,8,9]. The antioxidative properties of CBs may be of high relevance for neuroprotection. Clinical data from PD patients support this assumption: nigrostriatal lesions are associated with an increase in CB1 receptors in the basal ganglia [12]
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