Cannabidiol Effects on Phospholipid Metabolism in Keratinocytes from Patients with Psoriasis Vulgaris

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by dysregulated keratinocyte differentiation, but oxidative stress also plays an important role in the pathogenesis of this disease. Here, we examined the effect of cannabidiol (CBD), a phytocannabinoid with antioxidant and anti-inflammatory properties, on the redox balance and phospholipid metabolism in UVA/UVB-irradiated keratinocytes isolated from the skin of psoriatic patients or healthy volunteers. CBD accumulates mainly in membrane keratinocytes, especially from patients with psoriasis. This phytocannabinoid reduces the redox imbalance observed in the UV-irradiated keratinocytes of healthy subjects. It does so by decreasing reactive oxygen species (ROS) generation, increasing the Trx-dependent system efficiency, and increasing vitamin A and E levels. Consequently, a reduction in lipid peroxidation products, such as 8-isoprostanes and 4-hydroxynonenal, was also observed. Moreover, CBD modifies redox balance and lipid peroxidation in psoriatic patient keratinocytes following UV-irradiation. Interestingly, these changes are largely in the opposite direction to the case of keratinocytes from healthy subjects. CBD also regulates metabolic changes by modulating the endocannabinoid system that is disturbed by psoriasis development and UV irradiation. We observed a decrease in anandamide level in the UV-irradiated keratinocytes of healthy controls following CBD treatment, while in keratinocytes from patients treated with CBD, anandamide level was increased. However, the level of palmitoylethanolamide (PEA) was decreased in both groups treated with CBD. We further demonstrate that CBD increases CB1 receptor expression, primarily in the keratinocytes of patients, and increases CB2 receptor expression in both the psoriatic and control groups. However, CBD decreases CB2 receptor expression in UV-irradiated keratinocytes taken from patients. The UV- and psoriasis-induced activity of transmembrane transporters (Multidrug-Resistance (MDR) and breast cancer resistance protein (BCRP)) is normalized after CBD treatment. We conclude that CBD partially reduces oxidative stress in the keratinocytes of healthy individuals, while showing a tendency to increase the oxidative and inflammatory state in the keratinocytes of patients with psoriasis, especially following UV-irradiation.

Cannabidiol-Mediated Changes to the Phospholipid Profile of UVB-Irradiated Keratinocytes from Psoriatic Patients

“…The redox imbalance in apoptotic cells promotes the oxidation of PS by ROS, the overproduction of which is observed during inflammatory processes [47]. In addition, increased ROS production and reduced antioxidant capacity lead to increased lipid peroxidation [16]. This increase may, to some extent, explain the reduction in PS and PI levels observed in keratinocytes of patients with psoriasis ( Supplementary Table S4 and Figure S1).…”

“…Moreover, CBD reduces lipid peroxidation (measured as the levels of unsaturated α,β-reactive aldehydes) by preventing the generation of ROS and reducing the levels of enzymes involved in the metabolism of phospholipids. CBD also increases the level of endocannabinoids [16,22].…”

“…Treatment for psoriasis usually involves the use of topical medications and UV therapy. However, the use of UVB radiation can also disturb the redox balance in cells, leading to a change in the metabolism of phospholipids [16][17][18]. Therefore, there is a need for new approaches to prevent such disorders of the metabolism of phospholipids, and natural compounds are being considered of particular interest.…”

“…CBD, which is not psychoactive, has antioxidant and anti-inflammatory properties and has been shown to improve symptoms of autoimmune diseases (including skin diseases like psoriasis) in animal models [20,21]. CBD restores redox imbalances, which result from medical conditions as well as the effects of physicochemical factors [16,22]. This effect is mediated by reducing the level of reactive oxygen species (ROS) and increasing the level and activity of endogenous antioxidants [16,22].…”

“…CBD restores redox imbalances, which result from medical conditions as well as the effects of physicochemical factors [16,22]. This effect is mediated by reducing the level of reactive oxygen species (ROS) and increasing the level and activity of endogenous antioxidants [16,22]. In addition, CBD together with vitamins A, E, C, and enzymes such as glutathione peroxidase and thioredoxin peroxidase, protects membrane phospholipids and prevents oxidation of non-enzymatic cellular antioxidants such as glutathione and thioredoxin [23].…”