Catechol-O-methyltransferase activity is higher in psoriasis patients and is down-regulated by narrowband ultraviolet B treatment.

BACKGROUND: Narrowband ultraviolet B (nbUVB) phototherapy is widely used in psoriasis treatment. UVB irradiation decreases catechol-O-methyltransferase (COMT) activity in human keratinocytes and melanoma cells. COMT activity is higher in psoriatic lesions than in normal skin but the effect of nbUVB on COMT activity in psoriasis patients is unknown. OBJECTIVES: To evaluate COMT activity in patients with psoriasis and determine whether nbUVB modifies this activity. METHODS: An open observational study was conducted with 20 psoriasis patients and 15 healthy volunteers. Patients were treated with nbUVB thrice weekly during six weeks and evaluated at baseline, three and six weeks after phototherapy and four weeks after stopping. In each evaluation body mass index (BMI), Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) were calculated and blood samples for erythrocytes soluble (S-) COMT activity assessment were taken. RESULTS: Before phototherapy (baseline), using a single concentration of substrate adreneline (1,000 µM), S-COMT activity levels (pmol/mg protein/h) were significantly higher in psoriasis patients than in controls. After nbUVB treatment, S-COMT activity significantly decreased. This decrease correlated positively with baseline activity. Four weeks after stopping phototherapy, S-COMT activity returned to baseline levels. After phototherapy, PASI score improved significantly but no correlation to baseline S-COMT values or decrease in S-COMT activity was found. CONCLUSIONS: This study shows that baseline S-COMT activity is higher in psoriasis patients than in controls and that this activity is significantly decreased by nbUVB treatment for psoriasis. This decrease is more evident in patients with higher baseline S-COMT activity.

Weight variation before and after surgery in Parkinson's disease: a noradrenergic modulation?

Changes in the nutritional profile of patients with Parkinson's disease have been reported before and after deep brain stimulation surgery. The major determinants of the weight variation in Parkinson's disease are not yet understood, and the mechanism seems complex. Based on the influence of the sympathetic nervous system in metabolic syndrome obesity, the intent of the present review is to consider the role of noradrenergic modulation on weight variations in Parkinson's disease. In this review the authors raise the following hypothesis: weight variation in Parkinson's disease before and after deep brain stimulation of the subthalamic nucleus could be influenced by noradrenergic interaction between the locus coeruleus, subthalamic nucleus, and hypothalamic nucleus.

Ultraviolet B radiation differentially modifies catechol-O-methyltransferase activity in keratinocytes and melanoma cells.

BACKGROUND: Catechol-O-methyltransferase (COMT) is a ubiquitous enzyme inactivating catecholic compounds. COMT is expressed also in human skin samples, and in melanoma cells it may be cytoprotective. A role of COMT in keratinocytes (HaCat) is unknown. OBJECTIVE: The objective of this study is: to investigate whether ultraviolet-B (UVB) radiation modifies COMT activity in melanocytes and HaCat and whether COMT inhibition plays a role in UVB-induced cell death. METHODS: Human cell lines of melanotic melanoma (SK-mel-1) and HaCat were used. COMT activity was evaluated under basal conditions and after UVB irradiation (311 nm) at a low (8 mJ/cm(2)) and a high dose (60 mJ/cm(2)). Tolcapone 1 µM was used to inhibit COMT. RESULTS: Both SK-mel-1 and Ha-Cat cells express COMT activity. In SK-mel-1, COMT activity is reduced nearly 50% both 24 h and 48 h after a high dose UVB. In Ha-Cat cells, COMT activity increased 24 h after a high dose UVB but decreased at 48 h. Tolcapone increases significantly the cytotoxic effect of high dose UVB irradiation only in HaCat. High concentrations of tolcapone reduced melanin levels in melanoma cells parallel to reduced cell numbers. CONCLUSIONS: Ultraviolet radiation differentially modifies COMT activity in melanoma cells and HaCat. Furthermore, tolcapone increased death of HaCat after irradiation but did not affect melanoma cells.

Inhibition of basal and ultraviolet B-induced melanogenesis by cannabinoid CB(1) receptors: a keratinocyte-dependent effect.

Ultraviolet radiation is the major environmental insult to the skin and stimulates the synthesis of melanin in melanocytes, which then distribute it to the neighboring keratinocytes where it confers photo-protection. Skin color results from the paracrine interaction between these two cell types. Recent studies suggest that endocannabinoids are potential mediators in the skin. Here, we investigated whether cannabinoid drugs play a role in melanogenesis and if ultraviolet radiation modifies the cutaneous endocannabinoid system. We used human melanotic melanoma cell line (SK-mel-1) in monoculture or co-culture with human keratinocytes (HaCat). Endocannabinoid levels, cannabinoid receptors expression, and melanin content were evaluated under basal conditions and after ultraviolet-B irradiation (311 nm). We provide evidence that human melanoma cells (SK-mel-1) express CB(1) receptors, and when in co-culture with keratinocytes (HaCat), the selective CB(1) receptor agonist arachidonyl-2-chloroethylamide (ACEA 1 and 10 µM) inhibited (by 33.4 and 37.3%, respectively) basal melanogenesis. In addition, ultraviolet-B-induced melanogenesis in co-cultures was abolished by ACEA 10 µM. Both ACEA inhibitory effects were reversed by AM251 (1 µM), a selective CB(1) antagonist. Furthermore, ultraviolet-B radiation increased endocannabinoids levels only in keratinocytes, whereas CB(1) cannabinoid receptor expression was up-regulated only in melanoma cells. Our results collectively suggest that ultraviolet radiation activates paracrine CB(1)-mediated endocannabinoid signaling to negatively regulate melanin synthesis. The endocannabinoid system in the skin may be a possible target for future therapies in pigmentary disorders.

Kinetic inhibitory profile of BIA 3-202, a novel fast tight-binding, reversible and competitive catechol-O-methyltransferase inhibitor.

The present study reports the kinetic inhibitory profile of 1-[3,4-dihydroxy-5-nitrophenyl]-2-phenyl-ethanone (BIA 3-202), a novel inhibitor of soluble catechol-O-methyltransferase (COMT) in rat liver. After an oral single dose (30 mg kg(-1)), there was a time-dependent recovery of enzyme activity from 98+/-2% inhibition at 30 min to total recovery at 24 h after treatment. The inhibitory effect produced by BIA 3-202 on soluble COMT was reversible after gel filtration of the samples. BIA 3-202 acted as a fast inhibitor of rat liver soluble COMT, interacting immediately with the enzyme after mixing. No differences were observed in the metanephrine formation rates (in nmol mg protein(-1) min(-1)) obtained without and with a 60-min preincubation with 30 nM of BIA 3-202 (1.30+/-0.02 and 1.35+/-0.03, respectively). The tight-binding nature of the inhibition produced by BIA 3-202 was evaluated by performing an Ackermann-Potter plot. The true K(i) for BIA 3-202, derived from the nonlinear regression analysis, was 0.19+/-0.02 nM. In substrate competition studies, an increase in the concentration of adrenaline resulted in a linear increase in IC(50) values for BIA 3-202. In conclusion, BIA 3-202 behaves as a reversible, potent and fast tight-binding COMT inhibitor that acts competitively at the substrate binding site of rat liver soluble COMT.