Dihydroxyphenylacetaldehyde Lowering Treatment Improves Locomotor and Neurochemical Abnormalities in the Rat Rotenone Model: Relevance to the Catecholaldehyde Hypothesis for the Pathogenesis of Parkinson's Disease.

The catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease centers on accumulation of 3,4-dihydroxyphenylacetaldehyde (DOPAL) in dopaminergic neurons. To test the hypothesis, it is necessary to reduce DOPAL and assess if this improves locomotor abnormalities. Systemic administration of rotenone to rats reproduces the motor and central neurochemical abnormalities characterizing Parkinson's disease. In this study, we used the monoamine oxidase inhibitor (MAOI) deprenyl to decrease DOPAL production, with or without the antioxidant N-acetylcysteine (NAC). Adult rats received subcutaneous vehicle, rotenone (2 mg/kg/day via a minipump), or rotenone with deprenyl (5 mg/kg/day i.p.) with or without oral NAC (1 mg/kg/day) for 28 days. Motor function tests included measures of open field activity and rearing. Striatal tissue was assayed for contents of dopamine, DOPAL, and other catechols. Compared to vehicle, rotenone reduced locomotor activity (distance, velocity and rearing); increased tissue DOPAL; and decreased dopamine concentrations and inhibited vesicular sequestration of cytoplasmic dopamine and enzymatic breakdown of cytoplasmic DOPAL by aldehyde dehydrogenase (ALDH), as indicated by DA/DOPAL and DOPAC/DOPAL ratios. The addition of deprenyl to rotenone improved all the locomotor indices, increased dopamine and decreased DOPAL contents, and corrected the rotenone-induced vesicular uptake and ALDH abnormalities. The beneficial effects were augmented when NAC was added to deprenyl. Rotenone evokes locomotor and striatal neurochemical abnormalities found in Parkinson's disease, including DOPAL buildup. Administration of an MAOI attenuates these abnormalities, and NAC augments the beneficial effects. The results indicate a pathogenic role of DOPAL in the rotenone model and suggest that treatment with MAOI+NAC might be beneficial for Parkinson's disease treatment.

Neutral endopeptidase inhibitor versus angiotensin converting enzyme inhibitor in a rat model of the metabolic syndrome.

The antihypertensive treatment in patients with metabolic syndrome is unclear. We therefore used a rat model of the metabolic syndrome and compared the effects of enalapril, an angiotensin-converting-enzyme inhibitor, with candoxatril, a neutral endopeptidase inhibitor that inhibits degradation of atrial natriuretic peptide and, in addition to lowering blood pressure, exerts metabolically beneficial activity. Ten male Sprague Dawley rats were fed regular rat chow for 5 weeks. Fifty male Sprague Dawley rats were fed a high-fructose diet for 3 weeks, followed by addition of enalapril, 10 mg/Kg/d, or candoxatril, 25, 50, or 100 mg/Kg/d, for 2 weeks. Systolic blood pressure, plasma triglyceride level, and insulin level were measured at baseline and after 3 weeks and 5 weeks. Three weeks of a high-fructose diet led to a significant increase in all metabolic parameters. Candoxatril and enalapril lowered systolic blood pressure significantly (candoxatril -10 ± 1 to -22 ± 1 mm Hg and enalapril -27 ± 2 mm Hg). High-dose candoxatril and enalapril significantly decreased plasma triglyceride levels (by 17.8% and 32.8%, respectively), but only high-dose candoxatril decreased plasma insulin levels significantly (by 25.3%). High-dose candoxatril is a metabolically favorable option for lowering blood pressure in a rat model of metabolic syndrome.

The role of melatonin in the pathogenesis of hypertension in rats with metabolic syndrome.

BACKGROUND: Melatonin, the primary hormone of the pineal gland, is a known modulator of various physiological processes. The aim of this study was to evaluate the role of melatonin in the pathogenesis of hypertension in rats with metabolic syndrome and to assess whether melatonin supplementation prevents the development of hypertension in this model. METHODS: Twenty male Sprague-Dawley (SD) rats were fed either a high fructose diet (n = 10) or a regular diet (control; n = 10) for 5 weeks. Urinary excretion of 6-hydroxymelatoninsulfate (a metabolite of melatonin) was measured at the beginning and the end of the study. An additional 20 SD rats were fed with the same diets but with a supplementation of melatonin (30 mg/kg/day) in their drinking water. Blood pressure (BP) was measured every week. RESULTS: BP increased significantly in rats fed with a high fructose diet and remained unchanged in the control group. The BP rise was associated with a significant decrease in melatonin secretion during sleep. Melatonin supplementation prevented the BP rise in fructose fed rats. BP increased by 14.6 +/- 1.0 mm Hg in the fructose fed rats, whereas it increased by only 3 +/- 2.6 mm Hg in rats fed with fructose and melatonin (P < 0.001 between groups). CONCLUSIONS: Melatonin secretion decreased in fructose fed rats that developed hypertension. Administration of melatonin blunted this BP rise. These data suggested that melatonin plays a role in the pathogenesis of hypertension in rats with metabolic syndrome.