Unraveling the Cardiac Effects Induced by Carvacrol in Spontaneously Hypertensive Rats: Involvement of Transient Receptor Potential Melastatin Subfamily 4 and 7 Channels.

ABSTRACT: Accumulating evidence indicates that transient receptor potential (TRP) channels are involved in the pathophysiological process in the heart, and monoterpenes, such as carvacrol, are able to modulate these channels activity. In this article, our purpose was to evaluate the direct cardiac effect of carvacrol on the contractility of cardiomyocytes and isolated right atria from spontaneously hypertensive and Wistar Kyoto rats. In this way, in vitro experiments were used to evaluate the ventricular cardiomyocytes contractility and the Ca2+ transient measuring, in addition to heart rhythm in the right atria. The role of TRPM channels in carvacrol-mediated cardiac activities was also investigated. The results demonstrated that carvacrol induced a significant reduction in ventricular cell contractility, without changes in transient Ca2+. In addition, carvacrol promoted a significant negative chronotropic response in spontaneously hypertensive and Wistar Kyoto rats' atria. Selective blockage of TRPM channels suggests the involvement of TRP melastatin subfamily 2 (TRPM2), TRPM4, and TRPM7 in the carvacrol-mediated cardiac effects. In silico studies were conducted to further investigate the putative role of TRPM4 in carvacrol-mediated cardiac action. FTMap underscores a conserved pocket in both TRPM4 and TRPM7, revealing a potential carvacrol binding site, and morphological similarity analysis demonstrated that carvacrol shares a more than 85% similarity to 9-phenanthrol. Taken together, these results suggest that carvacrol has direct cardiac actions, leading to reduced cellular contractility and inducing a negative chronotropic effect, which may be related to TRPM7 and TRPM4 modulation.

Involvement of astrocytic CYP1A1 isoform in the metabolism and toxicity of the alkaloid pyrrolizidine monocrotaline.

Monocrotaline (MCT) and its pyrrole derivative, dehydromonocrotaline (DHMC), interact with molecular targets in cells of the central nervous system. DHMC presents higher toxicity than MCT indicating that its metabolism of MCT is a critical step of this alkaloid toxicity. This study sought to elucidate the metabolism and the toxicity of MCT in C6 astrocyte cell line and primary cultures of rat astrocytes by investigating metabolic enzymatic mechanisms of the cytochrome P450 (CYP) system and conjugation with glutathione. Treatment with omeprazole (OMP) (20 µM), a non-specific inducer of CYP450 induced approximately 10-fold increase in CYP1A1 activity after 2 h of treatment. Similarly, the 7-Ethoxyresorufin-O-deethylase (EROD) activity was induced by treatment with MCT (100-500 µM), indicating that the P450 CYP1A1 isoform was active and involved in the metabolism of MCT. Analysis of conjugation with glutathione showed a significant depletion of GSH after MCT (500 µM) treatment, and this was partially reversed by pretreatment with a P450 inhibitor (cimetidine 100 µM). These results suggest that not only the alkaloid MCT but, also its metabolite may deplete GSH. Rosenfeld staining showed intense vacuolization after MCT treatment, which was partially inhibited in the presence of a P450 activator. MTT test showed that association of MCT with OMP induced a reduction in cell viability in C6 and primary astrocytic cells. These results demonstrate that MCT is metabolized by astrocytic CYP1A1 to generate metabolites that can deplete GSH. Moreover, changes in the activity of the P450 enzymes interfere with the cytotoxic effects induced by the alkaloid.

Sleep disorders in machado-joseph disease: frequency, discriminative thresholds, predictive values, and correlation with ataxia-related motor and non-motor features.

Sleep disorders are common complaints in patients with neurodegenerative diseases such as spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD)--SCA3/MJD. We evaluated the frequency of sleep disorders in SCA3/MJD patients against controls matched by age and gender, and correlated data with demographic and clinical variables. The main sleep disorders evaluated were rapid eye movement (REM) sleep behavior disorder (RBD), restless leg syndrome (RLS), and excessive daytime sleepiness (EDS). We recruited 40 patients with clinical and molecular-proven SCA3/MJD and 38 controls. We used the following clinical scales to evaluate our primary outcome measures: RBD Screening Questionnaire, International RLS Rating Scale, and Epworth Sleepiness Scale. To evaluate ataxia-related motor and non-motor features, we applied the International Cooperative Ataxia Rating Scale, the Scale for the Assessment and Rating of Ataxia, and the Unified Parkinson's Disease Rating Scale part III. Psychiatric manifestations were tested with the Hamilton Anxiety Scale, and Beck Depression Inventory. The frequency of RBD and RLS were significantly higher in the SCA3/MJD group than in the control group (p < 0.001). There was no difference between both groups with regard to EDS. The accuracy of RDBSQ to discriminate between cases and controls was considered the best area under the ROC curve (0.86). Within-SCA3/MJD group analysis showed that anxiety and depression were significantly correlated with RDB, but not with RLS. Additionally, depression was considered the best predictive clinical feature for RDB and EDS.

Bilateral horizontal gaze palsy with unilateral peripheral facial paralysis caused by pontine tegmentum infarction.

Clinical features of pontine infarction depend on the topography of vascular lesion and most remarkably sometimes the same topographic region can lead to different clinical syndromes (e.g., dorsal pontine tegmentum). In this report we describe an elderly patient with acute dorsal pontine infarction leading to a unique syndrome of bilateral horizontal gaze palsy and unilateral peripheral facial paralysis. We propose that this syndrome could be included as a part of a continuum that involves one-and-a-half syndrome, eight-and-a-half syndrome, and other variants of pontine tegmentum infarction.