ABSTRACT
We herein report a 45-year-old man with dentatorubropallidoluysian atrophy (DRPLA) who presented with mild dementia, ataxia, and involuntary movement and developed constipation, dysuria, and orthostatic hypotension. Thermography revealed an abnormal thermal response of the skin to cold stimulation. Skin temperature reflects the skin blood flow and is regulated by the sympathetic nervous system. Thermography is currently used to study diseases associated with vasomotor dysfunction of the skin. The thermography results suggested the possibility of autonomic dysfunction. Although little is known regarding autonomic dysfunction in DRPLA, this report demonstrates the importance of autonomic dysfunction in DRPLA.
Subject(s)
Autonomic Nervous System Diseases , Cerebellar Ataxia , Dementia , Male , Humans , Middle Aged , Autonomic Nervous System Diseases/complications , Autonomic Nervous System Diseases/diagnosis , Ataxia , AtrophyABSTRACT
Although ebselen, a seleno-organic compound, inhibits inflammation in various animal models, its efficacy as an anti-asthma drug remains to be clarified. In this study, we investigated the inhibitory effect of ebselen on a guinea pig asthma model. Ebselen was orally administered at dosages of 1-20 mg/kg 2 h before an ovalbumin (OA) challenge, and then airway responses, airway inflammation, the generation of superoxide, H(2)O(2), and nitrotyrosine, and the induction of inducible nitric oxide synthase (iNOS) were evaluated. Sensitized animals challenged with OA aerosol showed dual airflow limitations, i.e., immediate and late airway responses (IAR and LAR). Ebselen significantly inhibited LAR at dosages greater than 10 mg/kg, but did not inhibit IAR at any dosage. Bronchoalveolar lavage (BAL) examination showed that airway inflammation was significantly suppressed by ebselen at 10 mg/kg. The generation of superoxide and H(2)O(2) occurred on endothelial cells of LAR bronchi, and was inhibited by 10 mg/kg of ebselen. Superoxide generation was inhibited by diphenyleneiodonium chloride (DPI), a NAD(P)H oxidase inhibitor, but not by allopurinol, a xanthine oxidase inhibitor. Immunoreactivities for iNOS and nitrotyrosine were also observed on endothelial cells of LAR bronchi and were abolished in ebselen-treated animals. The present findings suggest that ebselen can be applied as a new therapeutic agent for asthma. The possible mechanisms by which ebselen inhibits LAR likely involve suppression of oxidant formation and iNOS induction in endothelial cells.
Subject(s)
Airway Resistance/drug effects , Antioxidants/pharmacology , Asthma/drug therapy , Azoles/pharmacology , Bronchitis/drug therapy , Endothelium, Vascular/drug effects , Organoselenium Compounds/pharmacology , Respiratory Hypersensitivity/drug therapy , Tyrosine/analogs & derivatives , Animals , Antineoplastic Agents, Alkylating/administration & dosage , Area Under Curve , Asthma/pathology , Bronchitis/pathology , Bronchoalveolar Lavage Fluid/cytology , Cyclophosphamide/administration & dosage , Disease Models, Animal , Endothelium, Vascular/pathology , Enzyme Activation , Female , Guinea Pigs , Hydrogen Peroxide/pharmacology , Immunoenzyme Techniques , Isoindoles , Lung/drug effects , Lung/metabolism , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II , Ovalbumin/administration & dosage , Peptide Fragments/immunology , Rabbits , Reactive Nitrogen Species/metabolism , Reactive Oxygen Species/metabolism , Respiratory Function Tests , Superoxides/metabolism , Tyrosine/metabolismABSTRACT
The aim of this study was to elucidate the role of thromboxane A(2) (TxA(2)) on asthma-related cough in guinea pigs. Animals were immunosensitized and repeatedly challenged with ovalbumin as an antigen. Coughs were induced by the inhalation of 10(-5) M capsaicin solution for 10 min. Thromboxane synthetase (TxS) inhibitor OKY-046 and thromboxane-receptor antagonist AA-2414 significantly inhibited cough responses in repeatedly challenged animals. Inhalation of TxA(2) mimic STA-2- potentiated cough responses in normal and immunosensitized animals but not in repeatedly challenged ones. Moreover, STA-2-potentiated coughs were inhibited by administration of neurokinin-receptor antagonist FK-224. In repeatedly challenged animals, concentration of TxB(2) in airway lavage fluid, expression of TxS mRNA in tracheal epithelia, and the immunostaining intensity against TxS in mucous cells of the epithelium significantly increased compared with normal and sensitized animals. These results suggest that TxA(2) derived from mucous cells potentiated cough responses to capsaicin in allergic airway inflammation.
