European journal of pharmacology
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The anti-diabetic drug glibenclamide inhibits K(ATP) channels in pancreatic β-cells and stimulates insulin release. It also causes adverse effects, among which are abdominal pain, gastrointestinal disturbances and nocturia. We report that glibenclamide activates human TRPA1 in a concentration range that is commonly used to induce inhibition of K(ATP) channels in vitro. ⋯ Glibenclamide activates a subpopulation of mouse primary sensory neurons, most of which are also sensitive to the selective TRPA1 agonist mustard oil. This glibenclamide sensitivity is completely abolished by genetic ablation of TRPA1. Taken together, our data demonstrate that glibenclamide is an agonist of human TRPA1, which may explain some of the adverse effects of the drug.
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Ventilatory depression is a serious side-effect of opioid analgesics. Naloxone, an antagonist of opioid receptors, eliminates not only ventilatory depression but also analgesic effect of opioids. Pharmacological dissociation of adverse reactions from the main action is important clinically and basically. ⋯ In unanesthetized animals, hypercapnic ventilatory response was measured by using whole-body plethysmography. Physostigmine (0.3mg/kg, i.p.), donepezil (1.0mg/kg, i.p.), 8-OH-DPAT (0.3mg/kg, i.p.) and buspirone (3.0mg/kg, i.p.) all recovered the morphine (10mg/kg, i.p.)-induced depression of hypercapnic ventilatory response. The present study suggests that activation of cholinergic or serotonergic (5-HT1A) mechanisms may be a useful therapeutic approach for morphine-induced ventilatory depression without loss of its analgesic action.
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Alzheimer's disease is characterized by a progressive decline in cognitive function and involves β-amyloid (Aβ) in its pathogenesis. To characterize cognitive deficits associated with Aβ accumulation, we analyzed PS1/APP mice overexpressing mutant presenilin-1 (PS1, M146L; line 6.2) and amyloid precursor protein (APP, K670N/M671L; line Tg2576), a mouse model of Alzheimer's disease with accelerated Aβ production. Age-dependent changes in working and spatial memory behaviors were investigated using Y-maze and Morris water maze tasks, respectively, in female PS1/APP mice at ages of 2, 4, 6, and 12 months. ⋯ No age-related dramatic changes were observed in expression levels of several proteins relating to memory dysfunction and also the mechanisms of donepezil and memantine in the cerebral cortex of PS1/APP mice until 6 months of age. Taken together, these results suggest dysfunctions in cholinergic and/or glutamatergic transmissions may be involved in the cognitive deficits associated with Aβ toxicity. Since donepezil and memantine have been widely used for treating patients of Alzheimer's disease, these results also suggest that cognitive deficits in PS1/APP mice assessed in the Y-maze and Morris water maze tasks are a useful animal model for evaluating novel Alzheimer's disease therapeutics.