Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Different Classes of Antidepressants

Various antidepressants are commonly used for the treatment of depression and several other neuropsychiatric disorders. In addition to their primary effects on serotonergic or noradrenergic neurotransmitter systems, antidepressants have been shown to interact with several receptors and ion channels. However, the molecular mechanisms that underlie the effects of antidepressants have not yet been sufficiently clarified. G protein-activated inwardly rectifying K+ (GIRK, Kir3) channels play an important role in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to have therapeutic potential for several neuropsychiatric disorders and cardiac arrhythmias. In the present study, we investigated the effects of various classes of antidepressants on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2 or GIRK1/GIRK4 subunits, extracellular application of sertraline, duloxetine, and amoxapine effectively reduced GIRK currents, whereas nefazodone, venlafaxine, mianserin, and mirtazapine weakly inhibited GIRK currents even at toxic levels. The inhibitory effects were concentration-dependent, with various degrees of potency and effectiveness. Furthermore, the effects of sertraline were voltage-independent and time-independent during each voltage pulse, whereas the effects of duloxetine were voltage-dependent with weaker inhibition with negative membrane potentials and time-dependent with a gradual decrease in each voltage pulse. However, Kir2.1 channels were insensitive to all of the drugs. Moreover, the GIRK currents induced by ethanol were inhibited by sertraline but not by intracellularly applied sertraline. The present results suggest that GIRK channel inhibition may reveal a novel characteristic of the commonly used antidepressants, particularly sertraline, and contributes to some of the therapeutic effects and adverse effects

Action of MDL 646, a new synthetic prostaglandin, on gastric acid secretion of some experimental animals.

The new synthetic prostaglandin 11,15-dihydroxy-16-methyl-16-methoxy-9-oxo-prost-13-en-1-oic acid,methyl ester (8 alpha,11 alpha,15R,16R) (compound marked MDL 646), belonging to the 16-methyl-16-methoxy series, was tested for its activity on gastric secretion of different animal species and in different experimental conditions. In the dog provided with gastric fistula and Heidenhain pouch, MDL 646 (25 micrograms/kg by intragastric administration) caused a remarkable inhibition of the histamine- and bethanechol-induced acid secretion, an effect which was more evident in the main stomach than on the Heidenhain pouch. In the cat, but not in the dog, the compound inhibited not only the hypersecretion induced by histamine and bethanechol but also that induced by pentagastrin. However, in this case, high doses (50-100 micrograms/kg) had to be used to obtain a significant inhibition. Similar results were obtained with the perfused stomach of the anaesthetized rat in which the natural PGE2 appeared to be from 3 to 5 times less potent. In the conscious rat provided with gastric fistula MDL 646 (15 and 50 micrograms/kg) significantly inhibited spontaneous gastric secretion. Untoward reactions, represented by salivation and vomiting lasting 30 min, were experienced by some dogs following administration of 50-100 micrograms/kg of the synthetic prostaglandin. These data appear of considerable interest in view of the possibility of the use of MDL 646 also in humans

Cerebrotendinous xanthomatosis (van Bogaert-Scherer-Epstein disease): CT and MR findings.

PURPOSE: To describe the CT and MR findings in the brain and spinal cord of patients with cerebrotendinous xanthomatosis and to seek possible correlations between clinical, biochemical (cholestanol levels), and neuroimaging findings. METHODS: Ten patients with well-defined clinical and biochemical diagnoses of cerebrotendinous xanthomatosis were examined. Brain CT was performed in eight cases. In all patients MR was obtained using spin-echo and gradient-echo sequences. In eight patients spine MR was also performed. RESULTS: Neuroradiologic findings included diffuse cerebral and cerebellar atrophy. In half the cases, atrophy of the brain stem and corpus callosum was also found. In the majority of patients cerebellar bilateral focal lesions and mild white matter signal alterations were present. Spinal cord MR did not show signal abnormalities or atrophy. CONCLUSIONS: We found cranial alterations in patients with severe neurologic impairment, but there was no correlation with cholestanol plasma levels. No spinal cord abnormalities were present

Unusual clinical features and early brain MRI lesions in a family with cerebral autosomal dominant arteriopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently described inherited disorder. The pathologic gene maps on chromosome 19. The clinical spectrum of the disease consists of recurrent strokes, migraine, transient ischemic attacks, mood changes, and dementia. We report a genetically assessed CADASIL family with atypical clinical presentations of epileptic seizures. In two asymptomatic family members there were early brain abnormalities on MRI. Our report expands the clinical spectrum of CADASIL and suggests that it is possibly an undiagnosed disorde

Correction to: Managing the link and strengthening transition from child to adult mental health Care in Europe (MILESTONE): background, rationale and methodology.

Following publication of the original article [1], the authors reported they wanted to reinstate a co-author, who previously declined his authorship due to a misinterpretation of authorship limitations per research center.status: Published onlin