Frontiers in pharmacology
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Frontiers in pharmacology · Jan 2013
2-Aminoethoxydiphenyl borate activates the mechanically gated human KCNK channels KCNK 2 (TREK-1), KCNK 4 (TRAAK), and KCNK 10 (TREK-2).
Two-pore domain K(+) (KCNK, K2P) channels underlie the "leak" (background) potassium conductance in many types of excitable cells. They oppose membrane depolarization and cell excitability. These channels have been reported to be modulated by several physical and chemical stimuli. ⋯ TREK channels are widely expressed in the central nervous system and peripheral tissues, where they play roles in several key processes. However, little is known regarding their pharmacology; therefore, the identification of a common, stable and inexpensive agonist should aid further investigations of these channels. Additionally, 2-APB has been used to study native receptors in cell systems that endogenously express members of the TREK subfamily (e.g., rat dorsal root ganglia); our results thus warn against the use of 2-APB at high concentrations in these systems.
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Frontiers in pharmacology · Jan 2013
Antidepressant activity: contribution of brain microdialysis in knock-out mice to the understanding of BDNF/5-HT transporter/5-HT autoreceptor interactions.
Why antidepressants vary in terms of efficacy is currently unclear. Despite the leadership of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression, the precise neurobiological mechanisms involved in their therapeutic action are poorly understood. A better knowledge of molecular interactions between monoaminergic system, pre- and post-synaptic partners, brain neuronal circuits and regions involved may help to overcome limitations of current treatments and identify new therapeutic targets. ⋯ Finally, we will summarize main advantages of using ICM in mice through recent examples obtained in knock-outs (drug infusion through the ICM probe allows the search of a correlation between changes in extracellular neurotransmitter levels and antidepressant-like activity) or alternatives (infusion of a small-interfering RNA suppressing receptor functions in the mouse brain). We will also focus this review on post-synaptic components such as brain-derived neurotrophic factor in adult hippocampus that plays a crucial role in the neurogenic and anxiolytic/antidepressant-like activity of chronic SSRI treatment. Limitations of ICM will also be considered.
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Frontiers in pharmacology · Jan 2012
Apolipoprotein mimetic peptides: a new approach for the treatment of asthma.
New treatments are needed for severe asthmatics to improve disease control and avoid severe toxicities associated with oral corticosteroids. We have used a murine model of house dust mite (HDM)-induced asthma to identify steroid-unresponsive genes that might represent targets for new therapeutic approaches for severe asthma. This strategy identified apolipoprotein E as a steroid-unresponsive gene with increased mRNA expression in the lungs of HDM-challenged mice. ⋯ Similarly, apolipoprotein A-I may have therapeutic potential in asthma based upon its anti-inflammatory, anti-oxidative, and anti-fibrotic properties. Furthermore, administration of apolipoprotein A-I mimetic peptides has attenuated airway inflammation, airway remodeling, and airway hyperreactivity in murine models of experimental asthma. Thus, site-directed delivery of inhaled apolipoprotein E or apolipoprotein A-I mimetic peptides may represent novel treatment approaches that can be developed for asthma, including severe disease.
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Frontiers in pharmacology · Jan 2012
Associations of Cigarette Smoking and Polymorphisms in Brain-Derived Neurotrophic Factor and Catechol-O-Methyltransferase with Neurocognition in Alcohol Dependent Individuals during Early Abstinence.
Chronic cigarette smoking and polymorphisms in brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT) are associated with neurocognition in normal controls and those with various neuropsychiatric conditions. The influence of BDNF and COMT on neurocognition in alcohol dependence is unclear. The primary goal of this report was to investigate the associations of single nucleotide polymorphisms (SNPs) in BDNF Val66Met (rs6265) and COMT Val158Met (rs4680) with neurocognition in a treatment-seeking alcohol dependent cohort and determine if neurocognitive differences between non-smokers and smokers previously observed in this cohort persist when controlled for these functional SNPs. ⋯ The findings are consistent with studies in normal controls and neuropsychiatric cohorts that reported COMT Met carriers demonstrated better performance on measures of executive skills and general intelligence. Results also indicated that the poorer performance of smoking compared to non-smoking ALC across multiple neurocognitive domains was not mediated by COMT or BDNF genotype. Overall, the findings lend support to the expanding clinical movement to make smoking cessation programs available to smokers at the inception of treatment for alcohol/substance use disorders.