Current pharmaceutical design
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Long-term potentiation (LTP), referring to a lasting increase in efficacy of synaptic transmission, is a common mechanism of memory storage in central nervous system (CNS). LTP at C-fiber synapses in spinal dorsal horn is considered as a synaptic model of pathological pain, as the spinal LTP is only induced by noxious electrical and natural stimuli but not by innoxious ones and LTPinducible stimulation is capable of leading to lasting behavioral signs of pathological pain in human and in animals. The molecular mechanisms of spinal LTP at C-fiber synapses are similar to hippocampal LTP in following aspects. ⋯ Therefore, the drugs targeting at the above molecules may impair memory function of hippocampus. The striking difference between hippocampal LTP and spinal LTP at C-fiber synapses is that activation of glial cells and the over-expression of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin- beta (IL-1β), inhibit LTP in hippocampus, but promote LTP in spinal dorsal horn. The drugs targeting at the neuroinflammatory process may not only attenuate pathological pain but also improve memory in hippocampus.
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Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia in adult population and confers significant thromboembolic risk. Endothelial dysfunction has been recognized as a possible contributor to thrombogenesis in AF. ⋯ Importantly, endothelial dysfunction has been documented in AF patients without cardio-pulmonary comorbidities or risk factors (so-called 'lone AF'), as well. In this review, we provide an overview of contemporary evidence for the alterations in endothelial function and endothelial injury in AF, with a focus on endothelial (dys)function in lone AF.
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The acid-sensing ion channel (ASIC) has emerged as a novel type of ion channel that is activated by extracellular protons as well as nonproton ligands. Advances in ASIC research have resolved its multifaceted structural and functional properties, including its widespread distribution, polymodal activation, and activity-dependent regulation of its expression. ⋯ Here we review the contribution of ASICs at the peripheral and central levels to the development of acute pain, inflammatory pain, neuropathic pain, and anxiety-related disorders, as well as their potential underlying mechanisms. Accumulating evidence suggests that ASICs represent a novel class of promising targets for developing effective therapies for pain and anxiety.
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Recent investigations of the cellular and molecular mechanisms of pain provide new hopes for more effective treatments for patients with chronic pain. At the molecular and genetic levels, new proteins and genes related to sensory sensation have been identified. ⋯ This disconnect between discovery and better treatment options is due, in part to the negative side effects associated with new treatment options, and also as a result of the ineffectiveness of these new drugs for inhibiting chronic pain. In this review, I will explore this disconnect between discovery and treatment, and propose that the failure of previous medicines can be due to their limited effects on injury-related plasticity, and question the common misperception of seeking compounds for high efficacy before understanding basic mechanisms of the target proteins in pain-related plasticity.
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This article reviews our current understanding of the relationships between critical illness, circadian disruption, and delirium. ⋯ Delirium is a common and morbid complication of hospitalization, particularly in the setting of critical illness and intensive care unit (ICU) admission. Critical illness involves a host of acute metabolic, hormonal and inflammatory responses that appear to disrupt normal sleep architecture and precipitate cerebral dysfunction. The intervention-heavy environment of the ICU further disrupts normal circadian rhythms and increases delirium risk. Despite strong evidence for correlation of sleep disruption, critical illness and delirium, causal relationships remain difficult to prove. Delirium is almost certainly a multifactorial condition. This article reviews proposed pathophysiologic mechanisms and potential therapeutic targets. In the absence of definitive pharmacologic therapy, interventions prioritizing maintenance of normal circadian, sleep, and behavioral patterns have shown promise in delirium risk reduction.