Frontiers in pharmacology
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Frontiers in pharmacology · Jan 2019
Repeated Sigma-1 Receptor Antagonist MR309 Administration Modulates Central Neuropathic Pain Development After Spinal Cord Injury in Mice.
Up to two-thirds of patients affected by spinal cord injury (SCI) develop central neuropathic pain (CNP), which has a high impact on their quality of life. Most of the patients are largely refractory to current treatments, and new pharmacological strategies are needed. Recently, it has been shown that the acute administration of the σ1R antagonist MR309 (previously developed as E-52862) at 28 days after spinal cord contusion results in a dose-dependent suppression of both mechanical allodynia and thermal hyperalgesia in wild-type CD-1 Swiss female mice. ⋯ In addition, changes in pro-inflammatory cytokine (TNF-α, IL-1β) expression and both the expression and activation (phosphorylation) of the N-methyl-D-aspartate receptor subunit 2B (NR2B-NMDA) and extracellular signal-regulated kinases (ERK1/2) were analyzed. The repeated treatment of SCI-mice with MR309 resulted in significant pain behavior attenuation beyond the end of the administration period, accompanied by reduced expression of central sensitization-related mechanistic correlates, including extracellular mediators (TNF-α and IL-1β), membrane receptors/channels (NR2B-NMDA) and intracellular signaling cascades (ERK/pERK). These findings suggest that repeated MR309 treatment after SCI may be a suitable pharmacologic strategy to modulate SCI-induced CNP development.
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Frontiers in pharmacology · Jan 2019
Influence of CYP2C19 Metabolizer Status on Escitalopram/Citalopram Tolerability and Response in Youth With Anxiety and Depressive Disorders.
In pediatric patients, the selective serotonin reuptake inhibitors (SSRIs) escitalopram and citalopram (es/citalopram) are commonly prescribed for anxiety and depressive disorders. However, pharmacogenetic studies examining CYP2C19 metabolizer status and es/citalopram treatment outcomes have largely focused on adults. We report a retrospective study of electronic medical record data from 263 youth < 19 years of age with anxiety and/or depressive disorders prescribed escitalopram or citalopram who underwent routine clinical CYP2C19 genotyping. ⋯ Meanwhile, faster metabolizers responded more quickly to es/citalopram (p = 0.005) and trended toward less time spent in subsequent hospitalizations (p = 0.06). These results highlight a disparity in treatment outcomes with es/citalopram treatment in youth with anxiety and/or depressive disorders when standardized dosing strategies were used without consideration of CYP2C19 metabolizer status. Larger, prospective trials are warranted to assess whether tailored dosing of es/citalopram based on CYP2C19 metabolizer status improves treatment outcomes in this patient population.
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Frontiers in pharmacology · Jan 2019
Gastrodin Alleviates Oxidative Stress-Induced Apoptosis and Cellular Dysfunction in Human Umbilical Vein Endothelial Cells via the Nuclear Factor-Erythroid 2-Related Factor 2/Heme Oxygenase-1 Pathway and Accelerates Wound Healing In Vivo.
Aims: To explore the effect and mechanism of gastrodin (GAS) on human umbilical vein endothelial cells (HUVECs) apoptosis induced by oxidative stress and its function in wound healing. Main methods: HUVECs were incubated with tert-butyl hydroperoxide (TBHP) to induce endothelial cell dysfunction and GAS was used as a protector. Cell viability was detected by Counting Kit-8 (CCK-8). ⋯ Mechanistically, we found that GAS protects HUVECs from TBHP-induced cellular apoptosis by activating the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. An in vivo study illustrated that the oral administration of GAS enhances vascularization in regenerated tissue and facilitates wound healing. Significance: The findings of this study demonstrated that GAS may serve as a potential agent that accelerates wound healing.
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Frontiers in pharmacology · Jan 2019
The Nimodipine-Sparing Effect of Perioperative Dexmedetomidine Infusion During Aneurysmal Subarachnoid Hemorrhage: A Prospective, Randomized, Controlled Trial.
Background: Nimodipine can block the influx of calcium into the vascular smooth muscle cell and prevent secondary ischemia in patients with aneurysmal subarachnoid hemorrhage. However, the reduction of blood pressure after long-term intravenous administration of nimodipine has been associated with neurological deterioration. Yet, no effective solutions have been suggested to address this phenomenon. ⋯ There were no significant differences among the three groups in consumption of propofol, cisatracurium, fentanyl, and vasoactive drugs during operation, recovery time at PACU, satisfaction of patients and neurosurgeon, and number of applied urapidil and GCS during the first 48 h after surgery. The incidence of symptomatic cerebral vasospasm during 7 days after surgery, GOS of 3 months, and cerebral infarction after 30 days were also comparable among the three groups. Conclusions: Dexmedetomidine (infusion at 0.5 µg·kg-1 for 10 min, then adjusted to 0.4 µg·kg-1·h-1 during the surgery) significantly reduced the total consumption of nimodipine during the first 48 h after surgery and promoted early rehabilitation of patients although the incidences of symptomatic cerebral vasospasm, GOS, and cerebral infarction were not reduced.
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Frontiers in pharmacology · Jan 2019
Edgeworthia gardneri (Wall.) Meisn. Water Extract Ameliorates Palmitate Induced Insulin Resistance by Regulating IRS1/GSK3β/FoxO1 Signaling Pathway in Human HepG2 Hepatocytes.
The flower of Edgeworthia gardneri (Wall.) Meisn is commonly used in beverage products in Tibet and has potential health benefits for diabetes. However, the mechanisms underlying anti-insulin resistance (IR) action of the flower of E. gardneri are not fully understood. This study aims to investigate the effects of the water extract of the flower of E. gardneri (WEE) on IR in palmitate (PA)-exposed HepG2 hepatocytes. ⋯ The GLUT2 and GLUT4 translocation were also promoted by WEE treatment in PA-treated HepG2 cells. Taken together, WEE has potential anti-IR effect in PA-exposed HepG2 cells; the underlying mechanism of this action may be associated with the regulation of IRS1/GSK3β/FoxO1 signaling pathway. This study provides a pharmacological basis for the application of WEE in the treatment of metabolic diseases such as type 2 diabetes mellitus.