Neuropathic pain has been hypothesized to be the result of aberrant expression and function of sodium channels at the site of injury. To investigate the effects of NaV1.8 antisense oligonucleotide on the expression of...Neuropathic pain has been hypothesized to be the result of aberrant expression and function of sodium channels at the site of injury. To investigate the effects of NaV1.8 antisense oligonucleotide on the expression of sodium channel mRNA in dorsal root ganglion （DRG） neurons in chronic neuropathic pain. 24 Sprague-Dawley rats weighing 200--260 g were anesthetized with the intraperitoneal injection of 300 mg· kg^-1 choral hydrate. The CCI model was made by loose ligation of sciatic nerve trunk by 4--0 chromic gut. The mechanical and thermal pain threshold were measured before operation and 1, 3, 5, 7, 9, 11, 13 days after operation. A PE-10 catheter was implanted in subarachnoid space at lumbar region. On the 7th postoperative day the animals were randomly divided into 4 groups. The drugs were injected intrathecally twice a day for 5 consecutive days in group 2--4. The animals were decapitated 14 days after the surgery. The L4--L6 DRG of the operated side was removed and crushed, and total RNA was extracted with Trizol reagent. The contralateral side was used as control. The change of NaV1.8 sodium channel transcripts was determined by RT-PCR. Pain threshold was significantly lowered after CCI as compared with that in control group and was elevated 3 days after antisense oligonucleotide injection. Sensory neuron specific TTX-R sodium channel NaV1.8 transcript was down-regulated after antisense oligonucleotide injection at the dosage of 45 μg as compared with that in CCI group （P〈0.01）, and it was even greater at the dosage of 90 μg. The intrathecally injected NaV1.8 antisense oligonucleotide can reduce the mechanical allodynia and thermal hyperalgesia partially by downregulating the SNS transcript expression.展开更多
Atrial fibrillation(AF)is the most common cardiac arrhythmia worldwide.The prevalence of the disease increases with age,strongly implying an age-related process underlying the pathology.At a time when people are livin...Atrial fibrillation(AF)is the most common cardiac arrhythmia worldwide.The prevalence of the disease increases with age,strongly implying an age-related process underlying the pathology.At a time when people are living longer than ever before,an exponential increase in disease prevalence is predicted worldwide.Hence unraveling the underlying mechanics of the disease is paramount for the development of innovative treatment and prevention strategies.The role of voltage-gated sodium channels is fundamental in cardiac electrophysiology and may provide novel insights into the arrhythmogenesis of AF.Na_v1.5 is the predominant cardiac isoform,responsible for the action potential upstroke.Recent studies have demonstrated that Na_v1.8(an isoform predominantly expressed within the peripheral nervous system)is responsible for cellular arrhythmogenesis through the enhancement of pro-arrhythmogenic currents.Animal studies have shown a decline in Na_v1.5 leading to a diminished action potential upstroke during phase 0.Furthermore,the study of human tissue demonstrates an inverse expression of sodium channel isoforms;reduction of Na_v1.5 and increase of Na_v1.8 in both heart failure and ventricular hypertrophy.This strongly suggests that the expression of voltage-gated sodium channels play a crucial role in the development of arrhythmias in the diseased heart.Targeting aberrant sodium currents has led to novel therapeutic approaches in tackling AF and continues to be an area of emerging research.This review will explore how voltage-gated sodium channels may predispose the elderly heart to AF through the examination of laboratory and clinical based evidence.展开更多
Parkinson's disease(PD)is a neurodegenerative disorder due to gradual loss of dopaminergic neurons in the substantia nigra in the midbrain,however the pathogenesis is unclear.There is a correlation between the exc...Parkinson's disease(PD)is a neurodegenerative disorder due to gradual loss of dopaminergic neurons in the substantia nigra in the midbrain,however the pathogenesis is unclear.There is a correlation between the excitability of striatal neurons and PD.Ion channels are important to maintain membrane potential and regulate excitability of neurons,while ionic mechanisms for modulation of neurons excitability are not fully understood.This article reviews the relationship between ion channels and excitability of striatal neurons in PD and ion channel changes in the pathogenesis of PD.In order to find new targets to treatment PD by intervening ion channels.展开更多
Growth differentiation factor 15(GDF-15)is a member of the transforming growth factor-βsuperfamily.It is widely distributed in the central and peripheral nervous systems.Whether and how GDF-15 modulates nociceptive s...Growth differentiation factor 15(GDF-15)is a member of the transforming growth factor-βsuperfamily.It is widely distributed in the central and peripheral nervous systems.Whether and how GDF-15 modulates nociceptive signaling remains unclear.Behaviorally,we found that peripheral GDF-15 significantly elevated nociceptive response thresholds to mechanical and thermal stimuli in naïve and arthritic rats.Electrophysiologically,we demonstrated that GDF-15 decreased the excitability of small-diameter dorsal root ganglia(DRG)neurons.Furthermore,GDF-15 concentration-dependently suppressed tetrodotoxin-resistant sodium channel Nav1.8 currents,and shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction.GDF-15 also reduced window currents and slowed down the recovery rate of Nav1.8 channels,suggesting that GDF-15 accelerated inactivation and slowed recovery of the channel.Immunohistochemistry results showed that activin receptor-like kinase-2(ALK2)was widely expressed in DRG medium-and small-diameter neurons,and some of them were Nav1.8-positive.Blockade of ALK2 prevented the GDF-15-induced inhibition of Nav1.8 currents and nociceptive behaviors.Inhibition of PKA and ERK,but not PKC,blocked the inhibitory effect of GDF-15 on Nav1.8 currents.These results suggest a functional link between GDF-15 and Nav1.8 in DRG neurons via ALK2 receptors and PKA associated with MEK/ERK,which mediate the peripheral analgesia of GDF-15.展开更多
目的布比卡因是长效酰胺类局麻药,本研究旨在观察布比卡因对人肺上皮细胞短路电流的影响,并探讨可能的机制。方法应用尤斯灌流室装置测定H441单层细胞的短路电流。由总电流减去阿米洛利抑制后的电流算得阿米洛利敏感性电流,以用药前H44...目的布比卡因是长效酰胺类局麻药,本研究旨在观察布比卡因对人肺上皮细胞短路电流的影响,并探讨可能的机制。方法应用尤斯灌流室装置测定H441单层细胞的短路电流。由总电流减去阿米洛利抑制后的电流算得阿米洛利敏感性电流,以用药前H441单层细胞的阿米洛利敏感性电流初始值为100%对照。用100μmol·L^(-1)布比卡因处理H441细胞,在0、15、30、60 min 4个时间点提取蛋白用于Western blot,研究布比卡因对ERK1/2蛋白磷酸化的影响。结果布比卡因能够剂量依赖性抑制H441单层细胞的短路电流,此电流可被阿米洛利抑制;Western blot结果显示,布比卡因能够促进ERK1/2蛋白磷酸化。结论布比卡因通过抑制人肺上皮细胞阿米洛利敏感性电流而降低肺泡上皮离子转运,其机制可能与其促进ERK1/2蛋白磷酸化有关。临床上对伴有肺部疾患的病人应用布比卡因时应考虑其可能对肺泡上皮液体清除的影响。展开更多
文摘Neuropathic pain has been hypothesized to be the result of aberrant expression and function of sodium channels at the site of injury. To investigate the effects of NaV1.8 antisense oligonucleotide on the expression of sodium channel mRNA in dorsal root ganglion （DRG） neurons in chronic neuropathic pain. 24 Sprague-Dawley rats weighing 200--260 g were anesthetized with the intraperitoneal injection of 300 mg· kg^-1 choral hydrate. The CCI model was made by loose ligation of sciatic nerve trunk by 4--0 chromic gut. The mechanical and thermal pain threshold were measured before operation and 1, 3, 5, 7, 9, 11, 13 days after operation. A PE-10 catheter was implanted in subarachnoid space at lumbar region. On the 7th postoperative day the animals were randomly divided into 4 groups. The drugs were injected intrathecally twice a day for 5 consecutive days in group 2--4. The animals were decapitated 14 days after the surgery. The L4--L6 DRG of the operated side was removed and crushed, and total RNA was extracted with Trizol reagent. The contralateral side was used as control. The change of NaV1.8 sodium channel transcripts was determined by RT-PCR. Pain threshold was significantly lowered after CCI as compared with that in control group and was elevated 3 days after antisense oligonucleotide injection. Sensory neuron specific TTX-R sodium channel NaV1.8 transcript was down-regulated after antisense oligonucleotide injection at the dosage of 45 μg as compared with that in CCI group （P〈0.01）, and it was even greater at the dosage of 90 μg. The intrathecally injected NaV1.8 antisense oligonucleotide can reduce the mechanical allodynia and thermal hyperalgesia partially by downregulating the SNS transcript expression.
文摘Atrial fibrillation(AF)is the most common cardiac arrhythmia worldwide.The prevalence of the disease increases with age,strongly implying an age-related process underlying the pathology.At a time when people are living longer than ever before,an exponential increase in disease prevalence is predicted worldwide.Hence unraveling the underlying mechanics of the disease is paramount for the development of innovative treatment and prevention strategies.The role of voltage-gated sodium channels is fundamental in cardiac electrophysiology and may provide novel insights into the arrhythmogenesis of AF.Na_v1.5 is the predominant cardiac isoform,responsible for the action potential upstroke.Recent studies have demonstrated that Na_v1.8(an isoform predominantly expressed within the peripheral nervous system)is responsible for cellular arrhythmogenesis through the enhancement of pro-arrhythmogenic currents.Animal studies have shown a decline in Na_v1.5 leading to a diminished action potential upstroke during phase 0.Furthermore,the study of human tissue demonstrates an inverse expression of sodium channel isoforms;reduction of Na_v1.5 and increase of Na_v1.8 in both heart failure and ventricular hypertrophy.This strongly suggests that the expression of voltage-gated sodium channels play a crucial role in the development of arrhythmias in the diseased heart.Targeting aberrant sodium currents has led to novel therapeutic approaches in tackling AF and continues to be an area of emerging research.This review will explore how voltage-gated sodium channels may predispose the elderly heart to AF through the examination of laboratory and clinical based evidence.
基金General Project of National Natural Science Foundation(No.81860243)。
文摘Parkinson's disease(PD)is a neurodegenerative disorder due to gradual loss of dopaminergic neurons in the substantia nigra in the midbrain,however the pathogenesis is unclear.There is a correlation between the excitability of striatal neurons and PD.Ion channels are important to maintain membrane potential and regulate excitability of neurons,while ionic mechanisms for modulation of neurons excitability are not fully understood.This article reviews the relationship between ion channels and excitability of striatal neurons in PD and ion channel changes in the pathogenesis of PD.In order to find new targets to treatment PD by intervening ion channels.
基金This work was supported by the National Natural Science Foundation of China(82021002,31771164,and 31930042)the National Key R&D Program of China(2017YFB0403803)+1 种基金the Innovative Research Team of High-level Local Universities in Shanghai,Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)Zhang Jiang Laboratory.
文摘Growth differentiation factor 15(GDF-15)is a member of the transforming growth factor-βsuperfamily.It is widely distributed in the central and peripheral nervous systems.Whether and how GDF-15 modulates nociceptive signaling remains unclear.Behaviorally,we found that peripheral GDF-15 significantly elevated nociceptive response thresholds to mechanical and thermal stimuli in naïve and arthritic rats.Electrophysiologically,we demonstrated that GDF-15 decreased the excitability of small-diameter dorsal root ganglia(DRG)neurons.Furthermore,GDF-15 concentration-dependently suppressed tetrodotoxin-resistant sodium channel Nav1.8 currents,and shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction.GDF-15 also reduced window currents and slowed down the recovery rate of Nav1.8 channels,suggesting that GDF-15 accelerated inactivation and slowed recovery of the channel.Immunohistochemistry results showed that activin receptor-like kinase-2(ALK2)was widely expressed in DRG medium-and small-diameter neurons,and some of them were Nav1.8-positive.Blockade of ALK2 prevented the GDF-15-induced inhibition of Nav1.8 currents and nociceptive behaviors.Inhibition of PKA and ERK,but not PKC,blocked the inhibitory effect of GDF-15 on Nav1.8 currents.These results suggest a functional link between GDF-15 and Nav1.8 in DRG neurons via ALK2 receptors and PKA associated with MEK/ERK,which mediate the peripheral analgesia of GDF-15.
文摘目的布比卡因是长效酰胺类局麻药,本研究旨在观察布比卡因对人肺上皮细胞短路电流的影响,并探讨可能的机制。方法应用尤斯灌流室装置测定H441单层细胞的短路电流。由总电流减去阿米洛利抑制后的电流算得阿米洛利敏感性电流,以用药前H441单层细胞的阿米洛利敏感性电流初始值为100%对照。用100μmol·L^(-1)布比卡因处理H441细胞,在0、15、30、60 min 4个时间点提取蛋白用于Western blot,研究布比卡因对ERK1/2蛋白磷酸化的影响。结果布比卡因能够剂量依赖性抑制H441单层细胞的短路电流,此电流可被阿米洛利抑制;Western blot结果显示,布比卡因能够促进ERK1/2蛋白磷酸化。结论布比卡因通过抑制人肺上皮细胞阿米洛利敏感性电流而降低肺泡上皮离子转运,其机制可能与其促进ERK1/2蛋白磷酸化有关。临床上对伴有肺部疾患的病人应用布比卡因时应考虑其可能对肺泡上皮液体清除的影响。
