Inhibition of Acid-Sensing Ion Channels by KB-R7943, a Reverse Na/Ca Exchanger Inhibitor.

KB-R7943, an isothiourea derivative, is widely used as a pharmacological inhibitor of reverse sodium-calcium exchanger (NCX). It has been shown to have neuroprotective and analgesic effects in animal models; however, the detailed molecular mechanisms remain elusive. In the current study, we investigated whether KB-R7943 modulates acid-sensing ion channels (ASICs), a group of proton-gated cation channels implicated in the pathophysiology of various neurological disorders, using the whole-cell patch clamp techniques.

Upregulation of acid sensing ion channel 1a (ASIC1a) by hydrogen peroxide through the JNK pathway.

Oxidative stress is intimately tied to neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, and acute injuries, such as ischemic stroke and traumatic brain injury. Acid sensing ion channel 1a (ASIC1a), a proton-gated ion channel, has been shown to be involved in the pathogenesis of these diseases. However, whether oxidative stress affects the expression of ASIC1a remains elusive.

Protein Kinase C Regulates ASIC1a Protein Expression and Channel Function via NF-kB Signaling Pathway.

Tissue acidosis is a common feature in many pathological conditions. Activation of acid-sensing ion channel 1a (ASIC1a) plays a key role in acidosis-mediated neurotoxicity. Protein kinase C (PKC) activity has been proved to be associated with many physiological processes and pathological conditions; however, whether PKC activation regulates ASIC1a protein expression and channel function remains ill defined.

TRPM7 channels play a role in high glucose-induced endoplasmic reticulum stress and neuronal cell apoptosis.

High-glucose (HG) levels and hyperglycemia associated with diabetes are known to cause neuronal damage. The detailed molecular mechanisms, however, remain to be elucidated. Here, we investigated the role of transient receptor potential melastatin 7 (TRPM7) channels in HG-mediated endoplasmic reticulum stress (ERS) and injury of NS20Y neuronal cells.

Effect of Redox-Modifying Agents on the Activity of Channelrhodopsin-2.

Background: The algal protein Channelrhodopsin-2 (ChR2) has been widely used in recent years in optogenetic technique to investigate the functions of complex neuronal networks through minimally invasive and temporally precise photostimulation of genetically defined neurons. However, as with any other new technique, current optogentic approaches have various limitations. In addition, how ChR2 may behave in response to complex biochemical changes associated with various physiological/pathological conditions is largely unknown.

Modulation of Acid-sensing Ion Channel 1a by Intracellular pH and Its Role in Ischemic Stroke.

An important contributor to brain ischemia is known to be extracellular acidosis, which activates acid-sensing ion channels (ASICs), a family of proton-gated sodium channels. Lines of evidence suggest that targeting ASICs may lead to novel therapeutic strategies for stroke. Investigations of the role of ASICs in ischemic brain injury have naturally focused on the role of extracellular pH in ASIC activation.

Amiloride Analogs as ASIC1a Inhibitors.

Background: ASIC1a, the predominant acid-sensing ion channels (ASICs), is implicated in neurological disorders including stroke, traumatic spinal cord injury, and ALS. Potent ASIC1a inhibitors should have promising therapeutic potential for ASIC1a-related diseases.

Aims: We examined the inhibitory effects of a number of amiloride analogs on ASIC1a currents, aimed at understanding the structure-activity relationship and identifying potent ASIC1a inhibitors for stroke intervention.

Characterization of a Synthetic Steroid 24-keto-cholest-5-en-3β, 19-diol as a Neuroprotectant.

Background: Neuroactive steroids represent promising candidates for the treatment of neurological disorders. Our previous studies identified an endogenous steroid cholestane-3β, 5α, 6β-triol (Triol) as a novel neuroprotectant.

Aim: We aimed to identify a potent candidate for stroke treatment through a screening of Triol analogs.

Suppression of TRPM7 inhibits proliferation, migration, and invasion of malignant human glioma cells.

Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with a dismal prognosis. Despite intensive study on tumor biology, the underlying mechanisms of the unlimited proliferation and progressive local invasion are still poorly understood, and no effective treatment has been developed for GBM patients.

Aims: We determine the role of TRPM7 channels in the growth, migration, and infiltration of malignant glioma cells.

Local anesthetic lidocaine inhibits TRPM7 current and TRPM7-mediated zinc toxicity.

Background: Previous study demonstrated that overstimulation of TRPM7 substantially contributes to zinc-mediated neuronal toxicity. Inhibition of TRPM7 activity and TRPM7-mediated intracellular Zn(2+) accumulation may represent a promising strategy in the treatment of stroke.

Aims: To investigate whether local anesthetics lidocaine could inhibit TRPM7 channel and TRPM7-mediated zinc toxicity.

The pharmacology and therapeutic potential of small molecule inhibitors of acid-sensing ion channels in stroke intervention.

In the nervous system, a decrease in extracellular pH is a common feature of various physiological and pathological processes, including synaptic transmission, cerebral ischemia, epilepsy, brain trauma, and tissue inflammation. Acid-sensing ion channels (ASICs) are proton-gated cation channels that are distributed throughout the central and peripheral nervous systems. Following the recent identification of ASICs as critical acid-sensing extracellular proton receptors, growing evidence has suggested that the activation of ASICs plays important roles in physiological processes such as nociception, mechanosensation, synaptic plasticity, learning and memory.

Synthesis and anti-glioma activity of 25(R)-spirostan-3beta,5alpha,6beta,19-tetrol.

Malignant gliomas are common and aggressive brain tumours in adults. The rapid proliferation and diffuse brain migration are the main obstacles to successful treatment. Here, we show 25(R)-spirostan-3beta,5alpha,6beta,19-tetrol, a polyhydroxy steroid, is capable of suppressing proliferation and migration of C6 malignant glioma cells in a concentration-dependent manner.

Aspirin inhibits proliferation of gemcitabine-resistant human pancreatic cancer cells and augments gemcitabine-induced cytotoxicity.

Aim: To investigate whether aspirin is able to augment gemcitabine-induced cytotoxicity in human pancreatic cancer cells.

Methods: Two gemcitabine-insensitive human pancreatic cancer cell lines, PANC-1 and Capan-1, were used. Cells were treated with either aspirin or gemcitabine alone or both of them.