Sodium channels activation

Neuropathic pain is initiated or caused by a primary lesion in the peripheral or central nervous system. The causative agent may be trauma, nerve-invading cancer, herpes zoster, HIV, stroke, diabetes, alcohol or other toxic substances. Neuropathic pain is refractory to most analgesic drugs. Altered sodium channel activity is characteristics of neuropathic pain states. 

Bloomquist JR, Soderlund DM (1988) Pyrethroid insecticides and DDT modify alkaloid-dependent sodium channel activation and its enhancement by sea anemone toxin. Mol Pharmacol 33 543-550... 

Liddle s syndrome is an autosomal dominant form of hypertension. It is a disorder of the renal epithelial sodium channel, which has three subunits, a, j, and y, and mutations within the first two are associated with increased sodium channel activity [7, 36]. This causes excessive sodium absorption in the distal nephron of the kidney. It gives rise to hypoglycemia, low -renin, and low aldosterone. 

Isbilen B., Fraser S. P., and Djamgoz M. B. A. (2006). Docosahexaenoic acid (omega-3) blocks voltage-gated sodium channel activity and migration of MDA-MB-231 human breast cancer cells. Int. J. Biochem. Cell Biol. 38 2173-2182. 

A medium throughput approach to evaluating sodium channel activity is the measurement of sodium flux across cell membranes [103]. In these experiments, a tracer that permeates the channel and is easily quantifiable is used to analyze sodium influx. Traditionally, radioactive tracers such as 22Na+ or [14C]guanidinium have been used. Alternatively, Li+ can be used as a tracer and analyzed by atomic absorption spectrometry. Sodium flux assays can be used to test approximately 105 compounds per year. They offer a robust readout of channel activity, but lack voltage control and temporal resolution. To examine sodium channel blockade by measuring sodium flux,... 

The effects of pumiliotoxin B on sodium channels appear to be due to interaction with a subdomain of the site at which batrachotoxin acts scorpion toxins and brevetoxin can potentiate the effects of pumiliotoxin B and of congeneric pumiliotoxins and allopumiliotoxins (102,112). Certain pumiliotoxin congeners appear to block sodium channel activation and may act as antagonists or reverse agonists (106). Structure-activity relationships with respect to stimulation of sodium flux and phosphoinositide breakdown have been studied (106). The nature of the side chain is critical to activity. For example, whereas pumiliotoxin B is one of the most potent of these alkaloids, its 15,16-erythro isomer has much lower activity (106,112). 

Bioactivity-guided fractionation of organic extracts from two Lyngbya majuscula collections led to the isolation of a new secondary metabolite, antillatoxin B 356, an unusual A -methyl homophenyl-alanine analogue of the potent neurotoxin antillatoxin 357. Compound 356 exhibited significant sodium channel-activating (ECso = 1-77 pM) and ichthyotoxic (LCso = 1 pM) properties. 

Acnisal salicylic acid, aconiazide [inn] is an isoniazid analogue and an ANTITUBERCULAR and ANTIBACTERIAL AGENT, aconitine is an alkaloid from monk s hood or wolfsbane (Aconitum napellus) and other Aconltum spp. (Ranunculaceae). It is a NEUROTOXiN implicated in poisoning by A. spp., especially, 4. chasmanthum in India. Experimentally, it is a SODIUM-CHANNEL ACTIVATOR that binds to Na -channels, slows inactivation, shifts inactivation to a more negative value, and alters ion specificity. This results in repetitive firing of neurons, with marked effects on the heart including positive inotropism and arrhythmias. Aconitine (and the related alkaloid delphinine) were formerly used in... 

Plant-derived insecticides for example, pyrethrum, which is a crude extract from flowers of the pyrethrum plant Chrysanthemum cincerariaefolium. Pyrethrin is a more refined extract containing the six naturally occurring pyrethrins. The greatest activity resides in pyrethrin I. Pyrethrum is regarded as one of the safest insecticides, at least in terms of primary toxicity. It resembles DDT in mode of action, and works at least in part by opening sodium channels in excitable membranes, so causing paralysis. See SODIUM-CHANNEL ACTIVATORS. 

PbTX-3, PbTX-9). ervatamlne, grayanotoxin. ciguatoxin, pumiliotoxins (pumiliotoxin A B), veratridine, and the pyrethroids have essentially similar actions. See sodium-CHANNEL activators SODIUM-CHANNEL BLOCKERS. 

Zn, Cd. Pb. A wide variety of other agents may block, modulate or open sodium channels (see SODIUM-CHANNEL activators), local anaesthetics block most of the channels, this being their major mechanism of action. 

IV) ANTIARRHYTHMIC. It is a SMOOTH MUSCLE RELAXANT and coronary VASODILATOR. It can be used as an antihypertensive and antianginal. and in antimigraine prophylaxis, verapamil hydrochloride verapamil, veratridine is an alkaloid from Schoenocaulon officinale (Liliaceae), and is a neurotoxin and sodium-Channel ACTIVATOR that binds to Na -channels, leading to depolarization. It has similar but weaker actions to batrachotoxin. Vercyte pipobroman. 

Kontis KJ, Rounaghi A, Goldin AL 1997 Sodium channel activation gating is affected by substitutions of voltage sensor positive charges in all four domains. J Gen Physiol 110 391— 401... 

Douglas AF 1996 The effects of the anticonvulsant lamotrigine on the sodium channel activity of rat hippocampal neurons in microculture. Undergraduate Thesis, Harvard University, Cambridge, MA, USA... 

Manger, R. L., Leja, L. S., Lee, S. Y, Hungerford, J. M., Kirkpatrick, M. A., Yasumoto, T. and Wekell, M. M. Detection of paralytic shellfish poison by rapid cell bioassay antagonism of voltagegated sodium channel active toxins in vitro. J. AOAC Int., 86, 540-543 (2003). 

Enhancement of Veratridine-Dependent Sodium Channel Activation by Pyrethroids and DDT Analogs... 

Sodium uptake assay. Assays using mouse brain synaptosomes were performed as described previously (6., ), except that insecticides were introduced to resuspended synaptosomes in 0.2-0.4 yl of ethanol rather than as a residue in the incubation tube. This amount of ethanol improved the delivery of insecticides, thereby increasing the reproducibility of the assay, and had no measurable effect on veratridine-dependent sodium channel activation. These methods were also used for assays with fish brain membranes, except that all buffers were augmented with sucrose to give osmolarities equivalent to the 0 7 M sucrose used for membrane isolation. 

Table II. Effects on Sodium Channel Activation and Acute Intracerebral Toxicity of Deltamethrin, NRDC 157, and Their Enantiomers in Mice3...

We have also defined both the effect of veratridine concentration on sodium channel activation in this system and the impact of , -DDT on the concentration-effect curve for veratridine-dependent activation (Figure 5). Half-maximal activation by veratridine oc-cured at approximately 50 PM, a value very close to that found for the action of this compound in mouse brain synaptosomes (7. , -... 

DDT significantly enhanced veratridine-dependent uptake at all veratridine concentrations above 10 pM, and maximum sodium uptake in the presence of both compounds was achieved at 50 pM, which is the approximate for veratridine alone These findings suggest that , -DDT notuonly enhances veratridine-dependent activation but also increases the potency of veratridine. This result contrasts with the interaction of deltamethrin and veratridine in mouse brain synaptosomes (Figure 1) where the insecticide enhanced activation but did not affect the potency of the activator The only previous report of insecticide-dependent potency shifts in sodium channel activation is in neuroblastoma cells, where pyrethroids increase the potency of batrachotoxin and dihydrograyanotoxin II as sodium channel activators, but do not alter the potency of veratridine (5). These experiments provide the basis for further studies to compare directly the selectivity and sensitivity of sodium channels from mammalian and fish brain in their interactions with insecticides ... 

Radiosodium uptake studies offer a new technical approach to the description of the actions of insecticides with sodium channels This method is particularly well suited to the study of CNS sodium channels, which pose serious technical difficulties for the application of intracellular recording and the current-voltage manipulations required to study normal and modified channel kinetics. Our studies to date have described an enhancement of sodium channel activation in this system by DDT analogs and pyrethroids that is consistent with... 

---