Novel approach using chloride manipulation to silence neurons.
You have read before of the EXCITATORY effects of positively charged ions around the membrane of the neuron (mainly sodium and calcium); and also of the INHIBITORY effects of negatively charged ions, chloride in particular. Failure of injured neurons to make a chloride carrier, KCC2, has even been considered primary in the evolution of hypersensitization, such as is seen in central pain.
Now, from Cal Tech, Lerchner et al in Neuron (2007) 54: 35-49 have reported that they have discovered a genetic strategy for quieting neurons. Not surprisingly it involves chloride. A system that DIRECTLY supresses membrane excitability via a systemmically (meaning not orally) administered drug has been developed.
You may recall that the outer brain is called cortex. The two halves of the brain are called the cerebral hemisphere. Deep to the cortex and surrounding the thalamus (more or less centrally located) and on either side are a group of structures known as the “basal ganglia” “Corpus striatum” (L. for striped body) is a name given to the basal ganglia, which surround the thalamus. Corpus striatum includes the caudate nucelus and the lentiform nucleus or putamen. These structures have both white and grey matter imparting a striped or striatal appearance on microscopic and gross sections. Hence, the name “striatum”. Again, we are talking about large amounts of brain structure BENEATH the cortex.
Ivermectin is a drug used in the past against microfilaria, a parasite. Using an ivermectin (IVM) gated chloride channel from the organism C. elegans, membrane silencing was near total at about 12 hours after dosage of what the investigators called, an “IVM/CaCl” admixture. The effect was maximal at 12 hours and worn off at 4 days. Basically, this mixture silences neurons.
The striatum could be put through multiple silencing and recovery cycles in a single animal. Effective duration of the effect was somewhere less than the four days. The chloride ingredient is known at “GluClalphabeta”. The ivermectin rapidly suppressed nerve spiking, with essential effect by 4 hours. Since a combo of ivermectin and GluCl were used, ie. there were two subunits whose composition could be slightly varied, it was possible to achieve some cellular specificity of effect based on the level to which GluCl was expressed.
Do not confuse ivermectin with invermectin, which is an animal drug, over which some controversy has occurred as to dosing of animals which appear in the meat for human consumption.
Ivermectin is an anti-parasitic human drug used to treat Strongyloides and Onchocerciasis (microfilaria). It has been suspected that treatment with ivermectin causes the central nervous system to become permeable to Loa Loa infection, another organism which causes a uncurable encephalopathy, or disease of the brain. Loa Loa is endemic is central and western Africa.
Whether this drug combo has promise as a membrane silencer for pain, we do not know, but study of its mechanisms should surely benefit our understanding of chloride and how it relates to the prevention of hypersensitization.
