Abstract
Huntington’s disease (HD) is a genetic disorder with autosomal dominant inheritance with progressive degeneration of neurons. It is characterized by affective, cognitive, behavioral, and motor dysfunctions. 3 nitropropionic acid is well established animal model which initiates a complex series of neurochemical and signaling changes that lead to pathological events including neuronal excitotoxicity by excessive glutamate release, neuroinflammation and energy impairment. Excitotoxins like NMDA and kainic acid which binds to these receptors to release high levels of glutamate that can cause excitotoxicity by allowing high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes increase apoptosis, oxidative stress and energy impairment thereby causing mitochondrial dysfunctions and go on to damage neuronal structures. The toxic venom used by the cone shells called conotoxin contains up to 50 different peptides that selectively inhibit the function of ion channels and excitatory amino acid receptors such as NMDA involved in the transmission of nerve signals in animals representing an extensive array of ion channel blockers each showing a high degree of selectivity for particular types of channels. Conotoxins selectively target a range of ion channels and NMDA receptors, making them widely useful tool for probing nervous system function. Here we hypothize the protective effect of conotoxins, from genus Conus geographus named w-conotoxin and conantoxin, against excitotoxic neuronal cell death using 3 NP induced Huntington’s model.
Highlights
Huntington’s disease (HD) is a genetic disorder with autosomal dominant inheritance with progressive degeneration of neurons. It is characterized by affective, cognitive, behavioral, and motor dysfunctions preferentially due to morphological abnormalities and cell death of the striate medium-sized spiny neurons. 3-Nitropropionic acid (3-NP), a neurotoxin irreversibly inhibits succinate dehydrogenase enzyme in the electron transport chain and produces HD like symptoms both in animals and human [1]. 3-NP intoxication leads to selective striate lesions which begin in the striatum and later spread to the entire brain [2]
The toxic venom used by the cone shells contains up to 50 different peptides that selectively inhibit the function of voltage gated N type of Ca++ ion channels involved in the transmission of nerve signals in animals and antagonizes the function of NMDA receptors [14,15]
Our literature review showed that ω-conotoxin and conantokins acts as the NMDA receptor antagonists as well as reduces the Ca++ signaling and extracellular glutamate release and thereby minimizing excitotoxicity, mitochondrial dysfunctions and energy impairments, enhancing the life span of neurons
Summary
Huntington’s disease (HD) is a genetic disorder with autosomal dominant inheritance with progressive degeneration of neurons. The toxic venom used by the cone shells contains up to 50 different peptides that selectively inhibit the function of voltage gated N type of Ca++ ion channels involved in the transmission of nerve signals in animals and antagonizes the function of NMDA receptors [14,15]. This hypothesis focuses the properties of conopeptides [16] and to use them as drug leads for the development of novel therapeutics for the treatment of Huntington’s disease (HD) occurring due to glutamate toxicity.
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