The sigma receptor was first reported in 1976, and we now know there are two receptor subtypes: sigma-1 and sigma-2. The sigma-1 receptor was originally thought to be a neurotransmitter receptor, however, in 2007, Hayashi and Su reported that the receptor is not found on the cellular membrane but exists inside cells. The sigma-1 receptor is located mainly on mitochondrial-associated endoplasmic reticulum (ER) membranes and seems to modulate other protein functions through a chaperone-like activity. Through this activity, the sigma-1 receptor can stimulate various physiological functions within the cells, such as ATP production, Ca2+ influx into mitochondria, and amelioration of ER stress. At the cellular level, the sigma-1 receptor protects neural cells from various types of cellular damage and prolongs cell survival. Therefore, sigma-1 receptor agonists, that enhance the function of sigma-1 receptor proteins, are expected to reduce neural damage and promote the survival of neural tissues. Hence, sigma-1 receptor agonists represent a new class of therapeutic drugs for the treatment of neurodegenerative diseases.
It should be noted that the sigma-1 receptor is distributed in non-neural tissue, where it also plays a protective role. At this stage, we are focused on the development of sigma-1 receptor agonists for treating CNS diseases, but eventually, these agonists may be applied for the treatment of various chronic diseases associated with tissue degeneration. The images below show the culture of rat embryo cortical neurons in the presence and absence of our sigma-1 receptor agonist (MC116). The neurons with MC116 show an obvious extension of their neurites.
- The primary culture of rat embryo cortical neuron. A sigma-1 receptor agonist (MC116) stimulates clearly the neurite outgrowth
As neurite extension requires a high amount of energy, mitochondrial mass is accumulated in the growth cone formed at the tip of the neurite. Interestingly, sigma-1 receptor levels are also high in this growth cone region, where they are thought to stimulate ATP production in the mitochondria.
Recently sigma-1 receptor has been shown to play an important role in motor neurons, and sigma-1 receptor dysfunction has been linked to ALS. Since 2010, more than 10 scientific papers have suggested a relationship between sigma-1 receptor dysfunction and ALS. Such research indicates that sigma-1 receptor agonists should be considered as new therapeutic drugs for motor neuron degradative diseases, such as ALS and Parkinson’s diseases. As a company with expertise in the sigma-1 receptor area, we are putting much effort into the development of new agonists for the treatment of motor neuron diseases.