Sigma receptors, particularly the sigma-1 receptor subtype, which are expressed in both neurons and glia of multiple regions within the central nervous system, are a unique class of intracellular proteins that can modulate many biological mechanisms associated with neurodegeneration. Therefore the sigma-1 receptor is attracting great interest as a potential target for neuroprotective treatments.
Now, researchers from the Georgia Regents University report the sigma-1 receptor also appears to play a key role in supporting the retina. The team state that without the sigma 1 receptor, the Müller cells that support the retina can’t seem to control their own levels of destructive oxidative stress, and consequently can’t properly support the millions of specialized neurons that enable the brain to transform light into images.
Previous studies show that the sigma 1 receptor has implications as well for other major diseases, such as cardiovascular disease and cancer as well as neurodegenerative disease, where oxidative stress plays a role. Earlier studies from the researchers showed that simply removing sigma 1 receptor from Müller cells significantly increased levels of reactive oxygen species, or ROS, indicating the receptor’s direct role in the oxidative stress response.
The current study looked further at the sigma 1 receptor knockouts compared with normal mice, and found significantly decreased expression in the knockouts of several, well-known antioxidant genes and their proteins. Further examination showed a change in the usual stress response.
Earlier studies show that these genes make natural antioxidants that contain antioxidant response element which in the face of oxidative stress, gets activated by NRF2. NRF2 is a transcription factor that usually stays in the fluid part of the cell, or cytoplasm and is considered one of the most important regulators of the expression of antioxidant molecules. Normally the protein KEAP1 keeps it essentially inactive in the cytoplasm until needed, then it moves to the cell nucleus where it can help mount a defense.
The current study showed that deleting the sigma receptor in the Müller cells altered the desired response, NRF2 expression decreased while KEAP1 expression increased. The data findings showed that ROS levels increased as well. The lab state that to their knowledge the study is believed to provide the first evidence of the direct impact of the sigma 1 receptor on the levels of NRF2 and KEAP1.
The group explain that while the ubiquitous receptor was known to help protect neurons in the brain and eye, its impact on Müller cell function was previously unknown. The results also show that when pentazocine was used in animal models of both retinitis pigmentosa and diabetic retinopathy, a dramatic change was observed. The team state that pentazocine, which binds to and activates the sigma 1 receptor, appears to preserve functional vision in these disease models by enabling many of the well-stratified layers of photoreceptor cells to survive.
For the future, next steps include the researchers clarifying whether it’s actually preservation or regeneration of the essential cell layers and how long the effect lasts.
Source: Georgia Regents Medical Center