Could rousing sedated patients one day be as easy as shining a light in their eyes?
German researchers have found a way to add a light-sensitive moiety to propofol that could control its effect on humans with light (Angewandte Chemie International Edition, October 15, 2012, Vol. 51:42, pp. 10500-10504).
In their study, the researchers from Ludwig Maximilian University (LMU) of Munich effectively anesthetized and revived tadpoles when irradiated with violet light. The tadpoles returned to their anesthetized state when the light was switched off, suggesting a reversible light-dependent effect.
Propofol's effectiveness lies in its interaction with receptors on neural cell membranes that typically bind the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), the study authors noted. While propofol has been studied since its discovery in 1980, there are persistent gaps in the knowledge of its function, they added.
"The analysis of their exact binding sites at a molecular level has been complicated by a lack of detailed structural data," they wrote. The data from their study suggest new ways to harness propofol's functionality.
"[We learned] that GABA receptors, which control inhibitory input in the brain and retina, can be controlled with light," study author Dirk Trauner, PhD, a professor of chemical biology and genetics at LMU, wrote in an email to DrBicuspid.com. Trauner, specializes in enabling "blind" nerve cells to react to light stimulation, according to an LMU press release.
Azobenzene derivatives of propofol
Trauner and his fellow researchers from the U.S. and Switzerland designed a series of azobenzene derivatives of propofol, called azo-propofols, that allow the action of the GABA receptor to be regulated by light.
One of the azo-propofols in particular, called AP2, had favorable pharmacological and photochemical features. Additionally, the molecular switch that was attached to the azo-propofol actually made it a more potent anesthetic in the dark.
The researchers established that AP2 had an impact on GABAA receptors, pentameric ligand-gated ion channels that are activated by GABA, and moved forward to investigate the light dependency of the current potentiation. They used pocket lights of different wattages to test egg yolk cells where GABA was coapplied with AP2 with promising results. "The current amplitude decreased rapidly and increased again upon turning off the light source," the researchers wrote.
Afterward, they tested the anesthetic activity and photoreversability of propofol and AP2 in animal models using tadpoles. The researchers noted that light "induced vigorous swimming activity in unanesthetized tadpoles," suggesting that it is a noxious stimulus. They places groups of the animals in solutions containing propofol or AP2 and tested them every five minutes for loss of righting reflexes (LORR), which is a standard assay for anesthesia, the researchers noted.
More research needed
The animals exposed to propofol were anesthetized as anticipated. In AP2, the animals expressed similar EC50 value (a measure of a drug's potency) to propofol, but light changed the value considerably.
"Propofol produced LORR in all tadpoles with or without light, whereas in AP2, all animals showed LORR without light and all spontaneously righted themselves during illumination with UV light," the researchers wrote. The demonstration supports a hypothesis of the researchers that "anesthesia caused by AP2 and propofol is largely mediated by GABAA receptors."
While the study's results are intriguing, considerable work needs to be done before dentists use a type of light-controlled propofol in their practices, Trauner noted.
"I think controlling the human brain and consciousness with light would be illusionary at this stage," he told DrBicuspid.com.
He was more optimistic that the data could be applied to vision restoration in the near future. In the next phase of his research, he said that he will apply their compounds to the retina to restore vision and see whether certain brain nuclei in rats can be made light-sensitive.
