A team of researchers at the Institute for Bioengineering of Catalonia (IBEC; Catalonia, Spain) and the Universitat Autònoma de Barcelona (UAB; Barcelona, Spain) used pulsed infrared (IR) light lasers to activate molecules located inside neural tissue with an efficiency of almost 100%. According to Pau Gorostiza, ICREA research professor and head of the Nanoprobes and Nanoswitches Group at IBEC, the work paves the way for targeted drugs that are free from unwanted side effects in other regions as well as spatial and temporal control of any protein's function, according to Pau Gorostiza, ICREA research professor and head of the Nanoprobes and Nanoswitches Group at IBEC.
The photoswitchable molecule that the researchers used is a variant of azobenzene, a chemical compound that has a flat shape in the dark, but bends when exposed to light. Photopharmacology seeks to take advantage of this peculiar property to control the activity of drugs, where an inactive drug combined with azobenzene is introduced into the body. The design of the drug only allows its operation when the azobenzene is bent. In this way, despite having a drug distributed throughout the body, it will only take effect at the points where the light that stimulates azobenzene is irradiated, thus avoiding the side effects associated with the drug's action in areas where azobenzene is present, as it is not necessary.
Techniques based on photoswitchable molecules used continuous-wave violet or blue lasers to activate these compounds, a method that does not allow focalizing the stimulus. "We wanted the molecule to be activated at a specific point, not along the whole beam of light that we irradiate. We saw that two-photon transitions using pulsed IR light allowed to achieve this, but the efficiency was very low and the applications were limited. The molecules we have developed now achieve this effect with 100% efficiency. It is a very robust and precise technology to manipulate neuronal activity," say Jordi Hernando and Ramon Alibés, researchers from the Department of Chemistry at UAB who supervised part of this work together with Josep Ma Lluch and Félix Busqué.
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The researchers have proven the effectiveness of the technique on mouse neurons and in an animal model for the study of neuronal circuits, the Caenorhabditis elegans worm. "Despite the cells in a neuronal tissue being very close together, we have managed to select those in which we wanted to activate the photoswitchable molecule," the researchers say.
Control of the activity of individual worm neurons through two-photon stimulation; in the image, a neuron in the tail of the worm (enlarged square region) is stimulated with pulses of IR light in the presence of the new molecule and an activation response occurs. (Image credit: Montserrat Porta, Aida Garrido)
Stimulation via two-photon absorption, predicted by Maria Göppert-Mayer and demonstrated using the pulsed lasers developed by the winners of the Nobel Prize in Physics in 2018, Donna Strickland and Gérard Mourou, has represented a revolution for visualizing and manipulating neuronal activity.
The results of this development have great potential since they open the door to new lines of research in the molecular field. With the technique, scientists will have unprecedented spatiotemporal control over any photoswitchable molecule they wish to investigate.
Full details of the work appear in the journal Nature Communications.