Inhaled general anesthetics make people unconscious, but they also suppress the immune system, a side effect that can lead to infections. How anesthetics do these two things hasn’t been clear, but researchers from PCMM/IDI were able to eavesdrop on the action of one anesthetic, isoflurane, shedding light on its two-pronged effects and providing clues to better drug design.
Scientists already knew that isoflurane binds to ion channels in the brain—“gatekeepers” that allow electrically charged particles to enter or exit cells. Last year, Motomu Shimaoka, M.D., Ph.D., of PCMM/IDI and colleagues including Sulpicio Soriano, M.D., of Children’s department of Anesthesiology, Perioperative and Pain Medicine, showed that isoflurane also binds to a protein called integrin LFA-1, preventing it from activating the immune system. Now, in collaboration with Jia-huai Wang, Ph.D., of Children’s Division of Molecular Medicine and the Dana-Farber Cancer Institute, they’ve managed to crystallize the two interlocked molecules, aim an X-ray beam through them and reveal their chemical interaction in 3D—at resolution down to the atom.
Shimaoka and Wang think isoflurane binds to ion channels in the brain in a nearly identical way. The crystallography data might help drug designers make anesthetics that don’t cause immune suppression and, on the flip side, create short-acting, more controllable drugs for autoimmune diseases, says Shimaoka. Intravenous drugs that inhibit LFA-1 (and a related molecule, VLA-4) have already been used to suppress immune activation and inflammation in psoriasis, multiple sclerosis and Crohn’s disease. However, these drugs were pulled from the market after causing serious immune suppression in several patients. “We want to go to the same target, but in a more controllable way,” Shimaoka says. “Isoflurane may help in designing very short-acting, fine-tunable anti-inflammatory agents.”
Since anesthetics like isoflurane are inhaled and their action ceases soon after inhalation is stopped, Shimaoka speculates that isoflurane-like drugs might be helpful in treating autoimmune disorders in which inflammation comes and goes, such as the relapsing-remitting form of multiple sclerosis. The paper will appear in the August issue of FASEB Journal. Hongmin Zhang, Ph.D., and Nathan Astorf, Ph.D., were co-first authors.
