Scientists at the Weizmann Institute of Science have identified a molecular pathway in the brain that can be targeted to reduce anxiety. Their studies showed how symptoms of anxiety were reduced in mice engineered to lack a single protein, while normal animals treated using an existing multiple sclerosis drug that impacts on the same pathway remained similarly calm in stressful situations. Describing the research in Cell Reports, the researchers suggested that their findings could pave the way to the development of effective new treatments for anxiety that have fewer side effects than existing drugs.

“Our findings have opened up a new direction for research into the mechanisms of anxiety,” said Nicolas Panayotis, Ph.D., at the Weizmann Institute’s department of biomolecular sciences. “If we understand exactly how the circuitry that we’ve discovered controls anxiety, this may help develop new drugs, or direct the use of existing ones, to alleviate its symptoms.” The studies are described in a paper titled, “Importin α5 Regulates Anxiety through MeCP2 and Sphingosine Kinase 1.”

Severe anxiety and stress-related disorders are estimated to affect up to one in three people in their lifetime. Several hormones and neurotransmitters have been implicated in anxiety, but intracellular transport systems haven’t been studied in this context, the authors wrote. Current drugs may also have limited utility, and cause unwanted side effects. “Current therapies for anxiety disorders either directly affect neurotransmitter receptor systems or modulate neurotransmitter levels or availability, but their long-term use is limited by problematic side effects and suboptimal efficacy,” the authors wrote.

The importin family of neural proteins is involved in shuttling molecules into the nucleus, and scientists in the laboratory of Mike Fainzilber, Ph.D., at the Weizmann’s department of biomolecular sciences, have for nearly 20 years been studying importins in the peripheral nervous system. The latest studies, headed by Dr. Panayotis, were designed to investigate the role of importins in the central nervous system. To do this they worked with scientists at the Max Delbrück Center for Molecular Medicine in Berlin, who genetically engineered five groups of mice, each lacking one of five different alpha subfamily importin proteins.

When the Weizmann Institute team subjected the different groups of knockout mice to well-recognized behavioral tests, the animals that were deficient in one particular importin protein, importin α5, showed no anxiety when placed in stressful situations. “Importin α5 knockout animals displayed a specific phenotype characterized by reduced anxiety in multiple tests, including open field, elevated plus maze, and acoustic startle response,” the researchers wrote.

To try and understand the mechanisms that might explain why the animals remain calm, the team evaluated how gene expression in brain regions, including the hippocampus, that are involved in controlling anxiety, was different between the stress-free importin α5-deficient mice. The studies highlighted MeCP2, a regulatory gene that is known to affect anxiety, and which is mutated in the rare genetic disorder, Rett Syndrome. The Weizmann team’s analyses showed that importin α5 is key to getting MeCP2 into the nuclei of neurons. Mice deficient in importin α5 effectively had less MeCP2 in the nuclei of key neurons. This reduction in MeCP2 resulted in increased expression of the enzyme sphingosine kinase 1 (Sphk1) and changes to sphingosine 1 phosphate (S1P) signaling, which dampened the anxiety responses.

When the team then treated the stress-free mice using a compound that blocked Sphk1, the animals’ anxiety levels returned to those of normal mice. The team next tested a commercial S1P receptor agonist fingolimod—which is a marketed drug that is used to treat multiple sclerosis—on normal mice. Animals given fingolimod showed lower levels of anxiety that were similar to those of the importin α5-deficient animals. “A Sphk1 blocker reverses anxiolysis in the importin α5 knockout mouse, while pharmacological activation of sphingosine signaling has robust anxiolytic effects in wild-type animals,” the researchers wrote. Interestingly, they also found a report from a previous fingolimod clinical trial, which suggested that the drug had a calming effect on multiple sclerosis patients. And, as the authors pointed out, several studies have linked sphingolipids to anxiety disorders, although the mechanisms underpinning this link aren’t well understood.

“Our data suggest that targeting importin α5 to reduce MeCP2 nuclear import can attenuate anxiety,” the authors concluded. “The clear anxiolytic effects of fingolimod suggest that this pathway provides new targets for anxiety drug development and demonstrate the possibility of repurposing existing drugs to anxiety therapy … Despite keen interest in the development of mechanistically novel anxiolytic drugs, these have not been forthcoming over the past two decades … We hope that the anxiety-regulating mechanisms identified here may provide new avenues to this end.”

“Current drugs for anxiety are limited in their efficacy or have undesirable side effects, which also limit their usefulness,” commented Dr. Fainzilber. “Our findings may help overcome these limitations. In follow-up research, we have already identified a number of drug candidates that target the newly discovered pathway.”

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