Using mice specially bred to lack certain cellular transport proteins, a team of Israeli scientists has discovered a new molecular pathway involved in anxiety.
The new work, described in the journal Cell Reports, provides sorely needed insight into biochemical mechanisms that lead to the behavioral symptoms of anxiety and could potentially lead to novel treatments. According to the World Health Organization, more than 260 million people currently suffer from anxiety disorders, and one in three will likely experience some form of this condition during their lifetime.
“Current drugs for anxiety are limited in their efficacy or have undesirable side effects, which also limit their usefulness,” lead author Mike Fainzilber said in a statement. “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.”
Fainzilber and his colleagues have spent the last several decades investigating the functions of importins, a family of molecules that transport proteins involved in gene expression and DNA regulation from the cytoplasm into the nucleus. All eukaryotic cells use importins, and their key roles in numerous physiological processes have been studied in great detail. Given that behavior patterns likely emerge from neurotransmitter signaling that causes changes in neuron gene transcription, and that said alterations to gene transcription can only occur when messages received at cell synapses are transmitted to the nucleus, it was a safe bet to assume that importins are also part of the anxiety pathway. However, according to the team no one has taken the time to look into it. Until now.
In their study, the group assessed the behavior of five mice lineages that lacked importins of the alpha subtype. The scientists were intrigued to observe that the animals without the a5 importin remained completely calm when placed in classically stressful (to mice) environments. Next, they examined slices of the animals’ hippocampi to see how the loss of a5 affected gene expression. This analysis revealed that the mice had reduced levels of a protein called MeCP2 in their neural nuclei. MeCP2 is itself known to mediate gene expression, particularly those involved in anxiety behaviors. With lowered MeCP2, the mice produced less of a lipid-based signaling molecule known as sphingosine-1-phosphate (S1P).
Hoping to explore what happens to regular mice when S1P is inhibited, Fainzilber’s team found that a drug blocking the molecule already exists, it’s called fingolimod, and it is used to treat the relapsing form of multiple sclerosis. When mice with all their integrins intact were given fingolimod, they exhibited the same serene calmness as the a5 knockout mice.
“Several studies have linked sphingolipids to anxiety disorders, but the mechanisms involved are not fully understood. We provide both molecular and pharmacological evidence for the involvement of Sphk1 [the enzyme that creates S1P] and S1P in anxiety pathways,” the authors wrote. “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.”
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