Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, China; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, 230026, China.
3 papers in the library · 26 citations · publishing 2025
In a mouse model of inflammation-induced depression, S-ketamine (S-KET) reduced depressive-like behaviors and lowered pro-inflammatory factors in the medial prefrontal cortex, while R-ketamine (R-KET) did not. S-KET bound directly to the protein SIRT2 at the Q167 residue, enhancing its interaction with NF-κB subunit p65, which reduced acetylation and suppressed pro-inflammatory gene expression. Experiments using RNA interference, a SIRT2 inhibitor (AK-7), and pharmacological blockade confirmed that SIRT2 is essential for these effects. The findings indicate that SIRT2 mediates the therapeutic actions of S-KET, suggesting a target for treating inflammation-associated depression.
The position of the hydroxyl group on the indole ring of psilocin analogs determines their ability to activate the 5-HT2A receptor and produce psychedelic-like effects. Analogs with the hydroxyl group at the 4th or 5th position (psilocin and bufotenine) show significantly higher agonistic activity and head-twitch responses than those with the group at the 6th or 7th position. Computer simulations reveal that the 4- and 5-position analogs form a crucial hydrogen bond with residue L229 and a stable salt bridge and hydrogen bond with residue D155, guiding them into the binding site. Analogs lacking these interactions fail to reach the orthosteric site and have poor receptor activity.
Neuropsychiatric disorders arise from disruptions in brain network dynamics that fall along a spectrum from order to complexity to chaos. Psychedelics may work therapeutically by increasing neural entropy, breaking maladaptive patterns, and enabling network reorganization. This framework focuses on dynamic remodeling of the brain's connectome rather than static molecular fixes, proposing that controlled neural destabilization and reconnection offers a new treatment strategy for psychiatric and neurological conditions.