Identification of kenpaullone and mechanism of analgesia (IMAGE)
Caption
Upper right: Screening compounds in the "Junkyard of cancer drugs", akin to sieving through sand, looking for gold nuggets. Kenpaullone was identified as a promising candidate owing to its ability to switch on the Kcc2 gene, which has been predicted to alleviate chronic pain. Upper left: Intractable chronic pain is a serious and pressing unmet medical need. Kenpaullone was shown to be highly effective in preclinical models of nerve injury pain and bone cancer pain. Left box (untreated pain): Pain-causing events such as constriction nerve injury or cancer cell expansion in bone activate GSK3ß, an enzyme that tags proteins with phosphate. In pain-relay neurons in the spinal cord, GSK3ß tags -catenin (-CAT), routing -CAT to the cellular garbage bin. Without -CAT in the cell's nucleus, Kcc2 remains switched off, thereby allowing maintenance of high chloride levels in the cell, which makes the cell electrically more jittery and thus results in refractory chronic pain. Right box (treatment): Kenpaullone treatment inhibits GSK3 phosphate-tagging, allowing untagged -CAT to enter the nucleus of a pain-relaying neuron. There it binds the region of DNA in the Kcc2 gene that switches it on and off, the promoter. By binding the promoter, -CAT switches on expression of Kcc2, thereby inducing production of KCC2 protein. KCC2 pumps chloride ions out of pain-relay neurons, making them less jittery. This stability enables circuit repair and pain relief, based on resetting of genetic switches. In this way, Kenpaullone, or -CAT delivered via gene therapy, can upregulate KCC2, thereby abating pain transmission in the spinal cord.
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Wolfgang Liedtke, MD, PhD
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