Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission.
Michele YeoYong ChenChangyu JiangGang ChenKaiyuan WangSharat ChandraAndrey BortsovMaria LioudynoQian ZengPeng WangZilong WangJorge BusciglioRu-Rong JiWolfgang B LiedtkePublished in: Nature communications (2021)
Inhibitory GABA-ergic neurotransmission is fundamental for the adult vertebrate central nervous system and requires low chloride concentration in neurons, maintained by KCC2, a neuroprotective ion transporter that extrudes intracellular neuronal chloride. To identify Kcc2 gene expression‑enhancing compounds, we screened 1057 cell growth-regulating compounds in cultured primary cortical neurons. We identified kenpaullone (KP), which enhanced Kcc2/KCC2 expression and function in cultured rodent and human neurons by inhibiting GSK3ß. KP effectively reduced pathologic pain-like behavior in mouse models of nerve injury and bone cancer. In a nerve-injury pain model, KP restored Kcc2 expression and GABA-evoked chloride reversal potential in the spinal cord dorsal horn. Delta-catenin, a phosphorylation-target of GSK3ß in neurons, activated the Kcc2 promoter via KAISO transcription factor. Transient spinal over-expression of delta-catenin mimicked KP analgesia. Our findings of a newly repurposed compound and a novel, genetically-encoded mechanism that each enhance Kcc2 gene expression enable us to re-normalize disrupted inhibitory neurotransmission through genetic re-programming.
Keyphrases
- spinal cord
- neuropathic pain
- gene expression
- poor prognosis
- spinal cord injury
- dna methylation
- chronic pain
- endothelial cells
- pain management
- transcription factor
- papillary thyroid
- genome wide
- signaling pathway
- mouse model
- cerebral ischemia
- cell proliferation
- neoadjuvant chemotherapy
- childhood cancer
- binding protein
- epithelial mesenchymal transition
- squamous cell
- squamous cell carcinoma
- lymph node metastasis
- mesenchymal stem cells
- bone mineral density
- postoperative pain
- cell therapy
- lymph node
- reactive oxygen species
- functional connectivity
- body composition
- climate change
- pluripotent stem cells