Insights into small-molecule neurotransmitter levels and distribution during tissue regeneration in an ear pinna...

Best known for their functions in the nervous system, neurotransmitters also play prominent roles in wound healing. The study analysed the spatiotemporal expression of acetylcholine, dopamine, gamma-aminobutyric acid, serotonin, and its metabolite, 5-hydroxyindoleacetic acid, in regenerating mouse ear pinna during normal healing and during enhanced regeneration induced by the epigenetic inhibitor zebularine and retinoic acid, using HPLC-MS/MS. In terms of time, acetylcholine, dopamine, and gamma-aminobutyric acid showed a gradual decrease during the acute phase on days 3 and 7 post-injury, while serotonin, after a sharp decline on day 3, increased markedly. Zebularine and retinoic acid reduced gamma-aminobutyric acid, acetylcholine, and serotonin in the acute phase. On day 42, over 4 weeks after drug administration and 3 weeks after wound closure, the epigenetic treatment resulted in an elevation in serotonin and a decline in acetylcholine. In spatial terms, the neurotransmitter responses showed similar trends in the wound vicinity and distal tissues, except for a significant increase in serotonin in the wound area and gamma-aminobutyric acid in distal tissues on days 7 and 3, respectively. Decoding the concerted tissue profiles of small-molecule neurotransmitters helps reveal their roles in wound healing and informs the design of regenerative therapies targeting neurotransmitter pathways.