Calpain-TRPC6 signaling pathway contributes to propofol-induced developmental neurotoxicity in rats

• Published in: Neurotoxicology (Park Forest South) Vol. 95; pp. 56 - 65
• Main Authors: She, Ying-Jun, Xu, Hai-Ping, Gao, Yin, Wang, Qiong, Zheng, Jun, Ruan, Xiangcai
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2023
• Subjects: Anesthetic neurotoxicity; Animals; Brain; Calpain; Calpain - metabolism; Child, Preschool; Humans; Propofol; Propofol - toxicity; Rats; Signal Transduction; Transient receptor potential canonical 6; TRPC Cation Channels - metabolism; TRPC Cation Channels - pharmacology; TRPC6 Cation Channel - metabolism; Anesthetic neurotoxicity; FDA; MWM; TRPC6; TUNEL; PND; Transient receptor potential canonical 6; Calpain; Propofol; ICV; SBDP145
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2023.01.004

Growing animal studies suggest a risk of neuronal damage following early childhood exposure to anesthesia and sedation drugs including propofol. Inhibition of transient receptor potential canonical 6 (TRPC6) degradation has been shown to protect neurons from neuronal damage induced by multiple brain injury models. Our aim was to investigate whether calpain-TRPC6 pathway is a target in propofol-induced neurotoxicity. Postnatal day (PND) 7 rats were exposed to five bolus injections of 25 mg/kg propofol or 10 % intralipid at hourly intervals. Neuronal injury was assessed by the expression pattern of TUNEL staining and cleaved–caspase-3. The Morris water maze test was used to evaluate learning and memory functions in later life. Pretreatments consisting of intracerebroventricular injections of a TRPC6 agonist, TRPC6 inhibitor, or calpain inhibitor were used to confirm the potential role of the calpain-TRPC6 pathway in propofol-induced neurotoxicity. Prolonged exposure to propofol induced neuronal injury, downregulation of TRPC6, and enhancement of calpain activity in the cerebral cortex up to 24 h after anesthesia. It also induced long-term behavioral disorders, manifesting as longer escape latency at PND40 and PND41 and as fewer platform-crossing times and less time spent in the target quadrant at PND42. These propofol-induced effects were attenuated by treatment with the TRPC6 agonist and exaggerated by the TRPC6 inhibitor. Pretreatment with the calpain inhibitor alleviated the propofol-induced TRPC6 downregulation and neuronal injury in the cerebral cortex. In conclusion, our data suggest that a calpain-TRPC6 signaling pathway contributes to propofol-induced acute cortical neuron injury and long-term behavioral disorders in rats. •Prolonged exposure to propofol induced downregulation of TRPC6.•Prolonged exposure to propofol induced enhancement of calpain activity.•Prolonged exposure to propofol induced long-term behavioral disorders.•Calpain-TRPC6 signaling pathway contributes to propofol-induced neurotoxicity.