Neuroprotective effects of a Smoothened receptor agonist against postoperative cognitive dysfunction by promoting autophagy in the dentate gyrus of aged rats

ABSTRACT

Objectives: To investigate the effect of purmorphamine (PUR), a Shh co-receptor Smoothened (Smo) agonist, on postoperative cognitive dysfunction (POCD) rat models.

Methods: Eighteen-month-old male Sprague–Dawley rats were subjected to intramedullary fixation of a tibial fracture with 7% chloral hydrate anesthesia to mimic human clinical surgery. PUR was administered via an intraperitoneal injection at a dose of 15mg/kg/day for 3 consecutive days at 6 h after surgery. The aged rats were sacrificed after performing a Morris water maze test 1, 3, and 7 days postoperatively to evaluate the expression of related proteins at the appointed time.

Results: Compared to the POCD + vehicle group and sham + PUR group, the POCD + PUR group restored neurological deficit (P = 0.01). PUR administration induced upregulation of Shh expression on postoperative day 1 (P = 0.02), which continued on the third day (P = 0.008) but dropped by the 7th day (P = 0.03). Immunofluorescent analysis, similar to western blot analysis, showed a significant increase in the autophagy-marker LC3 (P = 0.006) as well as p62 degradation (P = 0.000) in the dentate gyrus of the aged rats (P = 0.000) after PUR treatment. Importantly, LC3 was mainly found in the presynaptic and postsynaptic membranes of the hippocampus.

Conclusions: These results indicate a link between Shh and autophagy in the rat model of POCD, providing new insights into Shh signaling pathway-mediated mechanisms of neuroprotection and cognitive repair after POCD. It also provides a potential entry point for the development of clinical drugs.

KEYWORDS:

• POCD
• aged rat
• hippocampus
• Shh
• autophagy

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work were supported by the National Nature Science Foundation of China [81560214] and [81860233];The role and mechanism of Sonic Hedgehog signaling pathway in induction of cerebral ischemic tolerance by hyperbaric oxygen preconditioning [81860233];The role and mechanism of autophagy in postoperative cognitive function [81560241].

Notes on contributors

Pei-Jun Li

Pei-Jun Li is an anesthesiologist with the Master’s degree, who has engaged in basic experimental research for four years and published many papers in Chinese domestic journals. He is expert in neurological research.

Ying-Qiang Guo

Ying-Qiang Guo is an anesthesiologist with the Master’s degree who has worked in clinical practice for 20 years and published research in the Chinese medical journal.

Pei-Yan Ding

Pei-Yan Ding is an anesthesiologist with the Master’s degree. She has worked in clinical practice for 30 years and finished several publications about anesthesiology in Chinese journals.

Ruo-Bing Liu

Ruo-Bing Liu is an anesthesiologist with the Bachelor’s degree who has works in clinical practice for 32 years. He is very responsible and has a wealth of experience at work.

Fei Deng

Fei Deng is an anesthesiologist with the Master’s degree. She specializes in ultrasound-guided nerve block anesthesia.

Xiao-Xue Feng

Xiao-Xue Feng is an anesthesiologist with the Master’s degree. She published a paper in Chinese journal. Importantly, she is very rigorous treating her works.

Wen-Jun Yan

Wen-Jun Yan is an anesthesiologist with the Doctor’s degree who has several publication in the Journal of anesthesiology and brain research. She is a masters instructor in Ningxia Medical University and is also the director of quality control Center of Anesthesiology in Gansu province which has made great contributions to the development of anesthesiology in China.