Relationship between hippocampal RIPK1 and NLRP3 inflammasomes in postoperative neurocognitive dysfunction of aged rats with chronic knee arthritis pain / 中华麻醉学杂志

ABSTRACT

Objective:To evaluate the relationship between hippocampal receptor-interacting protein kinase-1 (RIPK1) and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasomes in postoperative neurocognitive dysfunction of aged rats with chronic knee arthritis pain.Methods:Sixty-four healthy male Sprague-Dawley rats, aged 18 months, weighing 500-550 g, were divided into 4 groups ( n=16 each) using a random number table method: chronic knee arthritis pain group (group P), chronic knee arthritis pain+ operation group (group PS), RIPK1 inhibitor necrostatin-1+ chronic knee arthritis pain+ operation group (group NPS), and DMSO+ chronic knee arthritis pain+ operation group (group DPS). The knee arthritis model was prepared by intra-articular injection of monosodium iodoacetate (MIA) 1 mg into the left knee joint, and 12 weeks later exploratory laparotomy was performed under sevoflurane anesthesia. Necrostatin-1 6.25 mg/kg and the equal volume of DMSO were intraperitoneally injected at 1 h before operation in NPS group and DPS group, respectively. Thermal pain threshold was measured at 1 week before MIA injection and 6 and 12 weeks after MIA injection. Morris water maze test was used to evaluate the cognitive function at 7 days after surgery. Hippocampal tissues were obtained for microscopic examination of the pathological changes (after HE staining) and for determination of the expression of RIPK1, phosphorylated RIPK1 (p-RIPK1), NLRP3, activated cysteine-aspartic protease caspase-1 (cl-caspase-1), apoptosis-associated speck-like protein containing a CARD (ASC) (by Western blot) and contents of interleukin-1beta (IL-1β) and IL-18 (by enzyme-linked immunosorbent assay). Results:Thermal pain threshold was significantly decreased at 6 and 12 weeks after MIA injection as compared with that before injection ( P<0.05), and there was no significant difference in thermal pain threshold among the four groups ( P>0.05). Compared with P group, the escape latency was significantly prolonged, the time of staying at the original platform quadrant was shortened, the number of crossing the original platform was reduced, the expression of RIPK1, p-RIPK1, NLRP3, cl-caspase-1 and ASC was up-regulated, and the contents of IL-1β and IL-18 were increased ( P<0.05), and pathological changes of hippocampal neurons were marked in PS group, DPS group and NPS group. Compared with PS group and DPS group, the escape latency was significantly shortened, the time of staying at the original platform quadrant was prolonged, the number of crossing the original platform was increased, the expression of RIPK1, p-RIPK1, NLRP3, cl-caspase-1 and ASC was down-regulated, the contents of IL-1β and IL-18 were decreased ( P<0.05), and pathological changes of hippocampal neurons were significantly attenuated in NPS group. Conclusions:Postoperative hippocampal RIPK1 function is enhanced in aged rats with chronic knee arthritis pain, which then activates NLRP3 inflammasomes, triggering neuroinflammation, and this process may be involved in the mechanism of postoperative neurocognitive dysfunction.