Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice

Abstract

Background: Postoperative cognitive decline (POCD) is a recognized clinical phenomenon characterized by cognitive impairments in patients following anesthesia and surgery, yet its underlying mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory via activation of TrkB-full length (TrkB-FL) receptors. It has been reported that an abnormal truncation of TrkB mediated by calpain results in dysregulation of BDNF/TrkB signaling and is associated with cognitive impairments in several neurodegenerative disorders. Calpains are Ca 2+ -dependent proteases, and overactivation of calpain is linked to neuronal death. Since one source of intracellular Ca 2+ is N-methyl-d-aspartate receptors (NMDARs) related and the function of NMDARs can be regulated by neuroinflammation, we therefore hypothesized that dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca 2+ /calpain might be involved in the pathogenesis of POCD.Methods: In the present study, 16-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to establish the POCD animal model. For the interventional study, mice were treated with either NMDAR antagonist memantine or calpain inhibitor MDL-28170. Behavioral tests were performed by open field, Y maze, and fear conditioning tests from 5 to 8 days post-surgery. The levels of Iba-1, GFAP, interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), NMDARs, calpain, BDNF, TrkB, bax, bcl-2, caspase-3, and dendritic spine density were determined in the hippocampus.Results: Anesthesia and surgery-induced neuroinflammation overactivated NMDARs and then triggered overactivation of calpain, which subsequently led to the truncation of TrkB-FL, BDNF/TrkB signaling dysregulation, dendritic spine loss, and cell apoptosis, contributing to cognitive impairments in aging mice. These abnormities were prevented by memantine or MDL-28170 treatment. Conclusion: Collectively, our study supports the notion that NMDAR/Ca2+/calpain is mechanistically involved in anesthesia and surgery-induced BDNF/TrkB signaling disruption and cognitive impairments in aging mice, which provides one possible therapeutic target for POCD.

Elamipretide Attenuates Pyroptosis and Perioperative Neurocognitive Disorders in Aged Mice

“…Exploratory laparotomy was performed under aseptic conditions with isoflurane anesthesia, as described in previous studies (Qiu et al, 2020 ; Wen et al, 2020 ). This model has been used in studies investigating both postoperative delirium (Peng et al, 2016 ; Lu et al, 2020 ) and postoperative cognitive dysfunction (Kawano et al, 2015 ; Qiu et al, 2020 ), and is referred to as a model for PND in this study, according to the nomenclature recently adopted in major anesthesiology journals. Briefly, mice were anesthetized with 1.8% isoflurane and oxygen at 2 L/min in an induction chamber for 30 min.…”

“…Previous studies have shown that cognitive deficits induced by surgery in aged mice can be observed on postoperative day 7 (Fu et al, 2020;Qiu et al, 2020). We used open field tests to FIGURE 2 | Effects of elamipretide on the canonical nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome-caspase-1 pathway in the hippocampus in aged mice after surgery.…”

“…In the present study, we used a mouse model involving exploratory laparotomy under isoflurane anesthesia to mimic clinical human abdominal surgery. This preclinical model has been shown to induce neuroinflammation and cognitive deficits and has been widely used to investigate the molecular basis of PND and to test potential therapeutic strategies (Qiu et al, 2020 ; Wen et al, 2020 ). We hypothesized that: (1) anesthesia and surgery would cause mitochondrial dysfunction and trigger the activation of NLRP3 inflammasome-caspase-1 dependent pyroptosis in the hippocampus in aged mice, thus contributing to PND pathogenesis; and (2) administration of elamipretide would protect against surgery-induced cognitive deficits by attenuating mitochondrial dysfunction and neuronal pyroptosis.…”

Parvabumin interneuron-mediated hippocampal network activity disruption in a two-hit model with relevance to postintensive care syndrome: prevention by fluoxetine

“…The Y-maze was used to evaluate spatial working memory [16], which was performed in a black Plexiglas Y-Maze with three arms (30 cm long × 14 cm wide ×15 cm high) at 120• angles, designated A, B, and C. Each mouse was placed in the center of Y-Maze facing arm A and allowed to explore all three arms of the maze freely for 8 min. The sequence and total number of arms entered were recorded.…”

Actin Reorganization in Hippocampal Neurons May Play Roles in Early Impairment of Learning and Memory in Rats After Propofol Anesthesia

“…However, the mechanisms underlying are still unclear. There are many causes that may contribute to the occurrence of PND, which would nally induce the changes in synaptic plasticity and the consequent observable dysfunction in learning and memory [1].…”