CB2R Activation Regulates TFEB-Mediated Autophagy and Affects Lipid Metabolism and Inflammation of Astrocytes in POCD

Abstract

Evidence suggests that the accumulation of lipid drots (LDs) accelerates damage to mitochondria and increases the release of inflammatory factors. These have been implicated as a mechanism underlying neurodegenerative diseases or tumors and aging-related diseases such as postoperative cognitive dysfunction (POCD), nevertheless, accumulation of lipid droplets has not been extensively studied in the central nervous system (CNS). Here, we found that after surgery, there was activation of astrocytes and lipid accumulation in the hippocampus. However, cannabinoid receptor type II (CB2R) activation significantly reduced lipid accumulation in astrocytes and change the expression of genes related to lipid metabolism. CB2R reduces the release of the inflammatory factors interleukin-1 beta (IL-1β) and interleukin 6 (IL-6) in peripheral serum and simultaneously improves cognitive ability in mice with POCD. Further research on mechanisms indicates that CB2R activation promotes the nuclear entry of the bHLH-leucine zipper transcription factor, the transcription factor EB (TFEB), and which is a master transcription factor of the autophagy–lysosomal pathway, also reduces TFEB-S211 phosphorylation. When CB2R promotes TFEB into the nucleus, TFEB binds at two sites within promoter region of PGC1α, promoting PGC1α transcription and accelerating downstream lipid metabolism. The aforementioned process leads to autophagy activation and decreases cellular lipid content. This study uncovers a new mechanism allowing CB2R to regulate lipid metabolism and inflammation in POCD.

Effects of NBP on postoperative cognitive dysfunction in rats via Nrf 2/ARE pathway

“…Moreover, oxidative stress and mitochondrial damage are essential links in the pathogenesis of POCD [ 11 ]. Furthermore, a considerably large number of research works have revealed that although the causes of neurocognitive disorders are different, there are some similar pathological injury mechanisms in these diseases, such as mitochondrial damage, excessive ROS production, nervous system inflammation, and so on [ 12 , 13 ]. Studies have confirmed that abnormal mitochondrial dynamics is an early sign of neurocognitive disorders [ 14 ], which happens before the amyloid beta protein aggregation, phosphorylation of Tau protein, and neuronal apoptosis.…”

Study on the Mechanism of Eerdun Wurile's Effects on Post-operative Cognitive Dysfuntion by the TLR4/NF-κB Pathway

“…Although the precise pathogenesis of POCD is still unclear, several investigations have veri ed that in ammatory cytokines-related mechanisms are involved in critical roles in the development and regression of POCD [8][9]19]. As immune effector cells intrinsic to the central nervous system, microglia are known to mediate CNS in ammation mediated [20].…”

“…Although the speci c pathogenesis of POCD is unclear, numerous investigations have con rmed that in ammation plays a critical role in the progression and development of POCD [8][9]. As a classical in ammatory pathway, TLR4/NF-κB has received growing interest in the study of POCD [10][11].…”

Transcutaneous electrical acupoint stimulation for reducing cognitive dysfunction in lumbar spine surgery: A randomized, controlled trail

“…Massive bleeding, a strong stress response and an inflammatory response are the main complications of lumbar spine surgery, and these may be the root cause of POCD, so it is necessary to intervene in this type of surgery in advance to minimize the occurrence of such complications. Although it is still uncertain whether the inflammatory response is the underlying cause of POCD, the levels of inflammatory factors in peripheral blood ( Zhang et al, 2022 ), the integrity of the BBB ( Cao et al, 2018 ), and the activation of astrocytes and microglia ( Li et al, 2020 ) appear to play an important role in the pathogenesis of POCD.…”