Mechanistic Study of PK2 Pathway in Alleviating Perioperative Neurocognitive Disorders by Improving Neurometabolic Uncoupling

Perioperative neurocognitive disorders (PND) originated from postoperative cognitive dysfunction (POCD) and have been renamed PND in recent years according to the latest international consensus. PND specifically refers to changes in mental, social and cognitive abilities in patients after surgery; in severe cases, personality changes and declined social functioning may also occur. As a serious complication of the central nervous system (CNS), besides surgical trauma itself, advanced age is widely recognized as a critical factor contributing to the occurrence and progression of PND. Its adverse impact has become a major challenge for the rapidly growing aging population in our society. Regarding the etiology of PND, a growing body of research suggests that neuroinflammation plays a vital role, and glial cell activation is key to CNS dysfunction. In recent years, genomic analysis of reactive astrocytes has revealed that, similar to macrophages, activated astrocytes can be broadly classified into two phenotypes: the pro-inflammatory and neurotoxic A1 phenotype, and the anti-inflammatory and neuroprotective A2 phenotype. Studies on various chronic neurodegenerative diseases such as ALS and PD have demonstrated the detrimental effects of A1 astrocytes on neurons and their promoting role in disease progression. Based on existing evidence, it is reasonable to hypothesize that surgery induces astrocytic activation toward the A1 phenotype, accompanied by intracellular energy metabolic disturbance, which further impairs energy supply to neurons, causes neuronal damage, and ultimately contributes to the development of PND. Our preliminary results also indicate that astrocytes in a mouse model of PND are predominantly activated to the A1 phenotype, and their energy metabolic disturbance may lead to uncoupled metabolic coupling with neurons. Prokineticin-2 (PK2) is a chemokine-like signaling protein. Through its two G protein-coupled receptors PKR1 and PKR2, PK2 mediates signal transduction involved in diverse systemic physiological functions, including angiogenesis, reproductive function and innate immunity. In addition, PK2 also plays important roles in circadian rhythm, energy expenditure and neuroprotection. Recent studies have shown that exogenous PK2 exerts protective effects against MPTP-induced motor impairment, dopamine depletion and dopaminergic neuronal degeneration in models of neurodegenerative diseases. In cultured astrocytes in vitro, PK2 has been found to induce astrocyte proliferation and intracellular calcium mobilization. Further investigations into the role of PK2 in astrocytes have demonstrated that PK2 treatment significantly modulates astrocyte migration, accompanied by altered mitochondrial energy metabolism, reduced pro-inflammatory cytokines, and increased antioxidants including Arginase-1 and Nrf2. Overexpression of PK2 in primary astrocytes induces the A2 astrocytic phenotype, upregulates A2 reactive markers, and enhances glutamate uptake by astrocytes. In our recent research, the Nrf2 agonist Resolvin D1 improved astrocytic energy metabolism, strengthened metabolic coupling and supportive function between astrocytes and neurons, and ultimately alleviated pathological cognitive impairment in a TBI animal model. Our preliminary experiments also found reduced PK2 expression in the brain, especially the hippocampus, of mice with PND. Administration of exogenous PK2 significantly improved astrocytic phenotype, neuronal energy metabolism and cognitive function in these mice. Therefore, PK2 may serve as a potential therapeutic strategy for PND by inducing the conversion of astrocytes to the A2 reactive phenotype and improving energy metabolic coupling between astrocytes and neurons. However, the association between changes in the biomarker PK2 and the incidence or severity of cognitive impairment in clinical patients has not been reported to date. This study aims to analyze the expression level and dynamic trend of PK2 in elderly patients undergoing hip replacement surgery at Nanjing First Hospital, combined with postoperative neuropsychological scale assessments, to investigate the correlation between circulating PK2 levels and the clinical incidence of PND, and further verify the intrinsic link between PK2 levels and the pathogenesis of PND.