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

The term perioperative neurocognitive disorders (PND) is derived from postoperative cognitive dysfunction (POCD), and has been renamed as PND in recent years in accordance with the latest international consensus. PND specifically refers to changes in mental, social and cognitive abilities in patients following surgery; in severe cases, personality changes and reduced social functioning may also occur. As a serious complication affecting the central nervous system (CNS), apart from surgical trauma, advanced age is widely recognized as a critical factor contributing to the development and progression of PND. Its adverse effects represent a major challenge for the rapidly growing elderly population worldwide.

It is currently believed that the decline in cognitive functions such as memory and attention observed in some patients after surgery may be associated with inflammatory responses in the brain. Surgical stress may activate supporting cells in the brain, such as astrocytes. When these cells are abnormally activated, they may fail to maintain normal neuronal function, thereby disrupting brain homeostasis and leading to cognitive impairment.

Recent studies have shown that these glial cells exert distinct effects on neurons under different phenotypes: some phenotypes promote neural repair and protection, whereas others exacerbate neural injury. Evidence suggests that in multiple neurological disorders, the pro-inflammatory phenotype of glial cells is closely associated with cognitive impairment.

Prokineticin-2 (PK2) is an endogenous signaling molecule involved in the regulation of diverse physiological processes, including inflammatory responses, energy metabolism, and neuroprotection. Previous studies have demonstrated that PK2 exerts protective effects in various neurological disease models, improving neuronal function and alleviating cognitive or motor deficits. Our preliminary animal experiments revealed reduced brain PK2 levels, especially in memory-related regions, in mice with postoperative cognitive dysfunction. Exogenous supplementation of PK2 significantly restored brain cell function and improved cognitive performance in these mice, suggesting that PK2 may play an important role in maintaining cerebral function after surgery.

However, it remains unclear whether changes in PK2 levels in clinical patients correlate with the occurrence and severity of postoperative cognitive dysfunction. This study aims to investigate changes in circulating PK2 levels and explore their association with postoperative cognitive alterations, so as to provide evidence for the improved prevention and identification of PND.

We plan to enroll elderly patients undergoing hip replacement surgery at Nanjing First Hospital. By analyzing PK2 expression levels and dynamic changes, combined with postoperative neuropsychological scale assessments, we will evaluate the correlation between serum PK2 levels and the clinical incidence of PND, and further verify the intrinsic link between PK2 levels and the pathogenesis of PND.

Study Overview

• Status: Not yet recruiting
• Conditions: Perioperative Neurocognitive Disorders

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 40

Contacts and Locations

• Study Contact: Name: Yajie Xu, MD; Phone Number: 86 18651815258; Email: xuyajiechina@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The study population consists of elderly patients aged 65 to 80 years with ASA physical status Class Ⅰ-Ⅲ who are undergoing hip replacement surgery. Patients are excluded if they have an MMSE score ≤ 24, severe cardiac, pulmonary, hepatic or renal dysfunction, recent use of sedatives/antidepressants or alcohol abuse, severe mental disorders (e.g., depression, schizophrenia, bipolar disorder, mental retardation), a history of severe craniocerebral injury, cerebrovascular disease, hydrocephalus, intracranial tumor or other neurological diseases (e.g., Parkinson's disease, Huntington's disease, epilepsy), severe visual or hearing impairment, or inability to complete cognitive function tests due to advanced age, low educational level or other factors.

Description

Inclusion Criteria:

• Age ≥ 65 years and ≤ 80 years
• ASA physical status Class Ⅰ-Ⅲ
• Elderly patients undergoing hip replacement surgery

Exclusion Criteria:

• Mini-Mental State Examination (MMSE) score ≤ 24
• Severe cardiac, pulmonary, hepatic or renal dysfunction
• Recent use of sedatives or antidepressants, or alcohol abuse
• Patients with severe mental disorders including depression, schizophrenia, bipolar disorder, mental retardation, etc.
• History of severe craniocerebral injury, cerebrovascular disease, hydrocephalus, intracranial tumor, or other neurological diseases (e.g., Parkinson's disease, Huntington's disease, epilepsy)
• Severe visual or hearing impairment
• Inability to complete cognitive function tests due to advanced age, low educational level, or other factors

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
PND group; Perioperative neurocognitive disorder (PND) developed as an adverse event during postoperative follow-up following hip replacement surgery.
non-PND group; No perioperative neurocognitive disorder (PND) occurred during follow-up after hip replacement surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK2 level	Venous blood samples will be collected from patients 1 day before surgery and on postoperative days 1 and 3 for the detection of PK2 levels	1 day before surgery and on postoperative days 1 and 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the levels of related oxidative markers including SOD	Venous blood samples will be collected from patients 1 day before surgery and on postoperative days 1 and 3 to detect the levels of related oxidative markers including SOD.	1 day before surgery and on postoperative days 1 and 3
the levels of related oxidative markers including GSH	Venous blood samples will be collected from patients 1 day before surgery and on postoperative days 1 and 3 to detect the levels of related oxidative markers including GSH.	1 day before surgery and on postoperative days 1 and 3
the levels of related oxidative markers including CAT	Venous blood samples will be collected from patients 1 day before surgery and on postoperative days 1 and 3 to detect the levels of related oxidative markers including CAT.	1 day before surgery and on postoperative days 1 and 3
Levels of inflammatory markers TNF-α	Venous blood samples will be collected from patients 1 day before surgery and on postoperative days 1 and 3 to detect the levels of inflammatory markers TNF-α.	1 day before surgery and on postoperative days 1 and 3
Levels of inflammatory markers IL-1β	Venous blood samples will be collected from patients 1 day before surgery and on postoperative days 1 and 3 to detect the levels of inflammatory markers IL-1β.	1 day before surgery and on postoperative days 1 and 3

Collaborators and Investigators

• Sponsor: Nanjing First Hospital, Nanjing Medical University
• Investigators: Principal Investigator: Xiaoliang Wang, MD, The First Affiliated Hospital with Nanjing Medical University

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: June 11, 2026
• First Submitted That Met QC Criteria: June 11, 2026
• First Posted (Actual): June 16, 2026

Study Record Updates

• Last Update Posted (Actual): June 16, 2026
• Last Update Submitted That Met QC Criteria: June 11, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: PND; Hip replacement surgery; PK2
• Other Study ID Numbers: KY20260402-01; ZKX21038 (Other Identifier: Nanajing Municipal Health Commision)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: In this clinical trial, we do not plan to share Individual Participant Data (IPD). The main reasons are as follows: first, to protect the privacy and personal information of the research participants, and avoid the disclosure of sensitive information such as personal identity, medical history and test results; second, the IPD involves the original research data related to the study design and research conclusions, which needs to be further sorted out, verified and analyzed before it can be standardized and shared. At present, it is not suitable for IPD sharing. We will strictly abide by relevant medical research norms and ethical requirements, and properly manage and store all research data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No