Abstract
BackgroundThe complement system plays an important role in many neurological disorders.Complement modulation, including C3/C3a receptor signaling, shows promising therapeutic effects on cognition and neurodegeneration. Yet, the implications for this pathway in perioperative neurocognitive disorders (PND) are not well established. Here, we evaluated the possible role for C3/C3a receptor signaling after orthopedic surgery using an established mouse model of PND.MethodsA stabilized tibial fracture surgery was performed in adult male C57BL/6 mice under general anesthesia and analgesia to induce PND-like behavior. Complement activation was assessed in the hippocampus and choroid plexus. Changes in hippocampal neuroinflammation, synapse numbers, choroidal blood-cerebrospinal fluid barrier (BCSFB) integrity, and hippocampal-dependent memory function were evaluated after surgery and treatment with a C3a receptor blocker.ResultsC3 levels and C3a receptor expression were specifically increased in hippocampal astrocytes and microglia after surgery. Surgery-induced neuroinflammation and synapse loss in the hippocampus were attenuated by C3a receptor blockade. Choroidal BCSFB dysfunction occurred 1 day after surgery and was attenuated by C3a receptor blockade. Administration of exogenous C3a exacerbated cognitive decline after surgery, whereas C3a receptor blockade improved hippocampal-dependent memory function.ConclusionsOrthopedic surgery activates complement signaling. C3a receptor blockade may be therapeutically beneficial to attenuate neuroinflammation and PND.
Highlights
The complement system plays an important role in many neurological disorders
Orthopedic surgery induces astrocytic C3 and microglial C3a receptor (C3aR) upregulation in the hippocampus To determine whether major surgery activates the complement system we assessed the level of the central complement component, C3, in the hippocampus after orthopedic surgery
Orthopedic surgery-induced neuroinflammation is attenuated by C3aR blockade To illustrate the role of C3/C3aR signaling in surgeryinduced neuroinflammation, we examined the effects of a selective C3aR antagonist on pro-inflammatory cytokines, microglial activation, and neutrophil infiltration in the hippocampus
Summary
The complement system plays an important role in many neurological disorders. Complement modulation, including C3/C3a receptor signaling, shows promising therapeutic effects on cognition and neurodegeneration. We evaluated the possible role for C3/C3a receptor signaling after orthopedic surgery using an established mouse model of PND. Cognitive impairments are common problems especially amongst older surgical patients [1]. These neurological complications, termed as perioperative neurocognitive disorders (PND) [2], associate with poor functional recovery and increased mortality after major surgery [3]. The pathogenesis of PND remains unclear, preclinical studies suggest that surgery triggers acute systemic inflammation [4] followed by neuroinflammation [5,6,7] and synaptic dysfunction [8, 9], which appear to contribute to hippocampal-dependent cognitive deficits. Abnormal activation of the complement system has been related to several CNS pathologies and neurodegenerative conditions [16, 17]
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