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Rationale: Clinically, chronic postsurgical pain (CPSP) is very common. Many CPSP patients may experience depression. Thus far, little is known about the mechanism of the comorbidity of CPSP and depression. Ketamine has been confirmed to possess analgesic and rapid antidepressant effects, but it is unclear whether ketamine can relieve the comorbidity of CPSP and depression. Objectives: The present study evaluated the effects of ketamine in rats with the comorbidity of CPSP and depression. Methods: We induced CPSP in rats by thoracotomy and screened for rats with or without depression-like phenotype by hierarchical cluster analysis based on the results of depression-related behavioral experiments. Subsequently, rats were intraperitoneally injected with ketamine (20 mg/kg) and were evaluated by mechanical withdrawal threshold, cold hyperalgesia test, sucrose preference test, forced swimming test, and open field test. The inflammatory-related cytokines (IL-1, IL-6, TNF-α, nuclear factor-kappaB), oxidative stress parameters (superoxide dismutase, malondialdehyde, glutathione, catalase), and brain-derived neurotrophic factor (BDNF) in rat hippocampus were detected. Results: In the hippocampus of rats with the comorbidity of CPSP and depression, IL-1, IL-6, TNF-α, nuclear factor-kappaB, and malondialdehyde were significantly increased, while superoxide dismutase, glutathione, catalase, and BDNF were significantly decreased. Ketamine relieved depression but did not attenuate hyperalgesia in CPSP rats. Additionally, ketamine reduced proinflammatory cytokines, inhibited oxidative stress, and elevated BDNF levels in rat hippocampus. Conclusions: Ketamine can rapidly relieve CPSP-induced depression in rats, which may be related to the reduction of proinflammatory cytokines, regulating oxidative stress and increasing BDNF in the hippocampus. [ABSTRACT FROM AUTHOR]

Background: It is widely accepted that mitochondria have a direct impact on neuronal function and survival. Oxidative stress caused by mitochondrial abnormalities play an important role in the pathophysiology of lipopolysaccharide (LPS)-induced memory impairment. Elamipretide (SS-31) is a novel mitochondrion-targeted antioxidant. However, the impact of elamipretide on the cognitive sequelae of inflammatory and oxidative stress is unknown.Methods: We utilized MWM and contextual fear conditioning test to assess hippocampus-related learning and memory performance. Molecular biology techniques and ELISA were used to examine mitochondrial function, oxidative stress, and the inflammatory response. TUNEL and Golgi-staining was used to detect neural cell apoptosis and the density of dendritic spines in the mouse hippocampus.Results: Mice treated with LPS exhibited mitochondrial dysfunction, oxidative stress, an inflammatory response, neural cell apoptosis, and loss of dendritic spines in the hippocampus, leading to impaired hippocampus-related learning and memory performance in the MWM and contextual fear conditioning test. Treatment with elamipretide significantly ameliorated LPS-induced learning and memory impairment during behavioral tests. Notably, elamipretide not only provided protective effects against mitochondrial dysfunction and oxidative stress but also facilitated the regulation of brain-derived neurotrophic factor (BDNF) signaling, including the reversal of important synaptic-signaling proteins and increased synaptic structural complexity.Conclusion: These findings indicate that LPS-induced memory impairment can be attenuated by the mitochondrion-targeted antioxidant elamipretide. Consequently, elamipretide may have a therapeutic potential in preventing damage from the oxidative stress and neuroinflammation that contribute to perioperative neurocognitive disorders (PND), which makes mitochondria a potential target for treatment strategies for PND. [ABSTRACT FROM AUTHOR]