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Fingolimod (FTY720) improves postoperative cognitive dysfunction in mice subjected to D-galactose-induced aging.

ABSTRACT: Neurocognitive dysfunction is a common postoperative complication, especially in older adult patients. Fingolimod (FTY720) is a sphingosine-1-phosphate receptor modulator that has been found to be neuroprotective in several animal models of central nervous system disease. However, few reports have examined whether FTY720 could mitigate postoperative cognitive dysfunction. In this study, we investigated whether FTY720 could prevent postoperative neurocognitive impairment in mice subjected to D-galactose-induced aging. We induced an accelerated model of aging by administering an intraperitoneal injection of D-galactose. Subsequently, we performed a partial hepatolobectomy under sevoflurane anesthesia. FTY720 (1 mg/kg) was administered intraperitoneally 3 hours before and 24 hours after anesthesia and surgery. Our results indicated that anesthesia and surgery significantly impaired spatial memory in the Y-maze test 6 hours after surgery. We also found that problem solving ability and long-term memory in the puzzle box test on postoperative days 2-4 were significantly improved by FTY720 treatment. Immunohistochemical staining and western blot assay demonstrated that FTY720 significantly inhibited microglial activation in the hippocampal CA1 region of mice 6 hours and 3 days after anesthesia, and down-regulated the expression of synaptic-related proteins postsynaptic density protein 95 and GluR2 in the hippocampus. These results indicate that FTY720 improved postoperative neurocognitive dysfunction in mice subjected to D-galactose-induced aging. This study was approved by the Experimental Animal Ethics Committee of the Third Xiangya Hospital of Central South University of China (approval No. LLSC (LA) 2016-025) on September 27, 2016.

SUBMITTER: Zhang J

PROVIDER: S-EPMC7047799 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Fingolimod (FTY720) improves postoperative cognitive dysfunction in mice subjected to D-galactose-induced aging.

Zhang Jie J Xiao Bin B Li Chen-Xu CX Wang Yi Y

Neural regeneration research 20200701 7

Neurocognitive dysfunction is a common postoperative complication, especially in older adult patients. Fingolimod (FTY720) is a sphingosine-1-phosphate receptor modulator that has been found to be neuroprotective in several animal models of central nervous system disease. However, few reports have examined whether FTY720 could mitigate postoperative cognitive dysfunction. In this study, we investigated whether FTY720 could prevent postoperative neurocognitive impairment in mice subjected to D-ga ...[more]

PMID: 31960817

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Project description:Mounting evidence shows that chronic stress can affect both the structure and function of the brain resulting in decreased synaptic plasticity and cognitive dysfunction. Although several studies have indicated that aged brains are more vulnerable to chronic stress, it remains unknown how to prevent stress-induced memory deficits in aged animals. Neuroinflammation plays an important role in the pathogenesis of chronic stress-related brain dysfunction. Receptor-interacting protein 1 (RIP1) is a key molecule that can modulate inflammation, apoptosis, and necroptosis. Here, we investigated whether inhibiting RIP1 using necrostatin-1 during chronic stress could improve chronic stress-related brain dysfunction in D-galactose-induced aging mice. The stressed mice underwent restraint stress for 14 days. Necrostatin-1 (6.25 mg/kg) or vehicle was administered intraperitoneally once every 3 days during the stress period. Locomotor activity was tested using the open field test and cognitive function was assessed using the novel object recognition and Barnes maze tests. The hippocampus was collected to assess neuroinflammation (Iba1, IL-1?, IL-1?, TNF-?, and C1q), necroptosis [RIP1, RIP3, mixed lineage kinase domain-like (MLKL), and NF-?B], neuroplasticity (doublecortin, NR1, NR2A, NR2B, GluA1, and GluA2), and the expression of glucocorticoid and mineralocorticoid receptors. Blood samples were collected to quantify the levels of corticosterone. We found that chronic stress induced obvious memory impairment and neuroinflammation, decreased neurogenesis and GluA2 expression, and increased the expression of RIP1 and NF-?B. Inhibiting RIP1 by necrostatin-1 during chronic stress rescued the memory impairment and alleviated the pathological changes induced by stress. These suggest that inhibiting RIP1 using necrostatin-1 improves chronic stress-related brain dysfunction in D-galactose-induced aging mice. The potential mechanisms include limitation of neuroinflammation and the rescue of neurogenesis and GluA2 expression.

Project description:BackgroundAging is closely associated to several deleterious conditions and cognitive impairment. Administration of low-dose paracetamol (APAP) has previously been reported to improve cognitive performance in both human and animal studies. However, the altered cognitive effects of low-dose APAP treatment in the aging brain have not been elucidated.ObjectivesThe purpose of this study was to determine whether low-dose APAP treatment improves cognitive dysfunction in a d-galactose (d-gal)-induced aging model.Materials and methodsAPAP (15 and 50 mg/kg p.o.) and vitamin E (Vit E 100 mg/kg p.o.) were administered once daily to d-gal-injected mice (200 mg/kg s.c.) for 6 weeks. The elevated plus maze (EPM), open field, novel object recognition (NOR), and Morris water maze (MWM) tests, respectively, were used to measure altered neurobehavioral functions, including anxiety-like behavior and exploratory locomotor activity, as well as learning and memory performance. The gene transcription of brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling in brain tissues was evaluated by real-time polymerase chain reaction.ResultsCompared to the control, d-gal significantly decreased exploratory locomotor activity and NOR and MWM performance but did not significantly change the activity in the EPM test. However, APAP50 and Vit E significantly reversed the effects of d-gal injection on exploratory locomotor activity. In addition, low-dose APAP (15 and 50 mg/kg) and Vit E significantly improved the reduction in NOR and MWM performance induced by d-gal. Real-time polymerase chain reaction analysis revealed that the mRNA expression of BDNF, neurotrophic tyrosine receptor kinase (NTRK), which is the gene coding TrkB receptor, and cAMP response element-binding protein (CREB) was significantly decreased in the frontal cortex and hippocampus of the d-gal mice. However, APAP50 and Vit E significantly increased BDNF and NTRK mRNA expression in both the frontal cortex and the hippocampus. A lower dose of APAP (15 mg/kg) significantly elevated the mRNA expression of NTRK, but only in the hippocampus. Moreover, APAP50 significantly increased CREB mRNA expression in the frontal cortex and hippocampus.ConclusionLow-dose APAP treatment has a neuroprotective effect on cognitive dysfunction in the d-gal aging model, and the underlying molecular mechanisms depend on the activation of BDNF/TrkB signaling.

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Project description:BACKGROUND:Postoperative cognitive decline (POCD) is a recognized clinical phenomenon characterized by cognitive impairments in patients following anesthesia and surgery, yet its underlying mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory via activation of TrkB-full length (TrkB-FL) receptors. It has been reported that an abnormal truncation of TrkB mediated by calpain results in dysregulation of BDNF/TrkB signaling and is associated with cognitive impairments in several neurodegenerative disorders. Calpains are Ca2+-dependent proteases, and overactivation of calpain is linked to neuronal death. Since one source of intracellular Ca2+ is N-methyl-d-aspartate receptors (NMDARs) related and the function of NMDARs can be regulated by neuroinflammation, we therefore hypothesized that dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might be involved in the pathogenesis of POCD. METHODS:In the present study, 16-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to establish the POCD animal model. For the interventional study, mice were treated with either NMDAR antagonist memantine or calpain inhibitor MDL-28170. Behavioral tests were performed by open field, Y maze, and fear conditioning tests from 5 to 8?days post-surgery. The levels of Iba-1, GFAP, interleukin-1? (IL-1?), IL-6, tumor necrosis factor-? (TNF-?), NMDARs, calpain, BDNF, TrkB, bax, bcl-2, caspase-3, and dendritic spine density were determined in the hippocampus. RESULTS:Anesthesia and surgery-induced neuroinflammation overactivated NMDARs and then triggered overactivation of calpain, which subsequently led to the truncation of TrkB-FL, BDNF/TrkB signaling dysregulation, dendritic spine loss, and cell apoptosis, contributing to cognitive impairments in aging mice. These abnormities were prevented by memantine or MDL-28170 treatment. CONCLUSION:Collectively, our study supports the notion that NMDAR/Ca2+/calpain is mechanistically involved in anesthesia and surgery-induced BDNF/TrkB signaling disruption and cognitive impairments in aging mice, which provides one possible therapeutic target for POCD.

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Fingolimod (FTY720) improves postoperative cognitive dysfunction in mice subjected to D-galactose-induced aging.

Publications

Fingolimod (FTY720) improves postoperative cognitive dysfunction in mice subjected to D-galactose-induced aging.

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