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      Naringenin Prevents Propofol Induced Neurodegeneration in Neonatal Mice Brain and Long-Term Neurocognitive Impacts on Adults

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          Abstract

          Background

          Natural products have shown neuroprotective effects in neurodegenerative conditions. Naringenin is a natural flavonoid with various pharmacological activities especially antioxidant, anti-inflammatory and neuroprotective properties. We investigated the effects of naringenin on anesthetic propofol-induced impacts on neonatal mouse brain development and consequent long-term neurocognitive impacts during adulthood.

          Materials and Methods

          Female C57Bl/6 and male CD-1 mice and postnatal day 7 (P7) pups were exposed to propofol (2.5 mg/kg) and propofol with naringenin (50 mg/kg). Mice pups were allowed to grow until week 10 (adulthood), and memory and learning were assessed.

          Results

          Propofol caused neurodegeneration by inducing apoptosis in the neonatal mouse brains while naringenin administration prevented neuronal cell loss by preventing neuronal apoptosis in neonatal mouse brains. Propofol caused degenerative alterations in metabolic factors pH, PO 2, glucose and lactate, which were subsequently restored by naringenin treatment. Propofol-exposed mice, when developed into adults, showed long-term neuronal deficits, impaired neurocognitive functions, and memory and learning restrictions.

          Conclusion

          Administration of naringenin to propofol-exposed mice resulted in significant neuroprotective effects by restoring long-term neurocognitive functions. The molecular mechanism behind the effects of naringenin was mediated by suppressing apoptosis and preventing cellular inflammation. These findings suggest that propofol administration requires careful consideration and that naringenin may prevent neurodegeneration and neurocognitive functions.

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          Most cited references 42

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          Flavonoids: antioxidants or signalling molecules?

          Many studies are accumulating that report the neuroprotective, cardioprotective, and chemopreventive actions of dietary flavonoids. While there has been a major focus on the antioxidant properties, there is an emerging view that flavonoids, and their in vivo metabolites, do not act as conventional hydrogen-donating antioxidants but may exert modulatory actions in cells through actions at protein kinase and lipid kinase signalling pathways. Flavonoids, and more recently their metabolites, have been reported to act at phosphoinositide 3-kinase (PI 3-kinase), Akt/protein kinase B (Akt/PKB), tyrosine kinases, protein kinase C (PKC), and mitogen activated protein kinase (MAP kinase) signalling cascades. Inhibitory or stimulatory actions at these pathways are likely to affect cellular function profoundly by altering the phosphorylation state of target molecules and by modulating gene expression. A clear understanding of the mechanisms of action of flavonoids, either as antioxidants or modulators of cell signalling, and the influence of their metabolism on these properties are key to the evaluation of these potent biomolecules as anticancer agents, cardioprotectants, and inhibitors of neurodegeneration
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            Morris water maze: procedures for assessing spatial and related forms of learning and memory.

            The Morris water maze (MWM) is a test of spatial learning for rodents that relies on distal cues to navigate from start locations around the perimeter of an open swimming arena to locate a submerged escape platform. Spatial learning is assessed across repeated trials and reference memory is determined by preference for the platform area when the platform is absent. Reversal and shift trials enhance the detection of spatial impairments. Trial-dependent, latent and discrimination learning can be assessed using modifications of the basic protocol. Search-to-platform area determines the degree of reliance on spatial versus non-spatial strategies. Cued trials determine whether performance factors that are unrelated to place learning are present. Escape from water is relatively immune from activity or body mass differences, making it ideal for many experimental models. The MWM has proven to be a robust and reliable test that is strongly correlated with hippocampal synaptic plasticity and NMDA receptor function. We present protocols for performing variants of the MWM test, from which results can be obtained from individual animals in as few as 6 days.
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              Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain.

              Brief isoflurane anesthesia induces neuroapoptosis in the developing rodent brain, but susceptibility of non-human primates to the apoptogenic action of isoflurane has not been studied. Therefore, we exposed postnatal day 6 (P6) rhesus macaques to a surgical plane of isoflurane anesthesia for 5 h, and studied the brains 3 h later for histopathologic changes. With the same intensity of physiologic monitoring typical for human neonatal anesthesia, five P6 rhesus macaques were exposed for 5 h to isoflurane maintained between 0.7 and 1.5 end-tidal Vol% (endotracheally intubated and mechanically ventilated) and five controls were exposed for 5 h to room air without further intervention. Three hours later, the brains were harvested and serially sectioned across the entire forebrain and midbrain, and stained immunohistochemically with antibodies to activated caspase-3 for detection and quantification of apoptotic neurons. Quantitative evaluation of brain sections revealed a median of 32.5 (range, 18.0-48.2) apoptotic cells/mm of brain tissue in the isoflurane group and only 2.5 (range, 1.1-5.2) in the control group (difference significant at P = 0.008). Apoptotic neuronal profiles were largely confined to the cerebral cortex. In the control brains, they were sparse and randomly distributed, whereas in the isoflurane brains they were abundant and preferentially concentrated in specific cortical layers and regions. The developing non-human primate brain is sensitive to the apoptogenic action of isoflurane and displays a 13-fold increase in neuroapoptosis after 5 h exposure to a surgical plane of isoflurane anesthesia.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                10 December 2020
                2020
                : 14
                : 5469-5482
                Affiliations
                [1 ]Department of Anesthesiology, General Hospital of NingXia Medical University , Yinchuan, NingXia 750000, People’s Republic of China
                [2 ]Department of Oncological Surgery, General Hospital of NingXia Medical University , Yinchuan, NingXia 750000, People’s Republic of China
                [3 ]Department of Anesthesiology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei 430000, People’s Republic of China
                Author notes
                Correspondence: Jing Lv Department of Anesthesiology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei430000, People’s Republic of ChinaTel/Fax +86-27-85351618 Email EmiliaAndrewsvpq@yahoo.com
                [*]

                These authors contributed equally to this work

                Article
                280443
                10.2147/DDDT.S280443
                7735719
                © 2020 Zou et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 6, Tables: 4, References: 42, Pages: 14
                Categories
                Original Research

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