Neuroprotective effects of dexmedetomidine on the ketamine-induced disruption of the proliferation and differentiation of developing neural stem cells in the subventricular zone

Abstract Background: Recently, the number of neonatal patients receiving surgery under general anesthesia has increased. Ketamine disrupts the proliferation and differentiation of developing neural stem cells (NSCs). Therefore, the safe use of ketamine in pediatric anesthesia has been an issue of increasing concern among anesthesiologists and the children’s parents. Dexmedetomidine (DEX) is widely used in sedation, as an antianxiety agent and for analgesia. DEX has recently been shown to provide neuroprotection against anesthetic-induced neurotoxicity in the developing brain. The aim of this in vivo study was to investigate whether DEX exerted neuroprotective effects on the proliferation and differentiation of NSCs in the subventricular zone (SVZ) following neonatal ketamine exposure. Methods: Postnatal day 7 (PND-7) male Sprague-Dawley rats were equally divided into the following 5 groups: Control group (n=8), Ketamine group (n=8), 1 μg/kg DEX+Ketamine group (n=8), 5 μg/kg DEX+Ketamine group (n=8) and 10 μg/kg DEX+Ketamine group (n=8). The proliferation and differentiation of NSCs in the SVZ were assessed using immunostaining with BrdU incorporation. The levels of Nestin and β-tubulin III in the SVZ were measured using Western blot analyses. Apoptosis was assessed by detecting the levels of the cleaved caspase-3 protein using Western blotting. Results: Neonatal ketamine exposure significantly inhibited NSC proliferation and astrocytic differentiation in the SVZ, and neuronal differentiation was markedly increased. Furthermore, pretreatment with moderate (5 μg/kg) or high doses (10 μg/kg) of DEX reversed the ketamine-induced disturbances in the proliferation and differentiation of NSCs. Meanwhile, neonatal ketamine exposure significantly decreased the expression of Nestin and increased the expression of β-tubulin III in the SVZ compared with the Control group. Treatment with 10 μg/kg DEX notably reversed the ketamine-induced changes in the levels of Nestin and β-tubulin III. In addition, a pretreatment with 10 μg/kg DEX before ketamine anesthesia prevented apoptosis in the SVZ induced by neonatal ketamine exposure. Conclusions: Based on our findings, DEX may exert neuroprotective effects on the proliferation and differentiation of NSCs in the SVZ of neonatal rats in a repeated ketamine anesthesia model.

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Neuroprotective effects of dexmedetomidine on the ketamine-induced disruption of the proliferation and differentiation of developing neural stem cells in the subventricular zone

10.21203/rs.2.23770/v2 ◽

2020 ◽

Author(s):

Huanhuan Sha ◽

Peipei Peng ◽

Bing Li ◽

Guohua Wei ◽

Juan Wang ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Subventricular Zone ◽

Pediatric Anesthesia ◽

Brdu Incorporation ◽

Control Group ◽

Neuroprotective Effects ◽

Proliferation And Differentiation ◽

Ketamine Anesthesia ◽

Β Tubulin

Abstract Background: Recently, the number of neonatal patients receiving surgery under general anesthesia has increased. Ketamine disrupts the proliferation and differentiation of developing neural stem cells (NSCs). Therefore, the safe use of ketamine in pediatric anesthesia has been an issue of increasing concern among anesthesiologists and the children’s parents. Dexmedetomidine (DEX) is widely used in sedation, as an antianxiety agent and for analgesia. DEX has recently been shown to provide neuroprotection against anesthetic-induced neurotoxicity in the developing brain. The aim of this in vivo study was to investigate whether DEX exerted neuroprotective effects on the proliferation and differentiation of NSCs in the subventricular zone (SVZ) following neonatal ketamine exposure.Methods: Postnatal day 7 (PND-7) male Sprague-Dawley rats were equally divided into the following 5 groups: Control group (n=8), Ketamine group (n=8), 1 μg/kg DEX+Ketamine group (n=8), 5 μg/kg DEX+Ketamine group (n=8) and 10 μg/kg DEX+Ketamine group (n=8). The proliferation and differentiation of NSCs in the SVZ were assessed using immunostaining with BrdU incorporation. The levels of Nestin and β-tubulin III in the SVZ were measured using Western blot analyses. Apoptosis was assessed by detecting the levels of the cleaved caspase-3 protein using Western blotting.Results: Neonatal ketamine exposure significantly inhibited NSC proliferation and astrocytic differentiation in the SVZ, and neuronal differentiation was markedly increased. Furthermore, pretreatment with moderate (5 μg/kg) or high doses (10 μg/kg) of DEX reversed the ketamine-induced disturbances in the proliferation and differentiation of NSCs. Meanwhile, neonatal ketamine exposure significantly decreased the expression of Nestin and increased the expression of β-tubulin III in the SVZ compared with the Control group. Treatment with 10 μg/kg DEX notably reversed the ketamine-induced changes in the levels of Nestin and β-tubulin III. In addition, a pretreatment with 10 μg/kg DEX before ketamine anesthesia prevented apoptosis in the SVZ induced by neonatal ketamine exposure.Conclusions: Based on our findings, DEX may exert neuroprotective effects on the proliferation and differentiation of NSCs in the SVZ of neonatal rats in a repeated ketamine anesthesia model.

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Neuroprotective effects of dexmedetomidine against the ketamine-induced disturbance of proliferation and differentiation of developing neural stem cells in the subventricular zone

10.21203/rs.2.23770/v1 ◽

2020 ◽

Author(s):

Huanhuan Sha ◽

Peipei Peng ◽

Bing Li ◽

Guohua Wei ◽

Juan Wang ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Subventricular Zone ◽

Pediatric Anesthesia ◽

Brdu Incorporation ◽

Control Group ◽

Sprague Dawley ◽

Neuroprotective Effects ◽

Proliferation And Differentiation

Abstract Background: Recent years, the number of neonatal patients receiving surgery under general anesthesia is increasing. Previous studies have indicated that ketamine can disturb the proliferation and differentiation of developing neural stem cells (NSCs). Therefore, the safe use of ketamine in pediatric anesthesia has drawn great concern among anesthesiologists and children’s parents. Dexmedetomidine (DEX) is widely used in sedation, antianxiety and analgesia. Recent studies have shown that DEX could provide neuroprotection against anesthetic-induced neurotoxicity in the developing brain. The aim of this in vivo study was to investigate whether DEX had neuroprotective effects on the proliferation and differentiation of NSCs in the subventricular zone (SVZ) following neonatal ketamine exposure. Methods: Postnatal day 7 (PND-7) male Sprague-Dawley rats were equally divided into the following 5 groups: Control group (n=8), ketamine group (n=8), 1 μg/kg DEX+ketamine group (n=8), 5 μg/kg DEX+ketamine group (n=8) and 10 μg/kg DEX+ketamine group (n=8). The proliferation and differentiation of NSCs in the SVZ were assessed by immunostaining with BrdU incorporation. Results: Neonatal ketamine exposure significantly inhibited NSC proliferation and astrocytic differentiation in the SVZ, and neuronal differentiation was markedly promoted. Furthermore, DEX pretreatment reversed the ketamine-induced disturbances in the proliferation and differentiation of NSCs at moderate (5 μg/kg) or high doses (10 μg/kg). Conclusion: Our findings demonstrate that DEX may have neuroprotective effects on NSCs in the SVZ of neonatal rats in a repeated ketamine anesthesia model.

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Neuroprotective Effects of Dexmedetomidine on the Ketamine-Induced Disruption of the Proliferation and Differentiation of Developing Neural Stem Cells in the Subventricular Zone

Frontiers in Pediatrics ◽

10.3389/fped.2021.649284 ◽

2021 ◽

Vol 9 ◽

Author(s):

Huanhuan Sha ◽

Peipei Peng ◽

Guohua Wei ◽

Juan Wang ◽

Yuqing Wu ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Cognitive Dysfunction ◽

Subventricular Zone ◽

Pediatric Anesthesia ◽

Control Group ◽

High Dose ◽

Neuroprotective Effects ◽

Proliferation And Differentiation ◽

High Doses

Background: Ketamine disrupts the proliferation and differentiation of developing neural stem cells (NSCs). Therefore, the safe use of ketamine in pediatric anesthesia has been an issue of increasing concern among anesthesiologists and children's parents. Dexmedetomidine (DEX) is widely used in sedation as an antianxiety agent and for analgesia. DEX has recently been shown to provide neuroprotection against anesthetic-induced neurotoxicity in the developing brain. The aim of this in vivo study was to investigate whether DEX exerted neuroprotective effects on the proliferation and differentiation of NSCs in the subventricular zone (SVZ) following neonatal ketamine exposure.Methods: Postnatal day 7 (PND-7) male Sprague-Dawley rats were equally divided into the following five groups: control group (n = 8), ketamine group (n = 8), 1 μg/kg DEX+ketamine group (n = 8), 5 μg/kg DEX+ketamine group (n = 8) and 10 μg/kg DEX+ketamine group (n = 8). Immediately after treatment, rats received a single intraperitoneal injection of BrdU, and the proliferation and differentiation of NSCs in the SVZ were assessed using immunostaining at 24 h after the BrdU injection. In the olfactory behavioral tests, rats in each group were raised until 2 months old, and the buried food test and olfactory memory test were performed.Results: The proliferation of NSCs and astrocytic differentiation in the SVZ were significantly inhibited at 24 h after repeated ketamine exposure in the neonatal period, and neuronal differentiation was markedly increased. Furthermore, pretreatment with moderately high (5 μg/kg) or high doses (10 μg/kg) of DEX reversed ketamine-induced disturbances in the proliferation and differentiation of NSCs. In the behavior tests, repeated neonatal ketamine exposure induced olfactory cognitive dysfunction in the adult stage, and moderately high and high doses of DEX reversed the olfactory cognitive dysfunction induced by ketamine.Conclusions: Based on the present findings, pretreatment with a moderately high (5 μg/kg) or high dose (10 μg/kg) of DEX may alleviate the developmental neurogenesis disorder in the SVZ at 24 h after repeated ketamine exposure and improve olfactory cognitive dysfunction in adulthood.

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Effects of the monomeric, oligomeric, and fibrillar Aβ42 peptides on the proliferation and differentiation of adult neural stem cells from subventricular zone

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2007.04499.x ◽

2007 ◽

Vol 102 (2) ◽

pp. 493-500 ◽

Cited By ~ 51

Author(s):

Chaejeong Heo ◽

Keun-A Chang ◽

Hee Soon Choi ◽

Hye-Sun Kim ◽

Seonghan Kim ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Subventricular Zone ◽

Adult Neural Stem Cells ◽

Proliferation And Differentiation

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Ketamine Interferes with the Proliferation and Differentiation of Neural Stem Cells in the Subventricular Zone of Neonatal Rats

Cellular Physiology and Biochemistry ◽

10.1159/000369698 ◽

2015 ◽

Vol 35 (1) ◽

pp. 315-325 ◽

Cited By ~ 22

Author(s):

He Huang ◽

Lu Liu ◽

Bing Li ◽

Pan-Pan Zhao ◽

Chun-Mei Xu ◽

...

Keyword(s):

Stem Cells ◽

Neuronal Differentiation ◽

Subventricular Zone ◽

Caspase 3 ◽

Neonatal Rats ◽

Double Positive ◽

Double Labeling ◽

Proliferation And Differentiation ◽

Β Tubulin

Background: Previous studies have shown ketamine can alter the proliferation and differentiation of neural stem cells (NSCs) in vitro. However, these effects have not been entirely clarified in vivo in the subventricular zone (SVZ) of neonatal rats. The present study was designed to investigate the effects of ketamine on the proliferation and differentiation of NSCs in the SVZ of neonatal rats in vivo. Methods: Postnatal day 7 (PND-7) male Sprague-Dawley rats were administered four injections of 40 mg/kg ketamine at 1-h intervals, and then 5-bromodeoxyuridine (BrdU) was injected intraperitoneally at PND-7, 9 and 13. NSC proliferation was assessed with Nestin/BrdU double-labeling immunostaining. Neuronal and astrocytic differentiation was evaluated with β-tubulin III/BrdU and GFAP/BrdU double-labeling immunostaining, respectively. The expressions of nestin, β-tubulin III and GFAP were measured using Western blot analysis. The apoptosis of NSCs and astrocytes in the SVZ of neonatal rats was evaluated using nestin/caspase-3 and GFAP/caspase-3 double-labeling immunostaining. Results: Neonatal ketamine exposure significantly reduced the number of nestin/BrdU and GFAP/BrdU double-positive cells in the SVZ. Meanwhile, the expressions of nestin and GFAP in the SVZ from the ketamine group were significantly decreased compared those in the control group. Still, no double-positive cells for nestin/caspase-3 and GFAP/caspase-3 were found after ketamine exposure. In addition, the neuronal differentiation of NSCs in the SVZ was markedly promoted by ketamine with an increased number of β-tubulin III/BrdU double-positive cells and enhanced expression of β-tubulin III. These effects of ketamine on the NSCs in the SVZ often lasted at least 1 week after ketamine anesthesia. Conclusion: In the present study, it was demonstrated that ketamine could alter neurogenesis by inhibiting the proliferation of NSCs, suppressing their differentiation into astrocytes and promoting the neuronal differentiation of the NSCs in the SVZ of neonatal rats during a critical period of their neurodevelopment.

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Effects of Panax Notoginseng Saponins on Proliferation and Differentiation of Rat Hippocampal Neural Stem Cells

The American Journal of Chinese Medicine ◽

10.1142/s0192415x11009366 ◽

2011 ◽

Vol 39 (05) ◽

pp. 999-1013 ◽

Cited By ~ 32

Author(s):

Yin-Chu Si ◽

Jian-Ping Zhang ◽

Chun-E Xie ◽

Li-Juan Zhang ◽

Xiang-Ning Jiang

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Ischemia Reperfusion ◽

Panax Notoginseng ◽

Control Group ◽

Panax Notoginseng Saponins ◽

Double Labeling ◽

Proliferation And Differentiation ◽

Hippocampal Neural Stem Cells

We aimed to investigate the effects of Panax notoginseng saponins (PNS) on proliferation, differentiation and self-renewal of rat hippocampal neural stem cells (NSCs) in vitro. Rat hippocampal NSCs were isolated from post-natal day 1 (P1) rats and cultured in a serum-free medium. The neurospheres were identified by the expressions of nestin, class III β-tublin (Tuj-1) and glial fibrillary acid protein (GFAP). The cells were given PNS and subjected to oxygen glucose deprivation (OGD) as an in vitro model of brain ischemia reperfusion. The proliferation of NSCs was determined by MTT colorimetry, nestin/BrdU immunofluorescent double-labeling and RT-PCR. Differentiation of NSCs was assessed by immunofluorescent double-labeling of nestin/BrdU, nestin/vimentin, and nestin/Tuj-1. The primary cells and the first two passages of cells formed certain amount of neurospheres, the cells derived from a single cell clone also formed neurospheres. Nestin, BrdU, GFAP and Tuj-1-positive cells appeared in those neurospheres. Compared to the control group, PNS significantly promoted NSC proliferation and the expression of nestin/BrdU, and also enhanced Tuj-1, vimentin, and nestin mRNA expressions in hippocampal NSCs. PNS significantly increased area density, optical density and numbers of nestin/BrdU, nestin/vimentin, and nestin/Tuj-1 positive cells following OGD. These results indicate that PNS can promote proliferation and differentiation of hippocampus NCSs in vitro after OGD, suggesting its potential benefits on neurogenesis and neuroregeneration in brain ischemic injury.

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