Dexmedetomidine alleviates cognitive impairment by promoting hippocampal neurogenesis via BDNF/TrkB/CREB signaling pathway in hypoxic–ischemic neonatal rats

Abstract Aims Dexmedetomidine (DEX) has been reported to alleviate hypoxic–ischemic brain damage (HIBD) in neonates. This study aimed to investigate whether DEX improves cognitive impairment by promoting hippocampal neurogenesis via the BDNF/TrkB/CREB signaling pathway in neonatal rats with HIBD. Methods HIBD was induced in postnatal day 7 rats using the Rice‐Vannucci method, and DEX (25 μg/kg) was administered intraperitoneally immediately after the HIBD induction. The BDNF/TrkB/CREB pathway was regulated by administering the TrkB receptor antagonist ANA‐12 through intraperitoneal injection or by delivering adeno‐associated virus (AAV)‐shRNA‐BDNF via intrahippocampal injection. Western blot was performed to measure the levels of BDNF, TrkB, and CREB. Immunofluorescence staining was utilized to identify the polarization of astrocytes and evaluate the levels of neurogenesis in the dentate gyrus of the hippocampus. Nissl and TTC staining were performed to evaluate the extent of neuronal damage. The MWM test was conducted to evaluate spatial learning and memory ability. Results The levels of BDNF and neurogenesis exhibited a notable decrease in the hippocampus of neonatal rats after HIBD, as determined by RNA‐sequencing technology. Our results demonstrated that treatment with DEX effectively increased the protein expression of BDNF and the phosphorylation of TrkB and CREB, promoting neurogenesis in the dentate gyrus of the hippocampus in neonatal rats with HIBD. Specifically, DEX treatment significantly augmented the expression of BDNF in hippocampal astrocytes, while decreasing the proportion of detrimental A1 astrocytes and increasing the proportion of beneficial A2 astrocytes in neonatal rats with HIBD. Furthermore, inhibiting the BDNF/TrkB/CREB pathway using either ANA‐12 or AAV‐shRNA‐BDNF significantly counteracted the advantageous outcomes of DEX on hippocampal neurogenesis, neuronal survival, and cognitive improvement. Conclusions DEX promoted neurogenesis in the hippocampus by activating the BDNF/TrkB/CREB pathway through the induction of polarization of A1 astrocytes toward A2 astrocytes, subsequently mitigating neuronal damage and cognitive impairment in neonates with HIBD.

[1]  Mei Wang,et al.  Telmisartan inhibits microglia-induced neurotoxic A1 astrocyte conversion via PPARγ-mediated NF-κB/p65 degradation. , 2023, International immunopharmacology.

[2]  P. Heagerty,et al.  Association of High-Dose Erythropoietin With Circulating Biomarkers and Neurodevelopmental Outcomes Among Neonates With Hypoxic Ischemic Encephalopathy , 2023, JAMA network open.

[3]  K. Blennow,et al.  Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer’s disease , 2023, Nature Medicine.

[4]  J. Meldolesi.  Role of Senescent Astrocytes in Health and Disease , 2023, International journal of molecular sciences.

[5]  Angelica Chen,et al.  Dexmedetomidine Attenuates Apoptosis and Neurological Deficits by Modulating Neuronal NADPH Oxidase 2-Derived Oxidative Stress in Neonates Following Hypoxic Brain Injury , 2022, Antioxidants.

[6]  Angelica Chen,et al.  Research advances in the role of endogenous neurogenesis on neonatal hypoxic-ischemic brain damage , 2022, Frontiers in Pediatrics.

[7]  Yunyi Zhao,et al.  The neuroprotective effect of dexmedetomidine and its mechanism , 2022, Frontiers in Pharmacology.

[8]  B. Tepper,et al.  Postnatal and Adult Neurogenesis in Mammals, Including Marsupials , 2022, Cells.

[9]  Angelica Chen,et al.  Dexmedetomidine alleviates olfactory cognitive dysfunction by promoting neurogenesis in the subventricular zone of hypoxic-ischemic neonatal rats , 2022, Frontiers in Pharmacology.

[10]  H. Sabir,et al.  Impact of Hypoxia-Ischemia on Neurogenesis and Structural and Functional Outcomes in a Mild–Moderate Neonatal Hypoxia-Ischemia Brain Injury Model , 2022, Life.

[11]  E. Salińska,et al.  Group II Metabotropic Glutamate Receptors Reduce Apoptosis and Regulate BDNF and GDNF Levels in Hypoxic-Ischemic Injury in Neonatal Rats , 2022, International journal of molecular sciences.

[12]  R. Chen,et al.  Effects of Dexmedetomidine on Immune Cells: A Narrative Review , 2022, Frontiers in Pharmacology.

[13]  Xiao-wen Li,et al.  Astrocytes Mediate Cholinergic Regulation of Adult Hippocampal Neurogenesis and Memory Through M1 Muscarinic Receptor , 2022, Biological Psychiatry.

[14]  Hao Sun,et al.  Astrocyte polarization in glaucoma: a new opportunity , 2022, Neural regeneration research.

[15]  Jian Xiong,et al.  Devil or angel: two roles of carbon monoxide in stroke , 2022, Medical gas research.

[16]  F. Pei,et al.  Mitochondrial Proteins Unveil the Mechanism by Which Physical Exercise Ameliorates Memory, Learning and Motor Activity in Hypoxic Ischemic Encephalopathy Rat Model , 2022, International journal of molecular sciences.

[17]  S. Back,et al.  The Vannucci Model of Hypoxic-Ischemic Injury in the Neonatal Rodent: 40 years Later , 2022, Developmental Neuroscience.

[18]  H. Monyer,et al.  Neurogenesis in the adult brain functionally contributes to the maintenance of chronic neuropathic pain , 2021, Scientific Reports.

[19]  M. Ruan,et al.  Synergic Neuroprotection Between Ligusticum Chuanxiong Hort and Borneol Against Ischemic Stroke by Neurogenesis via Modulating Reactive Astrogliosis and Maintaining the Blood–Brain Barrier , 2021, Frontiers in Pharmacology.

[20]  Zhao-Qiong Zhu,et al.  BDNF promotes neuronal survival after neonatal hypoxic-ischemic encephalopathy by up-regulating Stx1b and suppressing VDAC1 , 2021, Brain Research Bulletin.

[21]  W. Carlo,et al.  Early Determination of Prognosis in Neonatal Moderate or Severe Hypoxic-Ischemic Encephalopathy , 2021, Pediatrics.

[22]  Shengxi Wu,et al.  Mitochondria transplantation protects traumatic brain injury via promoting neuronal survival and astrocytic BDNF. , 2021, Translational research : the journal of laboratory and clinical medicine.

[23]  J. García-Segura,et al.  Post-stroke Neurogenesis: Friend or Foe? , 2021, Frontiers in Cell and Developmental Biology.

[24]  R. Angert,et al.  Dexmedetomidine versus intermittent morphine for sedation of neonates with encephalopathy undergoing therapeutic hypothermia , 2021, Journal of Perinatology.

[25]  Dongtai Chen,et al.  Dexmedetomidine Alleviates Hypoxia-Induced Synaptic Loss and Cognitive Impairment via Inhibition of Microglial NOX2 Activation in the Hippocampus of Neonatal Rats , 2021, Oxidative medicine and cellular longevity.

[26]  Tinghua Wang,et al.  Brain-derived neurotrophic factor and its related enzymes and receptors play important roles after hypoxic-ischemic brain damage , 2021, Neural regeneration research.

[27]  Yuqing Wu,et al.  Neuroprotective Effects of Dexmedetomidine on the Ketamine-Induced Disruption of the Proliferation and Differentiation of Developing Neural Stem Cells in the Subventricular Zone , 2020, Frontiers in Pediatrics.

[28]  C. Mulle,et al.  Vangl2 in the Dentate Network Modulates Pattern Separation and Pattern Completion , 2020, Cell reports.

[29]  T. Zalewska,et al.  Impact of a Histone Deacetylase Inhibitor—Trichostatin A on Neurogenesis after Hypoxia-Ischemia in Immature Rats , 2020, International journal of molecular sciences.

[30]  K. Park,et al.  Cellular Response of Ventricular-Subventricular Neural Progenitor/Stem Cells to Neonatal Hypoxic-Ischemic Brain Injury and Their Enhanced Neurogenesis , 2020, Yonsei medical journal.

[31]  Yuanyuan Zhang,et al.  Dexmedetomidine alleviates neurogenesis damage following neonatal midazolam exposure in rats through JNK and P38 MAPK pathways. , 2020, ACS chemical neuroscience.

[32]  G. Boylan,et al.  Two-Year Neurodevelopmental Outcomes After Mild Hypoxic Ischemic Encephalopathy in the Era of Therapeutic Hypothermia. , 2019, JAMA pediatrics.

[33]  R. Raman,et al.  SIPA1L2 controls trafficking and local signaling of TrkB-containing amphisomes at presynaptic terminals , 2019, Nature Communications.

[34]  T. Dawson,et al.  The A1 astrocyte paradigm: New avenues for pharmacological intervention in neurodegeneration , 2019, Movement disorders : official journal of the Movement Disorder Society.

[35]  D. Talmor,et al.  Effect of Intravenous Acetaminophen vs Placebo Combined With Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac Surgery: The DEXACET Randomized Clinical Trial , 2019, JAMA.

[36]  T. Zalewska,et al.  Effect of the HDAC Inhibitor, Sodium Butyrate, on Neurogenesis in a Rat Model of Neonatal Hypoxia–Ischemia: Potential Mechanism of Action , 2019, Molecular Neurobiology.

[37]  T. Numakawa,et al.  Actions of Brain-Derived Neurotrophin Factor in the Neurogenesis and Neuronal Function, and Its Involvement in the Pathophysiology of Brain Diseases , 2018, International journal of molecular sciences.

[38]  D. Brann,et al.  NADPH oxidase 2 deletion enhances neurogenesis following traumatic brain injury , 2018, Free radical biology & medicine.

[39]  Xingyu Wei,et al.  Silibinin exerts antidepressant effects by improving neurogenesis through BDNF/TrkB pathway , 2018, Behavioural Brain Research.

[40]  A. Kalueff,et al.  Dietary eicosapentaenoic acid normalizes hippocampal omega-3 and 6 polyunsaturated fatty acid profile, attenuates glial activation and regulates BDNF function in a rodent model of neuroinflammation induced by central interleukin-1β administration , 2018, European Journal of Nutrition.

[41]  T. Tamiya,et al.  Association between dexmedetomidine use and neurological outcomes in aneurysmal subarachnoid hemorrhage patients: A retrospective observational study , 2018, Journal of critical care.

[42]  Dong-Mei Wu,et al.  Dexmedetomidine exerts neuroprotective effect via the activation of the PI3K/Akt/mTOR signaling pathway in rats with traumatic brain injury. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[43]  Lian-wen Duan,et al.  Dexmedetomidine preconditioning plays a neuroprotective role and suppresses TLR4/NF-κB pathways model of cerebral ischemia reperfusion. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[44]  Z. Molnár,et al.  Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges , 2017, Front. Cell. Neurosci..

[45]  F. Northington,et al.  Therapeutic Hypothermia Provides Variable Protection against Behavioral Deficits after Neonatal Hypoxia-Ischemia: A Potential Role for Brain-Derived Neurotrophic Factor , 2017, Developmental Neuroscience.

[46]  D. Rowitch,et al.  Neurotoxic reactive astrocytes are induced by activated microglia , 2017, Nature.

[47]  G. Ronnett,et al.  AKAP-mediated feedback control of cAMP gradients in developing hippocampal neurons , 2017, Nature chemical biology.

[48]  Hong Ma,et al.  Dexmedetomidine Postconditioning Reduces Brain Injury after Brain Hypoxia-Ischemia in Neonatal Rats , 2016, Journal of Neuroimmune Pharmacology.

[49]  J. Leza,et al.  Stress Increases the Negative Effects of Chronic Pain on Hippocampal Neurogenesis , 2015, Anesthesia and analgesia.

[50]  R. Cruz-Rizzolo,et al.  Neonatal anoxia in rats: Hippocampal cellular and subcellular changes related to cell death and spatial memory , 2015, Neuroscience.

[51]  Mu-ming Poo,et al.  Neurotrophin regulation of neural circuit development and function , 2012, Nature Reviews Neuroscience.

[52]  J. Tobias,et al.  Safety and efficacy of prolonged dexmedetomidine use in critically ill children with heart disease* , 2012, Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.

[53]  Fu-hai Ji,et al.  Brain‐derived neurotrophic factor modulates N‐methyl‐D‐aspartate receptor activation in a rat model of cancer‐induced bone pain , 2012, Journal of neuroscience research.

[54]  S. Kanba,et al.  cAMP response element-binding protein (CREB) is required for epidermal growth factor (EGF)-induced cell proliferation and serum response element activation in neural stem cells isolated from the forebrain subventricular zone of adult mice. , 2011, Endocrine journal.

[55]  M. Mattson,et al.  When neurogenesis encounters aging and disease , 2010, Trends in Neurosciences.

[56]  P R Sanberg,et al.  Mannitol facilitates neurotrophic factor up-regulation and behavioural recovery in neonatal hypoxic-ischaemic rats with human umbilical cord blood grafts , 2010, Journal of cellular and molecular medicine.

[57]  J. Hell,et al.  Thrombospondins Are Astrocyte-Secreted Proteins that Promote CNS Synaptogenesis , 2005, Cell.

[58]  J. Parent,et al.  Neonatal hypoxic–ischemic injury increases forebrain subventricular zone neurogenesis in the mouse , 2004, Neurobiology of Disease.