|
1
|
Einenkel AM, Salameh A. Selective vulnerability of hippocampal CA1 and CA3 pyramidal cells: What are possible pathomechanisms and should more attention be paid to the CA3 region in future studies? J Neurosci Res 2024; 102:e25276. [PMID: 38284845 DOI: 10.1002/jnr.25276] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 06/22/2023] [Accepted: 10/29/2023] [Indexed: 01/30/2024]
Abstract
Transient ischemia and reperfusion selectively damage neurons in brain, with hippocampal pyramidal cells being particularly vulnerable. Even within hippocampus, heterogeneous susceptibility is evident, with higher vulnerability of CA1 versus CA3 neurons described for several decades. Therefore, numerous studies have focused exclusively on CA1. Pediatric cardiac surgery is increasingly focusing on studies of hippocampal structures, and a negative impact of cardiopulmonary bypass on the hippocampus cannot be denied. Recent studies show a shift in selective vulnerability from neurons of CA1 to CA3. This review shows that cell damage is increased in CA3, sometimes stronger than in CA1, depending on several factors (method, species, age, observation period). Despite a highly variable pattern, several markers illustrate greater damage to CA3 neurons than previously assumed. Nevertheless, the underlying cellular mechanisms have not been fully deciphered to date. The complexity is reflected in possible pathomechanisms discussed here, with numerous factors (NMDA, kainate and AMPA receptors, intrinsic oxidative stress potential and various radicals, AKT isoforms, differences in vascular architecture, ratio of pro- and anti-apoptotic Bcl-2 factors, vulnerability of interneurons, mitochondrial dysregulation) contributing to either enhanced CA1 or CA3 vulnerability. Furthermore, differences in expressed genome, proteome, metabolome, and transcriptome in CA1 and CA3 appear to influence differential behavior after damaging stimuli, thus metabolomics-, transcriptomics-, and proteomics-based analyses represent a viable option to identify pathways of selective vulnerability in hippocampal neurons. These results emphasize that future studies should focus on the CA3 field in addition to CA1, especially with regard to improving therapeutic strategies after ischemic/hypoxic brain injury.
Collapse
Affiliation(s)
- Anne-Marie Einenkel
- Clinic for Pediatric Cardiology, University of Leipzig, Heart Centre, Leipzig, Germany
| | - Aida Salameh
- Clinic for Pediatric Cardiology, University of Leipzig, Heart Centre, Leipzig, Germany
| |
Collapse
|
|
2
|
Saadh MJ, Castillo-Acobo RY, Baher H, Narayanan J, Palacios Garay JP, Yamaguchi MNV, Arias-Gonzáles JL, Cotrina-Aliaga JC, Akram SV, Lakshmaiya N, Amin AH, Mohany M, Al-Rejaie SS, Ahsan M, Bahrami A, Akhavan-Sigari R. The protective role of sulforaphane and Homer1a in retinal ischemia-reperfusion injury: Unraveling the neuroprotective interplay. Life Sci 2023; 329:121968. [PMID: 37487941 DOI: 10.1016/j.lfs.2023.121968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/10/2023] [Accepted: 07/18/2023] [Indexed: 07/26/2023]
Abstract
AIMS Retinal ischemia/reperfusion (I/R) injury is a common pathological basis for various ophthalmic diseases. This study aimed to investigate the potential of sulforaphane (SFN) and Homer1a in regulating cell apoptosis induced by retinal I/R injury and to explore the underlying regulatory mechanism between them. MATERIALS AND METHODS In in vivo experiments, C57BL/6J mice and Homer1flox/-/Homer1a+/-/Nestin-Cre+/- mice were used to construct retinal I/R injury models. In vitro experiments utilized the oxygen-glucose deprivation-reperfusion (OGD/R) injury model with primary retinal ganglion cells (RGCs). The effects of Homer1a and SFN on cell apoptosis were observed through pathological analyses, flow cytometry, and visual electrophysiological assessments. KEY FINDINGS We discovered that after OGD/R injury, apoptosis of RGCs and intracellular Ca2+ activity significantly increased. However, these changes were reversed upon the addition of SFN, and similar observations were reproduced in in vivo studies. Furthermore, both in vivo and in vitro studies confirmed the upregulation of Homer1a after I/R, which could be further enhanced by the administration of SFN. Moreover, upregulation of Homer1a resulted in a reduction in cell apoptosis and pro-apoptotic proteins, while downregulation of Homer1a had the opposite effect. Flash visual evoked potential, oscillatory potentials, and escape latency measurements in mice supported these findings. Furthermore, the addition of SFN strengthened the neuroprotective effects in the OGD/R + H+ group but weakened them in Homer1flox/-/Homer1a+/-/Nestin-Cre+/- mice. SIGNIFICANCE These results indicate that Homer1a plays a significant role in the therapeutic potential of sulforaphane for retinal I/R injury, thereby providing a theoretical basis for clinical treatment.
Collapse
Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan; Applied Science Research Center, Applied Science Private University, Amman 11152, Jordan
| | | | - Hala Baher
- Department of Radiology and Ultrasonography Techniques, College of Medical Techniques, Al-Farahidi University, Baghdad, Iraq
| | | | | | | | - José Luis Arias-Gonzáles
- Department of Social Sciences, Faculty of Social Studies, University of British Columbia, BC, Canada
| | | | - Shaik Vaseem Akram
- Uttaranchal Institute of Technology, Division of research and Innovation, Uttaranchal University, Dehradun, India
| | - Natrayan Lakshmaiya
- Department of Mechanical Engineering, Saveetha School of Engineering, SRM Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Ali H Amin
- Zoology Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
| | - Mohamed Mohany
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 55760, Riyadh 11451, Saudi Arabia
| | - Salim S Al-Rejaie
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 55760, Riyadh 11451, Saudi Arabia
| | - Muhammad Ahsan
- Department of Measurements and Control Systems, Silesian University of Technology, Gliwice, 44-100, Poland; Joint Doctoral School, Silesian University of Technology, Akademicka 2A, Gliwice, 44-100, Poland.
| | - Abolfazl Bahrami
- Department of Cell Biology, Tuebingen University, Tuebingen, Germany; Biomedical Center for Systems Biology Science Munich, Ludwig-Maximilians-University, Munich, Germany.
| | - Reza Akhavan-Sigari
- Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw, Poland; Department of Neurosurgery, University Medical Center Tuebingen, Germany
| |
Collapse
|
|
3
|
Zhuang Y, Xu J, Zheng K, Zhang H. Research progress of postoperative cognitive dysfunction in cardiac surgery under cardiopulmonary bypass. IBRAIN 2023; 10:290-304. [PMID: 39346790 PMCID: PMC11427806 DOI: 10.1002/ibra.12123] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 07/18/2023] [Accepted: 07/25/2023] [Indexed: 10/01/2024]
Abstract
Cardiopulmonary bypass (CPB) is often used in cardiothoracic surgery because its nonphysiological state causes pathophysiological changes in the body, causing multiorgan and multitissue damage to varying degrees. Postoperative cognitive dysfunction (POCD) is a common central nervous system complication after cardiac surgery. The etiology and mechanism of POCD are not clear. Neuroinflammation, brain mitochondrial dysfunction, cerebral embolism, ischemia, hypoxia, and other factors are related to the pathogenesis of POCD. There is a close relationship between CPB and POCD, as CPB can cause inflammation, hypoxia and reperfusion injury, and microemboli formation, all of which can trigger POCD. POCD increases medical costs, seriously affects patients' quality of life, and increases mortality. Currently, there is a lack of effective treatment methods for POCD. Commonly used methods include preoperative health management, reducing inflammation response during surgery, preventing microemboli formation, and implementing individualized rehabilitation programs after surgery. Strengthening preventive measures can minimize the occurrence of POCD and its adverse effects.
Collapse
Affiliation(s)
- Yi‐Ming Zhuang
- Department of AnesthesiologyAffiliated Hospital of Zunyi Medical UniversityZunyiChina
| | - Ji‐Yang Xu
- Department of AnesthesiologyJudicial Police Hospital of Guizhou ProvinceGuiyangChina
| | - Kun Zheng
- Department of AnesthesiologyGuizhou Provincial People's HospitalGuiyangChina
| | - Hong Zhang
- Department of AnesthesiologyAffiliated Hospital of Zunyi Medical UniversityZunyiChina
| |
Collapse
|
|
4
|
Kumar H, Chakrabarti A, Sarma P, Modi M, Banerjee D, Radotra BD, Bhatia A, Medhi B. Novel therapeutic mechanism of action of metformin and its nanoformulation in Alzheimer's disease and role of AKT/ERK/GSK pathway. Eur J Pharm Sci 2023; 181:106348. [PMID: 36496166 DOI: 10.1016/j.ejps.2022.106348] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 12/03/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Brain Insulin-resistance plays a critical role in pathogenesis of Alzheimer's disease (AD). Current study explored the therapeutic mechanism of metformin (insulin sensitizer) and its solid-lipid nanoformulation (SLN) in rat-model of AD. In our study, SLN was prepared using microemulsion method. AD was induced with ICV-Aβ whereas the control-group (sham) received ICV-NS. Treatment arms included, disease-control (no treatment), Metformin (50 mg/kg, 100 mg/kg and 150 mg/kg), SLN-metformin 50 mg/kg and memantine 1.8 mg/kg (positive-control). Animals were tested for cognitive performance (EPM, MWM) after 21 days of therapy and sacrificed. Aβ (1-42), hyperphosphorylated tau, pAKTser473, GSK-3β, p-ERK (ELISA), metformin level(HPLC), neuronal injury score(H&E), Bcl2 and Bax(IHC) was evaluated in isolated brain. In our study, metformin-SLN were of spherical shape (size<200 nm) with 94.08% entrapment efficiency. Metformin was detectable in brain. Compared to sham, the disease-control group showed significantly higher (p ≤ 0.05) memory impairment(MWM and EPM), hyperphosphorylated tau, Aβ(1-42), neuronal-injury, Bax and lower Bcl-2 expression. Treatment with metformin and nanoformulation significantly reverse these parameters. AKT-ERK-GSK3β-Hyperphosphorylated tau pathway was found to be involved in the protective efficacy of metformin. To conclude, both metformin and its SLN were found to be effective as therapeutic agents in AD which act through the AKT-ERK-GSK3β-Hyperphosphorylated tau pathway. We need population based studies to confirm the same.
Collapse
Affiliation(s)
| | | | | | | | | | - B D Radotra
- Department of Histopathology, PGIMER, Chandigarh
| | - Alka Bhatia
- Department of Experimental Medicine & Biotechnology, PGIMER, Chandigarh.
| | | |
Collapse
|
|
5
|
Wang L, Bao S, Liu X, Wang F, Zhang J, Dang P, Wang F, Li B, Lin Y. Low-dose exposure to black carbon significantly increase lung injury of cadmium by promoting cellular apoptosis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 224:112703. [PMID: 34479021 DOI: 10.1016/j.ecoenv.2021.112703] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/18/2021] [Accepted: 08/23/2021] [Indexed: 06/13/2023]
Abstract
Particulate matter 2.5 (PM2.5) has adverse biological effects on major living organs in the body, including lungs. The complex composition of PM2.5, including carbon black and heavy metals, cause toxic effects to the lung. Nonetheless, there exists considerable knowledge gaps regarding the impact of carbon black (CB) on environmental health and safety (EHS). Thus far, the synergistic effects of CB have not gained much attention in past decades. Here, we showed that combined exposure of CB and Cadmium (Cd) enhance the cytotoxicity by altering the state of cell membrane. Specially, CB caused cell membrane collapse and increased the permeability of cells, and remarkedly enhanced the metal Cd toxicity. Furthermore, upon pre-treatment sublethal-dose CB, the increased intracellular Cd brought about a significantly amount of lactate dehydrogenase (LDH) and high expression of metallothionein-1 (MT-1) in human lung epithelial cell line (BEAS-2B) cells, and ultimately resulted an increased cellular toxicity. The lung of mice exposed CBs and Cd presented remarkably inflammation than Cd alone. Mechanistic exploration deciphered that CB pre-treatment triggered cell damage via apoptosis due to Cd exposure. Collectively, our findings reveal a novel path for understanding the impact of CB on EHS with its synergistic effects, through which nanomaterials might exert detrimental effects on organisms.
Collapse
Affiliation(s)
- Lingjuan Wang
- Tianjin Medical University General Hospital, Tianjin 300211, China; Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Shanyu Bao
- Tianjin Medical University General Hospital, Tianjin 300211, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Xiaolong Liu
- Tianjin Medical University General Hospital, Tianjin 300211, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Fan Wang
- Tianjin Medical University General Hospital, Tianjin 300211, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Jinwei Zhang
- Tianjin Medical University General Hospital, Tianjin 300211, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Pengyu Dang
- Tianjin Medical University General Hospital, Tianjin 300211, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Fengli Wang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
| | - Bin Li
- Tianjin Medical University General Hospital, Tianjin 300211, China; Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
| | - Yi Lin
- Tianjin Medical University General Hospital, Tianjin 300211, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| |
Collapse
|
|
6
|
Gao Z, Li Z, Deng R, Liu Q, Xiao Q, Han J, Pu C, Zhang Y. Dexmedetomidine improves postoperative neurocognitive disorder after cardiopulmonary bypass in rats. Neurol Res 2021; 43:164-172. [PMID: 33076786 DOI: 10.1080/01616412.2020.1833154] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 09/30/2020] [Indexed: 10/23/2022]
Abstract
PURPOSE To investigate whether dexmedetomidine can improve postoperative neurocognitive function after cardiopulmonary bypass in rats. METHODS A total of 45 male Sprague Dawley (SD) rats were randomly divided into sham group, control group, and dexmedetomidine (Dex) group. The rats in the sham group received skin excision and blood vessel ligation treatment, rats in the control group received cardiopulmonary bypass (CPB), and rats in the Dex group received CPB and Dex treatment. Morris water maze test and open-field tests were used to evaluate the rats' cognition. The expression of inflammatory mediators in the rats' central and peripheral regions, Aβ and Tau in the hippocampus and prefrontal cortex, and apoptosis in brain tissue were measured. RESULTS The CPB model rats were found to have significantly decreased cognitive function, increased expression of caspase-3 and Bax in the prefrontal cortex and hippocampus DG, increased apoptosis and activated microglia, and increased plasma levels of TNF-α, IL-6, and TNF-α. Dexmedetomidine reduced apoptosis in the prefrontal cortex and hippocampus DG region of rats, decreased the expression of caspase-3 and bax, inhibited microglia activation in the prefrontal cortex and hippocampus DG region of rats, and decreased the plasma levels of IL-β, IL-6, and TNF-α. CONCLUSIONS Dexmedetomidine plays a neuroprotective role by inhibiting inflammation, apoptosis, and microglia activation in the prefrontal cortex and hippocampal DG region, and attenuates the cognitive deficit identified in the control group.
Collapse
Affiliation(s)
- Zhiwei Gao
- Department of Anesthesiology, Hospital (T.C.M)) Affiliated to Southwest Medical University, Luzhou, Sichuan, China
| | - Zhengfen Li
- Department of Anesthesiology, Hospital (T.C.M)) Affiliated to Southwest Medical University, Luzhou, Sichuan, China
| | - Rui Deng
- Department of Anesthesiology, Hospital (T.C.M)) Affiliated to Southwest Medical University, Luzhou, Sichuan, China
| | - Qing Liu
- Department of Anesthesiology, Hospital (T.C.M)) Affiliated to Southwest Medical University, Luzhou, Sichuan, China
| | - Qiuxia Xiao
- Department of Anesthesiology, Hospital (T.C.M)) Affiliated to Southwest Medical University, Luzhou, Sichuan, China
| | - Jiang Han
- Department of Anesthesiology, Hospital (T.C.M)) Affiliated to Southwest Medical University, Luzhou, Sichuan, China
| | - Cuixia Pu
- Department of Anesthesiology, Hospital (T.C.M)) Affiliated to Southwest Medical University, Luzhou, Sichuan, China
| | - Ying Zhang
- Department of Anesthesiology, Hospital (T.C.M)) Affiliated to Southwest Medical University, Luzhou, Sichuan, China
| |
Collapse
|
|
7
|
Janata A, Magnet IAM, Schreiber KL, Wilson CD, Stezoski JP, Janesko-Feldman K, Kochanek PM, Drabek T. Minocycline fails to improve neurologic and histologic outcome after ventricular fibrillation cardiac arrest in rats. World J Crit Care Med 2019; 8:106-119. [PMID: 31853446 PMCID: PMC6918046 DOI: 10.5492/wjccm.v8.i7.106] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 09/17/2019] [Accepted: 10/27/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Prolonged cardiac arrest (CA) produces extensive neuronal death and microglial proliferation and activation resulting in neuro-cognitive disabilities. Among other potential mechanisms, microglia have been implicated as triggers of neuronal death after hypoxic-ischemic insults. Minocycline is neuroprotective in some brain ischemia models, either by blunting the microglial response or by a direct effect on neurons. AIM To improve survival, attenuate neurologic deficits, neuroinflammation, and histological damage after ventricular fibrillation (VF) CA in rats. METHODS Adult male isoflurane-anesthetized rats were subjected to 6 min VF CA followed by 2 min resuscitation including chest compression, epinephrine, bicarbonate, and defibrillation. After return of spontaneous circulation (ROSC), rats were randomized to two groups: (1) Minocycline 90 mg/kg intraperitoneally (i.p.) at 15 min ROSC, followed by 22.5 mg/kg i.p. every 12 h for 72 h; and (2) Controls, receiving the same volume of vehicle (phosphate-buffered saline). The rats were kept normothermic during the postoperative course. Neurologic injury was assessed daily using Overall Performance Category (OPC; 1 = normal, 5 = dead) and Neurologic Deficit Score (NDS; 0% = normal, 100% = dead). Rats were sacrificed at 72 h. Neuronal degeneration (Fluoro-Jade C staining) and microglia proliferation (anti-Iba-1 staining) were quantified in four selectively vulnerable brain regions (hippocampus, striatum, cerebellum, cortex) by three independent reviewers masked to the group assignment. RESULTS In the minocycline group, 8 out of 14 rats survived to 72 h compared to 8 out of 19 rats in the control group (P = 0.46). The degree of neurologic deficit at 72 h [median, (interquartile range)] was not different between survivors in minocycline vs controls: OPC 1.5 (1-2.75) vs 2 (1.25-3), P = 0.442; NDS 12 (2-20) vs 17 (7-51), P = 0.328) or between all studied rats. The number of degenerating neurons (minocycline vs controls, mean ± SEM: Hippocampus 58 ± 8 vs 76 ± 8; striatum 121 ± 43 vs 153 ± 32; cerebellum 20 ± 7 vs 22 ± 8; cortex 0 ± 0 vs 0 ± 0) or proliferating microglia (hippocampus 157 ± 15 vs 193 cortex 0 ± 0 vs 0 ± 0; 16; striatum 150 ± 22 vs 161 ± 23; cerebellum 20 ± 7 vs 22 ± 8; cortex 26 ± 6 vs 31 ± 7) was not different between groups in any region (all P > 0.05). Numerically, there were approximately 20% less degenerating neurons and proliferating microglia in the hippocampus and striatum in the minocycline group, with a consistent pattern of histological damage across the individual regions of interest. CONCLUSION Minocycline did not improve survival and failed to confer substantial benefits on neurologic function, neuronal loss or microglial proliferation across multiple brain regions in our model of rat VF CA.
Collapse
Affiliation(s)
- Andreas Janata
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
- Emergency Department, KA Rudolfstiftung, Vienna 1030, Austria
| | - Ingrid AM Magnet
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
- Department of Emergency Medicine, Vienna General Hospital, Medical University of Vienna, Vienna 1090, Austria
| | - Kristin L Schreiber
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, United States
| | - Caleb D Wilson
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
- Wyoming Otolaryngology, Wyoming Medical Center, Casper, WY 82604, United States
| | - Jason P Stezoski
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
| | - Keri Janesko-Feldman
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
| | - Patrick M Kochanek
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
| | - Tomas Drabek
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
| |
Collapse
|
|
8
|
Elbassuoni EA, Ragy MM, Ahmed SM. Evidence of the protective effect of l-arginine and vitamin D against monosodium glutamate-induced liver and kidney dysfunction in rats. Biomed Pharmacother 2018; 108:799-808. [DOI: 10.1016/j.biopha.2018.09.093] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 09/13/2018] [Accepted: 09/16/2018] [Indexed: 12/28/2022] Open
|
|
9
|
Neuregulin 1 Attenuates Neuronal Apoptosis Induced by Deep Hypothermic Circulatory Arrest Through ErbB4 Signaling in Rats. J Cardiovasc Pharmacol 2016; 66:551-7. [PMID: 26647012 DOI: 10.1097/fjc.0000000000000303] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Mounting evidence suggests that neurological injury occurs after deep hypothermic circulatory arrest (DHCA), a protocol widely used in surgery for congenital heart diseases and aortic repair. Neuregulin 1 (NRG1), a neurotrophic factor highly expressed in the central nervous system, is crucial for neuronal survival. However, whether NRG1 is protective against apoptosis induced by DHCA is still unclear, as are the putative mechanisms involved. In this study, exogenous human NRG1 pretreatment (2.5 and 3.75 ng/kg, intracarotid injection) significantly inhibited neuronal apoptosis in DHCA-treated male rats, and notably, endogenous NRG1 expression was also increased. Bcl-2, as well as phosphorylated phosphatidylinositol-3-kinase, Akt, and cAMP-response element binding protein, were all increased, resulting in phosphorylation and subsequent activation of the ErbB4 receptor. Finally, expression of the apoptosis-related protein cleaved-caspase-3 was decreased, resulting in the inhibition of neuronal apoptosis induced by DHCA. Thus, our data indicate that NRG1 treatment inhibited DHCA-induced neuronal apoptosis by activating ErbB4 signaling, providing a potential therapeutic pathway for the prevention of neurological injury induced by DHCA.
Collapse
|
|
10
|
Li M, Song S, Li S, Feng J, Hua Z. The Blockade of NF-κB Activation by a Specific Inhibitory Peptide Has a Strong Neuroprotective Role in a Sprague-Dawley Rat Kernicterus Model. J Biol Chem 2015; 290:30042-52. [PMID: 26499797 DOI: 10.1074/jbc.m115.673525] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Indexed: 12/22/2022] Open
Abstract
Kernicterus, the permanent nerve damage occurring as a result of bilirubin precipitation, still occurs worldwide and may lead to death or permanent neurological impairments. However, the underlying mechanisms remain unclear, and effective therapeutic strategies are lacking. The present study aims to investigate the activation of NF-κB and to identify the effect of NF-κB inhibition on the newborn rat kernicterus model. The NF-κB essential modifier-binding domain peptide (NBD), coupled with the HIV trans-activator of transcription peptide (TAT) was used to inhibit NF-κB. NF-κB was significantly activated in the cerebrum at 1 and 3 h (p < 0.05) after the model was established, as measured by EMSA. NF-κB activation was inhibited by intraperitoneal administration of TAT-NBD. The general conditions of the TAT-NBD-treated rats were improved; meanwhile, these rats performed much better on the neurological evaluation, the rotarod test, and the Morris water maze test (p < 0.05) than the vehicle-treated rats at 28 days. Furthermore, the morphology of the nerve cells was better preserved in the TAT-NBD group, and these cells displayed less neurodegeneration and astrocytosis. Simultaneously, apoptosis in the brain was attenuated, and the levels of the TNF-α and IL-1β proteins were decreased (p < 0.01). These results suggested that NF-κB was activated, and inhibition of NF-κB activation by TAT-NBD not only attenuated the acute neurotoxicity, apoptosis, and inflammation, but also improved the long term neurobehavioral impairments in the kernicterus model rats in vivo. Thus, inhibiting NF-κB activation might be a potential therapeutic approach for kernicterus.
Collapse
Affiliation(s)
- Mengwen Li
- From the Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, 400000, China, the Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400000, China, the Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, 400000, China
| | - Sijie Song
- From the Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, 400000, China, the Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400000, China, the Key Laboratory of Pediatrics in Chongqing, Chongqing, 400000, China, and
| | - Shengjun Li
- From the Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, 400000, China, the Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400000, China
| | - Jie Feng
- From the Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, 400000, China, the Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400000, China
| | - Ziyu Hua
- From the Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, 400000, China, the Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400000, China, the Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400000, China
| |
Collapse
|
|
11
|
Antibiotic-induced imbalances in gut microbiota aggravates cholesterol accumulation and liver injuries in rats fed a high-cholesterol diet. Appl Microbiol Biotechnol 2015; 99:9111-22. [PMID: 26129950 DOI: 10.1007/s00253-015-6753-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 06/02/2015] [Accepted: 06/05/2015] [Indexed: 01/12/2023]
Abstract
Increasing evidence suggests that maintenance of homeostasis between gut microbiota and host plays an important role in human health. Many diseases, such as those affecting the liver, have been linked to imbalances in gut microbial communities. However, it is not clear whether an imbalance in gut microbiota promotes the onset of liver injury or if the imbalance results from the pathological state. In the current study, antibiotics were used to disturb the gut microbiota of both rats fed a high-cholesterol diet and rats fed a normal diet (controls). The prevalence of Bacteroidetes and Firmicutes were reduced, and Proteobacteria was greatly increased in the guts of rats after antibiotic treatment. The antibiotic-induced perturbation of gut microbiota aggravated cholesterol accumulation and liver injury in rats fed a high-cholesterol diet. This may have been due to an increase in intestinal permeability and plasma lipopolysaccharide (LPS), which lead to an increase in LPS absorption and activation of TLR4 signaling, resulting in the synthesis of pro-inflammatory cytokines and chemokines in liver tissues. This study suggests that imbalances in gut microbiota may be a predisposing factor for the onset of metabolic diseases and liver injuries related to cholesterol and high-cholesterol diets. Modulation of gut microbiota could be a novel target for preventing cholesterol-related metabolic disorders.
Collapse
|
|
12
|
Ida KK, Otsuki DA, Sasaki ATC, Borges ES, Castro LUC, Sanches TR, Shimizu MHM, Andrade LC, Auler JOC, Dyson A, Smith KJ, Rocha Filho JA, Malbouisson LMS. Effects of terlipressin as early treatment for protection of brain in a model of haemorrhagic shock. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2015; 19:107. [PMID: 25888229 PMCID: PMC4373118 DOI: 10.1186/s13054-015-0825-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Accepted: 02/19/2015] [Indexed: 01/01/2023]
Abstract
Introduction We investigated whether treatment with terlipressin during recovery from hypotension due to haemorrhagic shock (HS) is effective in restoring cerebral perfusion pressure (CPP) and brain tissue markers of water balance, oxidative stress and apoptosis. Methods In this randomised controlled study, animals undergoing HS (target mean arterial pressure (MAP) 40 mmHg for 30 minutes) were randomised to receive lactated Ringer’s solution (LR group; n =14; volume equal to three times the volume bled), terlipressin (TERLI group; n =14; 2-mg bolus), no treatment (HAEMO group; n =12) or sham (n =6). CPP, systemic haemodynamics (thermodilution technique) and blood gas analyses were registered at baseline, shock and 5, 30, 60 (T60), 90 and 120 minutes after treatment (T120). After the animals were killed, brain tissue samples were obtained to measure markers of water balance (aquaporin-4 (AQP4)), Na+-K+-2Cl− co-transporter (NKCC1)), oxidative stress (thiobarbituric acid reactive substances (TBARS) and manganese superoxide dismutase (MnSOD)) and apoptotic damage (Bcl-x and Bax). Results Despite the HS-induced decrease in cardiac output (CO) and hyperlactataemia, resuscitation with terlipressin recovered MAP and resulted in restoration of CPP and in cerebral protection expressed by normalisation of AQP4, NKCC1, TBARS and MnSOD expression and Bcl-x/Bax ratio at T60 and T120 compared with sham animals. In the LR group, CO and blood lactate levels were recovered, but the CPP and MAP were significantly decreased and TBARS levels and AQP4, NKCC1 and MnSOD expression and Bcl-x/Bax ratio were significantly increased at T60 and T120 compared with the sham group. Conclusions During recovery from HS-induced hypotension, terlipressin was effective in normalising CPP and cerebral markers of water balance, oxidative damage and apoptosis. The role of this pressor agent on brain perfusion in HS requires further investigation.
Collapse
Affiliation(s)
- Keila Kazue Ida
- Laboratório de Investigação Médica (LIM-08), Disciplina de Anestesiologia, Faculdade de Medicina, Universidade de São Paulo, Avenida Doutor Arnaldo, 455, 2° andar, sala 2120, Cerqueira César, São Paulo, SP, 01246-903, Brazil. .,Department of Neuroinflammation, Institute of Neurology, University College London (UCL), 1 Wakefield Street, 2nd floor, WC1N 1PJ, London, UK.
| | - Denise Aya Otsuki
- Laboratório de Investigação Médica (LIM-08), Disciplina de Anestesiologia, Faculdade de Medicina, Universidade de São Paulo, Avenida Doutor Arnaldo, 455, 2° andar, sala 2120, Cerqueira César, São Paulo, SP, 01246-903, Brazil.
| | - Adolfo Toshiro Cotarelli Sasaki
- Laboratório de Investigação Médica (LIM-08), Disciplina de Anestesiologia, Faculdade de Medicina, Universidade de São Paulo, Avenida Doutor Arnaldo, 455, 2° andar, sala 2120, Cerqueira César, São Paulo, SP, 01246-903, Brazil.
| | - Emilyn Silva Borges
- Laboratório de Investigação Médica (LIM-08), Disciplina de Anestesiologia, Faculdade de Medicina, Universidade de São Paulo, Avenida Doutor Arnaldo, 455, 2° andar, sala 2120, Cerqueira César, São Paulo, SP, 01246-903, Brazil.
| | - Letícia Urbano Cardoso Castro
- Disciplina de Nefrologia, Faculdade de Medicina, Universidade de São Paulo (LIM-12 HC-FMUSP), Avenida Doutor Arnaldo, 455, 3rd floor, Cerqueira César, São Paulo, SP, 01246-903, Brazil.
| | - Talita Rojas Sanches
- Disciplina de Nefrologia, Faculdade de Medicina, Universidade de São Paulo (LIM-12 HC-FMUSP), Avenida Doutor Arnaldo, 455, 3rd floor, Cerqueira César, São Paulo, SP, 01246-903, Brazil.
| | - Maria-Heloisa Massola Shimizu
- Disciplina de Nefrologia, Faculdade de Medicina, Universidade de São Paulo (LIM-12 HC-FMUSP), Avenida Doutor Arnaldo, 455, 3rd floor, Cerqueira César, São Paulo, SP, 01246-903, Brazil.
| | - Lúcia Conceição Andrade
- Disciplina de Nefrologia, Faculdade de Medicina, Universidade de São Paulo (LIM-12 HC-FMUSP), Avenida Doutor Arnaldo, 455, 3rd floor, Cerqueira César, São Paulo, SP, 01246-903, Brazil.
| | - José-Otávio Costa Auler
- Laboratório de Investigação Médica (LIM-08), Disciplina de Anestesiologia, Faculdade de Medicina, Universidade de São Paulo, Avenida Doutor Arnaldo, 455, 2° andar, sala 2120, Cerqueira César, São Paulo, SP, 01246-903, Brazil.
| | - Alex Dyson
- Division of Medicine, University College London (UCL), Gower Street, WC1E 6BT, London, UK.
| | - Kenneth John Smith
- Department of Neuroinflammation, Institute of Neurology, University College London (UCL), 1 Wakefield Street, 2nd floor, WC1N 1PJ, London, UK.
| | - Joel Avancini Rocha Filho
- Divisão de Anestesiologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), Av. Dr. Enéas de Carvalho Aguiar,155, 8th floor, 05403-000, São Paulo, SP, Brazil.
| | - Luiz-Marcelo Sá Malbouisson
- Laboratório de Investigação Médica (LIM-08), Disciplina de Anestesiologia, Faculdade de Medicina, Universidade de São Paulo, Avenida Doutor Arnaldo, 455, 2° andar, sala 2120, Cerqueira César, São Paulo, SP, 01246-903, Brazil.
| |
Collapse
|
|
13
|
Salameh A, Einenkel A, Kühne L, Grassl M, von Salisch S, Kiefer P, Vollroth M, Dähnert I, Dhein S. Hippocampal Neuroprotection by Minocycline and Epigallo-Catechin-3-Gallate Against Cardiopulmonary Bypass-Associated Injury. Brain Pathol 2015; 25:733-42. [PMID: 25582287 DOI: 10.1111/bpa.12242] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 12/17/2014] [Indexed: 02/05/2023] Open
Abstract
Surgical correction of congenital cardiac malformations mostly implies the use of cardiopulmonary bypass (CPB). However, a possible negative impact of CPB on cerebral structures like the hippocampus cannot be neglected. Therefore, we investigated the effect of CPB on hippocampus CA1 and CA3 regions without or with the addition of epigallocatechin-3-gallate (EGCG) or minocycline. We studied 42 piglets and divided them into six experimental groups: control without or with EGCG or minocycline, CPB without or with EGCG or minocycline. The piglets underwent 90 minutes CPB and subsequently, a 120-minute recovery and reperfusion phase. Thereafter, histology of the hippocampus was performed and the adenosine triphosphate (ATP) content was measured. Histologic evaluation revealed that CPB produced a significant peri-cellular edema in both CA regions. Moreover, we found an increased number of cells stained with markers for hypoxia, apoptosis and nitrosative stress. Most of these alterations were significantly reduced to or near to control levels by application of EGCG or minocycline. ATP content was significantly reduced within the hippocampus after CPB. This reduction could not be antagonized by EGCG or minocycline. In conclusion, CPB had a significant negative impact on the integrity of hippocampal neural cells. This cellular damage could be significantly attenuated by addition of EGCG or minocycline.
Collapse
Affiliation(s)
- Aida Salameh
- Clinic for Pediatric Cardiology, University of Leipzig, Heart Centre, Leipzig, Germany
| | - Anne Einenkel
- Clinic for Pediatric Cardiology, University of Leipzig, Heart Centre, Leipzig, Germany
| | - Lydia Kühne
- Clinic for Pediatric Cardiology, University of Leipzig, Heart Centre, Leipzig, Germany
| | - Maria Grassl
- Clinic for Pediatric Cardiology, University of Leipzig, Heart Centre, Leipzig, Germany
| | - Sandy von Salisch
- Clinic for Cardiac Surgery, University of Leipzig, Heart Centre, Leipzig, Germany
| | - Phillip Kiefer
- Clinic for Cardiac Surgery, University of Leipzig, Heart Centre, Leipzig, Germany
| | - Marcel Vollroth
- Clinic for Cardiac Surgery, University of Leipzig, Heart Centre, Leipzig, Germany
| | - Ingo Dähnert
- Clinic for Pediatric Cardiology, University of Leipzig, Heart Centre, Leipzig, Germany
| | - Stefan Dhein
- Clinic for Cardiac Surgery, University of Leipzig, Heart Centre, Leipzig, Germany
| |
Collapse
|
|
14
|
Dixit S, Dhar P, Mehra RD. Alpha lipoic acid (ALA) modulates expression of apoptosis associated proteins in hippocampus of rats exposed during postnatal period to sodium arsenite (NaAsO 2). Toxicol Rep 2015; 2:78-87. [PMID: 28962340 PMCID: PMC5598373 DOI: 10.1016/j.toxrep.2015.01.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Revised: 01/20/2015] [Accepted: 01/20/2015] [Indexed: 12/15/2022] Open
Abstract
The present study focused on the role of exogenous alpha lipoic acid (ALA) in amelioration of inorganic arsenic (iAs) induced effects on apoptosis and apoptosis associated proteins in developing rat hippocampus. NaAsO2 (1.5/2.0 mg/kg bw) alone or along with ALA (70 mg/kg bw) was administered to rat pups (experimental groups) by intraperitoneal (i.p.) route from postnatal day (PND) 4-15. Controls received no treatment/distilled water/ALA. On PND 16, the animals were perfusion fixed and the brains were processed for paraffin embedding (CV and TUNEL staining) and cryopreservation (immunohistochemistry). The fresh brain tissue was used for Western blotting. Significant increase was observed in TUNEL positive cells and Bax (pro-apoptotic protein) expression in hippocampal sub-regions of iAs alone treated groups, whereas Bcl-2 expression was intensified in animals receiving ALA with iAs. Densitometric analysis (Western blots) revealed optimal restoration of Bax and Bcl-2 ratio in animals receiving ALA with iAs, thereby suggesting the protective role of ALA in iAs induced developmental neurotoxicity.
Collapse
Key Words
- ALA, alpha lipoic acid
- Arsenic (iAs)
- Bax
- Bcl-2
- CA1, CA2, CA3, cornu amonis subregions
- CV, cresyl violet
- DG, dentate gyrus
- Hippocampus
- Na2AsO2, sodium arsenite
- Oxidative stress
- PND, post natal day
- TUNEL, TdT mediated dUTP biotin nick-end labeling
- i.p., intraperitoneal
- iAs, arsenic
- α-Lipoic acid (ALA)
Collapse
Affiliation(s)
| | - Pushpa Dhar
- Department of Anatomy, All India Institute of Medical Sciences, New Delhi 110029, India
| | | |
Collapse
|
|
15
|
Evaluation of neuronal apoptosis precursors in an experimental model of acute normovolemic hemodilution. PLoS One 2014; 9:e108366. [PMID: 25254661 PMCID: PMC4177928 DOI: 10.1371/journal.pone.0108366] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 08/21/2014] [Indexed: 11/19/2022] Open
Abstract
Background The effects of acute anemia on neuronal cells and the safe limits of hematocrit are not well established. The objective of this study was to evaluate neuronal pro- and anti-apoptotic Bax and Bcl-x proteins, caspase-3 and -9 activity, and DNA fragmentation after acute normovolemic hemodilution (ANH). Methods Twenty-four pigs were anesthetized and randomized into 4 groups: Sham, ANH to 15% hematocrit (ANH15%), ANH to 10% hematocrit (ANH10%) and hypoxia (Hx). ANH was achieved by simultaneous blood withdrawal and hydroxyethyl starch infusion. Hx consisted of ventilation with a 6% inspired oxygen fraction for 60 minutes. Bax and Bcl-x proteins as well as DNA fragmentation were evaluated in cortical nuclear and mitochondrial fractions. Caspase-3 and -9 activity was evaluated in the cortical mitochondrial and hippocampal cytosolic fractions. The data were compared using analysis of variance followed by Tukey’s test (P<0.05). Results No changes were observed in Bax protein expression after hemodilution in the ANH15% and ANH10% groups compared to the Sham group. Bax expression in the Hx group was increased in the nuclear and mitochondrial fractions compared to all other groups. No significant difference was observed in Bcl-x expression. Caspase-3 and -9 activity in the cytosolic and mitochondrial fractions was different in the Hx group compared to all other groups. No statistical significance in DNA fragmentation was found among the Sham, ANH15% or ANH10% groups. Conclusion ANH to 10 and 15% hematocrit did not induce alterations in apoptosis precursors, suggesting that cerebral oxygenation was preserved during these anemic states.
Collapse
|
|
16
|
Song S, Hu Y, Gu X, Si F, Hua Z. A novel newborn rat kernicterus model created by injecting a bilirubin solution into the cisterna magna. PLoS One 2014; 9:e96171. [PMID: 24796550 PMCID: PMC4010446 DOI: 10.1371/journal.pone.0096171] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Accepted: 04/03/2014] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Kernicterus still occurs around the world; however, the mechanism of bilirubin neurotoxicity remains unclear, and effective treatment strategies are lacking. To solve these problems, several kernicterus (or acute bilirubin encephalopathy) animal models have been established, but these models are difficult and expensive. Therefore, the present study was performed to establish a novel kernicterus model that is simple and affordable by injecting unconjugated bilirubin solution into the cisterna magna (CM) of ordinary newborn Sprague-Dawley (SD) rats. METHODS On postnatal day 5, SD rat pups were randomly divided into bilirubin and control groups. Then, either bilirubin solution or ddH2O (pH = 8.5) was injected into the CM at 10 µg/g (bodyweight). For model characterization, neurobehavioral outcomes were observed, mortality was calculated, and bodyweight was recorded after bilirubin injection and weaning. Apoptosis in the hippocampus was detected by H&E staining, TUNEL, flow cytometry and Western blotting. When the rats were 28 days old, learning and memory ability were evaluated using the Morris water maze test. RESULTS The bilirubin-treated rats showed apparently abnormal neurological manifestations, such as clenched fists, opisthotonos and torsion spasms. Bodyweight gain in the bilirubin-treated rats was significantly lower than that in the controls (P<0.001). The early and late mortality of the bilirubin-treated rats were both dramatically higher than those of the controls (P = 0.004 and 0.017, respectively). Apoptosis and necrosis in the hippocampal nerve cells in the bilirubin-treated rats were observed. The bilirubin-treated rats performed worse than the controls on the Morris water maze test. CONCLUSION By injecting bilirubin into the CM, we successfully created a new kernicterus model using ordinary SD rats; the model mimics both the acute clinical manifestations and the chronic sequelae. In particular, CM injection is easy to perform; thus, more stable models for follow-up study are available.
Collapse
Affiliation(s)
- Sijie Song
- Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing Medical University, Chongqing, China
- Key Laboratory of Pediatrics in Chongqing, Chongqing Medical University, Chongqing, China
- Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Children's Hospital, Chongqing Medical University, Chongqing, China
| | - Ying Hu
- Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, China
- Department of Pediatrics, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Xianfang Gu
- Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, China
- Department of Neonatology, Children's Hospital of Kaifeng, Henan, China
| | - Feifei Si
- Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing Medical University, Chongqing, China
- Key Laboratory of Pediatrics in Chongqing, Chongqing Medical University, Chongqing, China
- Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Children's Hospital, Chongqing Medical University, Chongqing, China
| | - Ziyu Hua
- Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing Medical University, Chongqing, China
- Key Laboratory of Pediatrics in Chongqing, Chongqing Medical University, Chongqing, China
- Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Children's Hospital, Chongqing Medical University, Chongqing, China
- * E-mail:
| |
Collapse
|
|
17
|
Yuan L, Su D, Liu X, Lu H, Li Y, Tong S. Cerebral blood flow changes during rat cardiopulmonary bypass and deep hypothermic circulatory arrest model: a preliminary study. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2013; 2013:1807-10. [PMID: 24110060 DOI: 10.1109/embc.2013.6609873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) are important techniques often used in complex cardiac surgery for neonates and infants heart diseases. Cerebral blood flow (CBF) serves as an important physiological parameter and provides valuable hemodynamic information during the surgery. Laser speckle imaging (LSI), as an optical imaging technique, can provide full-field CBF information with a high spatiotemporal resolution. In this preliminary study, we acquired the real-time CBF images with a self-developed miniaturized head-mounted LSI system during the whole CPBillHCA rat model. Relative CBF velocity in veins and arteries in bilateral hemispheres dropped significantly during cooling period and reached to nearly zero during arrest period (n = 5). More interestingly, two rats showing more dramatic CBF variations in veins than in arteries during cooling period exhibited severe cerebral edema after surgery. The real-time full-field CBF imaging during the CPBillHCA surgery could add more insights into the operation and be utilized to study the surgical protocols with the ultimate goal ofreducing neurologic injury after surgery.
Collapse
|
|
18
|
Wang X, Xue Q, Yan F, Li L, Liu J, Li S, Hu S. Ulinastatin as a neuroprotective and anti-inflammatory agent in infant piglets model undergoing surgery on hypothermic low-flow cardiopulmonary bypass. Paediatr Anaesth 2013; 23:209-16. [PMID: 23384299 DOI: 10.1111/pan.12073] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/02/2012] [Indexed: 11/27/2022]
Abstract
OBJECTIVE Infants are potentially more susceptible to brain injury mediated via cell death attributed to cardiopulmonary bypass (CPB) especially with prolonged hypothermic low flow (HLF). We hypothesized that a human urinary protease inhibitor (ulinastatin), by its anti-inflammatory effect, would reduce central nervous system (CNS) injury during HLF. METHODS Fifteen general-type infant piglets were randomized to ulinastatin group (group U, n = 5), control group (group C, n = 5), and sham operation group (group S, n = 5). Routine CPB was established after median thoracotomy in group U and C under anesthesia. When the temperature of infant piglets dropped down to 25 °C, low-flow CPB (50 ml·kg(-1) ·min(-1) ) was instituted. After 120 min of aortic cross-clamping and 20- to 30-min rewarming, the aortic cross-clamp was removed and finally the piglet was weaned from CPB. Five thousand units per killogram of ulinastatin and equivalently normal saline were, respectively, given at the beginning of and at aortic declamping in group U and group C. group S just received sham median thoracotomy. Venous blood samples were taken immediately after anesthesia induction in all three groups, 5- and 120-min post CPB in both group U and C, respectively; plasma markers of inflammation and CNS injury were compared. Pathology results of hippocampus were observed by light microscopy. RESULTS Statistically significant differences between group C and U were noted in the expression of inflammatory markers such as IL-10, TNF-α and neuron-specific enolase at 120-min post CPB. Brain injuries were observed in both groups (index cases and controls) and were milder in group U. CONCLUSIONS In our study, HLF CPB on infant piglets resulted in brain injury, and ulinastatin might reduce the extent of such injury.
Collapse
Affiliation(s)
- Xiaocou Wang
- Department of Anesthesiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | | | | | | | | | | | | |
Collapse
|
|
19
|
Effect of streptozotocin-induced diabetes mellitus on the cerebellar cortex of adult male albino rats. ACTA ACUST UNITED AC 2013. [DOI: 10.1097/01.ehx.0000424090.98199.b8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
|
|
20
|
Raveendran AT, Skaria PC. Learning and Cognitive Deficits in Hypoxic Neonatal Rats Intensified by BAX Mediated Apoptosis: Protective Role of Glucose, Oxygen, and Epinephrine. Int J Neurosci 2012; 123:80-8. [DOI: 10.3109/00207454.2012.731457] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
|
|
21
|
Pastuszko P, Schears GJ, Pirzadeh A, Kubin J, Greeley WJ, Wilson DF, Pastuszko A. Effect of granulocyte-colony stimulating factor on expression of selected proteins involved in regulation of apoptosis in the brain of newborn piglets after cardiopulmonary bypass and deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg 2012; 143:1436-42. [PMID: 22306220 DOI: 10.1016/j.jtcvs.2012.01.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Revised: 09/08/2011] [Accepted: 01/04/2012] [Indexed: 02/02/2023]
Abstract
OBJECTIVE The study objective was to investigate the effect of granulocyte-colony stimulating factor on the expression of proteins that regulate apoptosis in newborn piglet brain after cardiopulmonary bypass and deep hypothermic circulatory arrest. METHODS The newborn piglets were assigned to 3 groups: (1) deep hypothermic circulatory arrest (30 minutes of deep hypothermic circulatory arrest, 1 hour of low-flow cardiopulmonary bypass); (2) deep hypothermic circulatory arrest with prior injection of granulocyte-colony stimulating factor (17 μg/kg 2 hours before cardiopulmonary bypass); and (3) sham-operated. After 2 hours of post-bypass recovery, the frontal cortex, striatum, and hippocampus were dissected. The expression of proteins was measured by gel electrophoresis or protein arrays. Data are presented in arbitrary units. Statistical analysis was performed using 1-way analysis of variance. RESULTS In the frontal cortex, only Fas ligand expression was significantly lower in the granulocyte-colony stimulating factor group when compared with the deep hypothermic circulatory arrest group. In the hippocampus, granulocyte-colony stimulating factor increased Bcl-2 (54.3 ± 6.4 vs 32.3 ± 2.2, P = .001) and serine/threonine-specific protein kinase (141.4 ± 19 vs 95.9 ± 21.1, P = .047) when compared with deep hypothermic circulatory arrest group. Caspase-3, Bax, Fas, Fas ligand, death receptor 6, and Janus protein tyrosine kinase 2 levels were unchanged. The Bcl-2/Bax ratio was 0.33 for deep hypothermic circulatory arrest group and 0.93 for the granulocyte-colony stimulating factor group (P = .02). In the striatum, when compared with the deep hypothermic circulatory arrest group, the granulocyte-colony stimulating factor group had higher levels of Bcl-2 (50.3 ± 7.4 vs 31.8 ± 3.8, P = .01), serine/threonine-specific protein kinase (132.7 ± 12.3 vs 14 ± 1.34, P = 2.3 × 10(6)), and Janus protein tyrosine kinase 2 (126 ± 17.4 vs 77.9 ± 13.6, P = .011), and lower levels of caspase-3 (12.8 ± 5.0 vs 32.2 ± 11.5, P = .033), Fas (390 ± 31 vs 581 ± 74, P = .038), Fas ligand (20.5 ± 11.5 vs 57.8 ± 15.6, P = .04), and death receptor 6 (57.4 ± 4.4 vs 108.8 ± 13.4, P = .007). The Bcl-2/Bax ratio was 0.25 for deep hypothermic circulatory arrest and 0.44 for the granulocyte-colony stimulating factor groups (P = .046). CONCLUSIONS In the piglet model of hypoxic brain injury, granulocyte-colony stimulating factor decreases proapoptotic signaling, particularly in the striatum.
Collapse
Affiliation(s)
- Peter Pastuszko
- Department of Surgery, University of California, San Diego, CA 92123, USA.
| | | | | | | | | | | | | |
Collapse
|
|
22
|
Allen JG, Weiss ES, Wilson MA, Arnaoutakis GJ, Blue ME, Talbot CC, Jie C, Lange MS, Troncoso JC, Johnston MV, Baumgartner WA. Hawley H. Seiler Resident Award. Transcriptional profile of brain injury in hypothermic circulatory arrest and cardiopulmonary bypass. Ann Thorac Surg 2010; 89:1965-71. [PMID: 20494057 PMCID: PMC3031914 DOI: 10.1016/j.athoracsur.2010.02.051] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2009] [Revised: 02/11/2010] [Accepted: 02/12/2010] [Indexed: 11/21/2022]
Abstract
BACKGROUND Little is known about the molecular mechanisms of neurologic complications after hypothermic circulatory arrest (HCA) with cardiopulmonary bypass (CPB). Canine genome sequencing allows profiling of genomic changes after HCA and CPB alone. We hypothesize that gene regulation will increase with increased severity of injury. METHODS Dogs underwent 2-hour HCA at 18 degrees C (n = 10), 1-hour HCA (n = 8), or 2-hour CPB at 32 degrees C alone (n = 8). In each group, half were sacrificed at 8 hours and half at 24 hours after treatment. After neurologic scoring, brains were harvested for genomic analysis. Hippocampal RNA isolates were analyzed using canine oligonucleotide expression arrays containing 42,028 probes. RESULTS Consistent with prior work, dogs that underwent 2-hour HCA experienced severe neurologic injury. One hour of HCA caused intermediate clinical damage. Cardiopulmonary bypass alone yielded normal clinical scores. Cardiopulmonary bypass, 1-hour HCA, and 2-hour HCA groups historically demonstrated increasing degrees of histopathologic damage (previously published). Exploratory analysis revealed differences in significantly regulated genes (false discovery rate < 10%, absolute fold change > or = 1.2), with increases in differential gene expression with injury severity. At 8 hours and 24 hours after insult, 2-hour HCA dogs had 502 and 1,057 genes regulated, respectively; 1-hour HCA dogs had 179 and 56 genes regulated; and CPB alone dogs had 5 and 0 genes regulated. CONCLUSIONS Our genomic profile of canine brains after HCA and CPB revealed 1-hour and 2-hour HCA induced markedly increased gene regulation, in contrast to the minimal effect of CPB alone. This adds to the body of neurologic literature supporting the safety of CPB alone and the minimal effect of CPB on a normal brain, while illuminating genomic results of both.
Collapse
Affiliation(s)
- Jeremiah G Allen
- Division of Cardiac Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Sharma K, Mehra RD. Long-term administration of estrogen or tamoxifen to ovariectomized rats affords neuroprotection to hippocampal neurons by modulating the expression of Bcl-2 and Bax. Brain Res 2008; 1204:1-15. [DOI: 10.1016/j.brainres.2008.01.080] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2007] [Revised: 01/17/2008] [Accepted: 01/23/2008] [Indexed: 10/22/2022]
|
|
24
|
Drabek T, Fisk JA, Dixon CE, Garman RH, Stezoski J, Wisnewski SR, Wu X, Tisherman SA, Kochanek PM. Prolonged deep hypothermic circulatory arrest in rats can be achieved without cognitive deficits. Life Sci 2007; 81:543-552. [PMID: 17658556 DOI: 10.1016/j.lfs.2007.06.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2007] [Revised: 06/11/2007] [Accepted: 06/16/2007] [Indexed: 02/07/2023]
Abstract
Cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) enable surgical repair of cardiovascular defects. However, neurological complications can result after both CPB and DHCA. We sought to investigate if 75 min of CPB or DHCA caused motor, cognitive or histological deficits in rats. Three groups were studied: DHCA, CPB, and sham. Rats in the DHCA group were subjected to 75 min DHCA at 15 degrees C, with a total CPB duration of 75 min. Rats in the CPB group were subjected to 75 min of normothermic CPB. Shams received the same anesthesia, cannulations and infusions. Motor function was assessed using beam testing on days 3-13. Cognitive performance was evaluated using Morris water maze tasks on days 7-13. Overall Performance Category (OPC) and Neurologic Deficit Score (NDS) were assessed daily. Histological Damage Score (HDS) was assessed in survivors on day 14. Sustained deficits on beam testing were seen only in the CPB group. Rats in the CPB and DHCA groups exhibited similar cognitive performance vs. sham. There were no differences in OPC or NDS between groups. Neuronal degeneration was present only in small foci in rats after DHCA (n=4/7). However, HDS was not different in individual brain regions or viscera between DHCA or CPB vs. sham. Surprisingly, CPB, but not DHCA was associated with motor deficits vs. sham, and no cognitive deficits were seen in either group vs. sham. Future studies with longer DHCA duration will be necessary to provide targets to assess novel preservation strategies.
Collapse
Affiliation(s)
- Tomas Drabek
- Safar Center for Resuscitation Research, University of Pittsburgh, School of Medicine, Pittsburgh PA 15260, USA.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Wang QS, Song F, Zhao X, Hou LY, Xie KQ. Expression changes of apoptotic-related proteins in nerve tissues of rats treated with allyl chloride. Toxicology 2006; 231:58-67. [PMID: 17194518 DOI: 10.1016/j.tox.2006.11.071] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2006] [Revised: 11/18/2006] [Accepted: 11/21/2006] [Indexed: 10/23/2022]
Abstract
Allyl chloride (AC) is widely used in industries as raw material and has been reported to produce occupational peripheral neuropathies in man chronically exposure to it. Although many studies have been done addressing to it, the mechanisms still remain unclear. To elucidate the molecular mechanism of neuropathy induced by AC, we measured the contents of glutathione (GSH), Bcl-2, Bax, cytochrome c (CytC) and Caspase-3 in a time-dependent manner by biochemical and quantitative immunoblotting techniques in rats' cerebrum and spinal cord after 3, 6, 9 and 12 weeks of AC intoxication. The results showed that the levels of Bcl-2 of cerebrum and spinal cord significantly (P<0.05) decreased after 9 and 6 weeks of AC intoxication, respectively, while GSH levels decreased after 12 week. However, the levels of Bax, CytC and Caspase-3 significantly (P<0.05) increased both in cerebrum and spinal cord. Bax levels of cerebrum and spinal cord increased after 12 and 9 weeks of AC administration, respectively. The levels of CytC and Caspase-3 also went up after 9 weeks of AC treatment in cerebrum and 9, 6 weeks in spinal cord, respectively. Thus, subchronic exposure to AC affected the expressions of apoptotic-related proteins in the central nervous system (CNS) and peripheral nervous system (PNS) tissues and the time dependent changes of these indexes occurred. The regulatory mechanism of apoptosis might be involved and served as one of mechanisms of toxic neuropathy induced by AC.
Collapse
Affiliation(s)
- Qing-Shan Wang
- Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan 250012, PR China
| | | | | | | | | |
Collapse
|