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Santiago-Castañeda C, Huerta de la Cruz S, Martínez-Aguirre C, Orozco-Suárez SA, Rocha L. Cannabidiol Reduces Short- and Long-Term High Glutamate Release after Severe Traumatic Brain Injury and Improves Functional Recovery. Pharmaceutics 2022; 14:pharmaceutics14081609. [PMID: 36015236 PMCID: PMC9414526 DOI: 10.3390/pharmaceutics14081609] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/16/2022] [Accepted: 07/29/2022] [Indexed: 12/04/2022] Open
Abstract
This study aimed to determine if orally administered cannabidiol (CBD) lessens the cortical over-release of glutamate induced by a severe traumatic brain injury (TBI) and facilitates functional recovery. The short-term experiment focused on identifying the optimal oral pretreatment of CBD. Male Wistar rats were pretreated with oral administration of CBD (50, 100, or 200 mg/kg) daily for 7 days. Then, extracellular glutamate concentration was estimated by cortical microdialysis before and immediately after a severe TBI. The long-term experiment focused on evaluating the effect of the optimal treatment of CBD (pre- vs. pre- and post-TBI) 30 days after trauma. Sensorimotor function, body weight, and mortality rate were evaluated. In the short term, TBI induced a high release of glutamate (738% ± 173%; p < 0.001 vs. basal). Oral pretreatment with CBD at all doses tested reduced glutamate concentration but with higher potency at when animals received 100 mg/kg (222 ± 33%, p < 0.01 vs. TBI), an effect associated with a lower mortality rate (22%, p < 0.001 vs. TBI). In the long-term experiment, the TBI group showed a high glutamate concentration (149% p < 0.01 vs. SHAM). In contrast, animals receiving the optimal treatment of CBD (pre- and pre/post-TBI) showed glutamate concentrations like the SHAM group (p > 0.05). This effect was associated with high sensorimotor function improvement. CBD pretreatment, but not pre-/post-treatment, induced a higher body weight gain (39% ± 2.7%, p < 0.01 vs. TBI) and lower mortality rate (22%, p < 0.01 vs. TBI). These results support that orally administered CBD reduces short- and long-term TBI-induced excitotoxicity and facilitated functional recovery. Indeed, pretreatment with CBD was sufficient to lessen the adverse sequelae of TBI.
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Affiliation(s)
- Cindy Santiago-Castañeda
- Department of Pharmacobiology, Center for Research and Advanced Studies (CINVESTAV), Mexico City 14330, Mexico; (C.S.-C.); (S.H.d.l.C.); (C.M.-A.)
| | - Saúl Huerta de la Cruz
- Department of Pharmacobiology, Center for Research and Advanced Studies (CINVESTAV), Mexico City 14330, Mexico; (C.S.-C.); (S.H.d.l.C.); (C.M.-A.)
| | - Christopher Martínez-Aguirre
- Department of Pharmacobiology, Center for Research and Advanced Studies (CINVESTAV), Mexico City 14330, Mexico; (C.S.-C.); (S.H.d.l.C.); (C.M.-A.)
| | - Sandra Adela Orozco-Suárez
- Unit for Medical Research in Neurological Diseases, Specialties Hospital, National Medical Center SXXI (CMN-SXXI), Mexico City 06720, Mexico;
| | - Luisa Rocha
- Department of Pharmacobiology, Center for Research and Advanced Studies (CINVESTAV), Mexico City 14330, Mexico; (C.S.-C.); (S.H.d.l.C.); (C.M.-A.)
- Correspondence: ; Tel.: +52-55-5483-2800
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Al Yacoub ON, Awwad HO, Zhang Y, Standifer KM. Therapeutic potential of nociceptin/orphanin FQ peptide (NOP) receptor modulators for treatment of traumatic brain injury, traumatic stress, and their co-morbidities. Pharmacol Ther 2022; 231:107982. [PMID: 34480968 DOI: 10.1016/j.pharmthera.2021.107982] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/12/2021] [Accepted: 08/12/2021] [Indexed: 12/22/2022]
Abstract
The nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor is a member of the opioid receptor superfamily with N/OFQ as its endogenous agonist. Wide expression of the NOP receptor and N/OFQ, both centrally and peripherally, and their ability to modulate several biological functions has led to development of NOP receptor modulators by pharmaceutical companies as therapeutics, based upon their efficacy in preclinical models of pain, anxiety, depression, Parkinson's disease, and substance abuse. Both posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are debilitating conditions that significantly affect the quality of life of millions of people around the world. PTSD is often a consequence of TBI, and, especially for those deployed to, working and/or living in a war zone or are first responders, they are comorbid. PTSD and TBI share common symptoms, and negatively influence outcomes as comorbidities of the other. Unfortunately, a lack of effective therapies or therapeutic agents limits the long term quality of life for either TBI or PTSD patients. Ours, and other groups, demonstrated that PTSD and TBI preclinical models elicit changes in the N/OFQ-NOP receptor system, and that administration of NOP receptor ligands alleviated some of the neurobiological and behavioral changes induced by brain injury and/or traumatic stress exposure. Here we review the past and most recent progress on understanding the role of the N/OFQ-NOP receptor system in PTSD and TBI neurological and behavioral sequelae. There is still more to understand about this neuropeptide system in both PTSD and TBI, but current findings warrant further examination of the potential utility of NOP modulators as therapeutics for these disorders and their co-morbidities. We advocate the development of standards for common data elements (CDE) reporting for preclinical PTSD studies, similar to current preclinical TBI CDEs. That would provide for more standardized data collection and reporting to improve reproducibility, interpretation and data sharing across studies.
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Affiliation(s)
- Omar N Al Yacoub
- Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, OUHSC, Oklahoma City, OK 73117, United States of America
| | - Hibah O Awwad
- Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, OUHSC, Oklahoma City, OK 73117, United States of America
| | - Yong Zhang
- Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, OUHSC, Oklahoma City, OK 73117, United States of America
| | - Kelly M Standifer
- Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, OUHSC, Oklahoma City, OK 73117, United States of America.
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3
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Gao P, Tang S, Chen H, Zhou X, Ou Y, Shen R, He Y. Preconditioning increases brain resistance against acute brain injury via neuroinflammation modulation. Exp Neurol 2021; 341:113712. [PMID: 33819449 DOI: 10.1016/j.expneurol.2021.113712] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/16/2021] [Accepted: 03/26/2021] [Indexed: 01/10/2023]
Abstract
Acute brain injury (ABI) is a broad concept mainly comprised of sudden parenchymal brain injury. Acute brain injury outcomes are dependent not only on the severity of the primary injury, but the delayed secondary injury that subsequently follows as well. These are both taken into consideration when determining the patient's prognosis. Growing clinical and experimental evidence demonstrates that "preconditioning," a prophylactic approach in which the brain is exposed to various pre-injury stressors, can induce varying degrees of "tolerance" against the impact of the ABI by modulating neuroinflammation. In this review, we will summarize the pathophysiology of ABI, and discuss the involved mechanisms of neuroinflammation in ABI, as well as existing experimental and clinical studies demonstrating the efficacy of preconditioning methods in various types of ABI by modulating neuroinflammation.
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Affiliation(s)
- Pan Gao
- Department of Translational Neurodegeneration, German Centre for Neurodegenerative Diseases (DZNE), Munich 81377, Germany.
| | - Sicheng Tang
- Medical Clinic and Polyclinic IV, Ludwig-Maximilians University Munich (LMU), Munich 80336, Germany
| | - Hanmin Chen
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
| | - Xiangyue Zhou
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
| | - Yibo Ou
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
| | - Ronghua Shen
- Department of Psychological Rehabilitation, Hankou Hospital, Wuhan, Hubei 430010, PR China.
| | - Yue He
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China.
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4
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Fleischmann C, Shohami E, Trembovler V, Heled Y, Horowitz M. Cognitive Effects of Astaxanthin Pretreatment on Recovery From Traumatic Brain Injury. Front Neurol 2020; 11:999. [PMID: 33178093 PMCID: PMC7593578 DOI: 10.3389/fneur.2020.00999] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 07/29/2020] [Indexed: 01/12/2023] Open
Abstract
Traumatic brain injury (TBI), caused by mechanical impact to the brain, is a leading cause of death and disability among young adults, with slow and often incomplete recovery. Preemptive treatment strategies may increase the injury resilience of high-risk populations such as soldiers and athletes. In this work, the xanthophyll carotenoid Astaxanthin was examined as a potential nutritional preconditioning method in mice (sabra strain) to increase their resilience prior to TBI in a closed head injury (CHI) model. The effect of Astaxanthin pretreatment on heat shock protein (HSP) dynamics and functional outcome after CHI was explored by gavage or free eating (in pellet form) for 2 weeks before CHI. Assessment of neuromotor function by the neurological severity score (NSS) revealed significant improvement in the Astaxanthin gavage-treated group (100 mg/kg, ATX) during recovery compared to the gavage-treated olive oil group (OIL), beginning at 24 h post-CHI and lasting throughout 28 days (p < 0.007). Astaxanthin pretreatment in pellet form produced a smaller improvement in NSS vs. posttreatment at 7 days post-CHI (p < 0.05). Cognitive and behavioral evaluation using the novel object recognition test (ORT) and the Y Maze test revealed an advantage for Astaxanthin administration via free eating vs. standard chow during recovery post-CHI (ORT at 3 days, p < 0.035; improvement in Y Maze score from 2 to 29 days, p < 0.02). HSP profile and anxiety (open field test) were not significantly affected by Astaxanthin. In conclusion, astaxanthin pretreatment may contribute to improved recovery post-TBI in mice and is influenced by the form of administration.
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Affiliation(s)
- Chen Fleischmann
- The Institute of Military Physiology, IDF Medical Corps, Tel-Hashomer, Israel.,Heller Institute of Medical Research, Sheba Medical Center, Ramat Gan, Israel.,Laboratory of Environmental Physiology, Hebrew University, Jerusalem, Israel
| | - Esther Shohami
- Department of Pharmacology, Institute for Drug Research, Hebrew University, Jerusalem, Israel
| | - Victoria Trembovler
- Department of Pharmacology, Institute for Drug Research, Hebrew University, Jerusalem, Israel
| | - Yuval Heled
- Heller Institute of Medical Research, Sheba Medical Center, Ramat Gan, Israel.,Kibbutzim College, Tel Aviv, Israel
| | - Michal Horowitz
- Laboratory of Environmental Physiology, Hebrew University, Jerusalem, Israel
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Kane WJ, Hassinger TE, Elwood NR, Dietch ZC, Krebs ED, Popovsky KA, Hedrick TL, Sawyer RG. Fever Is Associated with Reduced Mortality in Trauma and Surgical Intensive Care Unit-Acquired Infections. Surg Infect (Larchmt) 2020; 22:174-181. [PMID: 32379549 DOI: 10.1089/sur.2019.352] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background: Fever is a common response to both infectious and non-infectious physiologic insults in the critically ill, and in certain populations it appears to be protective. Fever is particularly common in trauma patients, and even more so in those with infections. The relationship between fever, trauma status, and mortality in patients with an infection is unclear. Patients and Methods: A review of a prospectively maintained institutional database over a 17-year period was performed. Surgical and trauma intensive care unit (ICU) patients with a nosocomial infection were extracted to compare in-hospital mortality among trauma and non-trauma patients with and without fever. Univariable analyses compared patient and infection characteristics between trauma and non-trauma patients. A multivariable logistic regression model was created to identify predictors of in-hospital mortality, with a focus on fever and trauma status. Results: Nine hundred forty-one trauma patients and 1,449 non-trauma patients with ICU-acquired infections were identified. Trauma patients were younger (48 vs. 59, p < 0.001), more likely to be male (73% vs. 56%, p < 0.001), more likely to require blood transfusion (74% vs. 47%, p < 0.001), had lower Acute Physiology and Chronic Health Evaluation (APACHE) II scores (18 vs. 19, p = 0.02), and had lower rates of comorbidities. Trauma patients were more likely to develop a fever (72% vs. 43%, p < 0.001) and had lower in-hospital mortality (9.6% vs. 22.6%, p < 0.001). In multivariable analysis, non-trauma patients with fever had a lower odds of mortality compared with non-trauma patients without fever (odds ratio [OR] 0.63, p = 0.004). Trauma patients with fever had the lowest odds ratio for mortality when compared to non-trauma patients without fever (OR 0.25, p < 0.001). Conclusions: In this large cohort of trauma and surgical ICU patients with ICU-acquired infections, fever was associated with a lower odds of mortality in both trauma and non-trauma patients. Further investigation is needed to determine the mechanisms behind the interplay between trauma status, fever, and mortality.
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Affiliation(s)
- William J Kane
- Department of Surgery, University of Virginia, Charlottesville, Virginia, USA
| | - Taryn E Hassinger
- Department of Surgery, University of Virginia, Charlottesville, Virginia, USA
| | - Nathan R Elwood
- Department of Surgery, University of Virginia, Charlottesville, Virginia, USA
| | - Zachary C Dietch
- Department of Surgery, University of California San Francisco, San Francisco, California, USA
| | - Elizabeth D Krebs
- Department of Surgery, University of Virginia, Charlottesville, Virginia, USA
| | | | - Traci L Hedrick
- Department of Surgery, University of Virginia, Charlottesville, Virginia, USA
| | - Robert G Sawyer
- Department of Surgery, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, Michigan, USA
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Continuous remote ischemic conditioning attenuates cognitive and motor deficits from moderate traumatic brain injury. J Trauma Acute Care Surg 2019; 85:48-53. [PMID: 29443855 DOI: 10.1097/ta.0000000000001835] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND While studies show that single-dose remote ischemic conditioning (RIC) improves outcomes, the effect of continuous (daily) RIC is unknown. Thus, we aimed to investigate the role of continuous RIC on cognitive and motor function following traumatic brain injury (TBI). METHODS We subjected 24 male C57BL mice to a cortical-controlled TBI. Two hours after TBI, the animals were randomly allocated to the RIC group (n = 12) or the sham group (n = 12). Remote ischemic conditioning was induced by noninvasive external compression of the hind limb using an occlusive band (six 4-minute cycles/24 hours) for six consecutive days. Before TBI, a baseline rotarod test and novel object recognition were performed. Post-TBI rotarod and novel object recognition tests were performed on Days 1 to 5, 7, 14, and 21. After the animals were sacrificed on Day 21, brain sections were analyzed using hematoxylin and eosin and glial fibrillary acidic protein staining to evaluate the hippocampal CA1 area for neuronal injury. RESULTS Both the RIC and sham groups had lower latency to fall compared with the baseline post-TBI. The RIC animals had a higher latency to fall compared with the sham animals at all time points, statistically significant after Day 3, until Day 21 post-TBI. Both the RIC and sham groups had lower recognition index compared with the baseline post-TBI. The RIC animals had a significantly higher recognition index than the sham animals after Day 1, until Day 21 post-TBI. Hematoxylin and eosin and glial fibrillary acidic protein staining of the brain samples of the sham group revealed that more neurons in the hippocampal CA1 area appeared shrunken with eosinophilic cytoplasm and pyknotic nuclei compared with the brain samples of the RIC group. CONCLUSION Postinjury continuous RIC resulted in improved cognitive functions and motor coordination in a mouse model of moderate TBI. Further studies are required to determine optimum dosage and frequency of this novel therapy to maximize its beneficial effects following TBI.
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7
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Camara-Lemarroy CR, Metz L, Smith EE, Dunn JF, Yong VW. Expanding the Potential Therapeutic Options for Remote Ischemic Preconditioning: Use in Multiple Sclerosis. Front Neurol 2018; 9:475. [PMID: 29971043 PMCID: PMC6018107 DOI: 10.3389/fneur.2018.00475] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 06/01/2018] [Indexed: 12/11/2022] Open
Affiliation(s)
- Carlos R Camara-Lemarroy
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,UANL School of Medicine and University Hospital, Monterrey, Mexico
| | - Luanne Metz
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Eric E Smith
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Jeff F Dunn
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - V Wee Yong
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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8
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Remote ischemic conditioning preserves cognition and motor coordination in a mouse model of traumatic brain injury. J Trauma Acute Care Surg 2017; 83:1074-1081. [DOI: 10.1097/ta.0000000000001626] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
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9
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Simon RP. Epigenetic modulation of gene expression governs the brain's response to injury. Neurosci Lett 2015; 625:16-9. [PMID: 26739198 DOI: 10.1016/j.neulet.2015.12.024] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 12/03/2015] [Accepted: 12/11/2015] [Indexed: 10/22/2022]
Abstract
Mild stress from ischemia, seizure, hypothermia, or infection can produce a transient neuroprotected state in the brain. In the neuroprotected state, the brain responds differently to a severe stress and sustains less injury. At the genomic level, the response of the neuroprotected brain to a severe stress is characterized by widespread differential regulation of genes with diverse functions. This reprogramming of gene expression observed in the neuroprotected brain in response to a stress is consistent with an epigenetic model of regulation mediated by changes in DNA methylation and histone modification. Here, we summarize our evolving understanding of the molecular basis for endogenous neuroprotection and review recent findings that implicate DNA methylation and protein mediators of histone modification as epigenetic regulators of the brain's response to injury.
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Affiliation(s)
- Roger P Simon
- Translational Stroke Program, Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA; Grady Memorial Hospital, Atlanta, GA, USA.
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10
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11
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Abstract
Diverse preconditioning (PC) stimuli protect against a wide variety of neuronal insults in animal models, engendering enthusiasm that PC could be used to protect the brain clinically. Candidate clinical applications include cardiac and vascular surgery, after subarachnoid hemorrhage, and prior to conditions in which acute neuronal injury is anticipated. However, disappointments in clinical validation of multiple neuroprotectants suggest potential problems translating animal data into successful human therapies. Thus, despite strong promise of preclinical PC studies, caution should be maintained in translating these findings into clinical applications. The Stroke Therapy Academic Industry Roundtable (STAIR) working group and the National institute of Neurological Diseases and Stroke (NINDS) proposed working guidelines to improve the utility of preclinical studies that form the foundation of therapies for neurological disease. Here, we review the applicability of these consensus criteria to preconditioning studies and discuss additional considerations for PC studies. We propose that special attention should be paid to several areas, including 1) safety and dosage of PC treatments; 2) meticulously matching preclinical modeling to the human condition to be tested; and 3) timing of both the initiation and discontinuation of the PC stimulus relative to injury ictus.
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Affiliation(s)
- Michael M Wang
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA ; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA ; Neurology Service, VA Ann Arbor Healthcare System, Ann Arbor, Michigan USA
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12
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Camara-Lemarroy CR. Remote ischemic preconditioning as treatment for non-ischemic gastrointestinal disorders: Beyond ischemia-reperfusion injury. World J Gastroenterol 2014; 20:3572-3581. [PMID: 24707140 PMCID: PMC3974524 DOI: 10.3748/wjg.v20.i13.3572] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 10/23/2013] [Accepted: 01/02/2014] [Indexed: 02/06/2023] Open
Abstract
Common gastrointestinal diseases such as radiation enteritis (RE), acute pancreatitis, inflammatory bowel diseases (IBD) and drug-induced hepatotoxicity share pathophysiological mechanisms at the molecular level, mostly involving the activation of many pathways of the immune response, ultimately leading to tissue injury. Increased oxidative stress, inflammatory cytokine release, inflammatory cell infiltration and activation and the up-regulation of inflammatory transcription factors participate in the pathophysiology of these complex entities. Treatment varies in each specific disease, but at least in the cases of RE and IBD immunosuppressors are effective. However, full therapeutic responses are not always achieved. The pathophysiology of ischemia-reperfusion (IR) injury shares many of these mechanisms. Brief and repetitive periods of ischemia in an organ or limb have been shown to protect against subsequent major IR injury in distant organs, a phenomenon called remote ischemic preconditioning (RIP). This procedure has been shown to protect the gut, pancreas and liver by modulating many of the same inflammatory mechanisms. Since RIP is safe and tolerable, and has shown to be effective in some recent clinical trials, I suggest that RIP could be used as a physiologically relevant adjunct treatment for non-ischemic gastrointestinal inflammatory conditions.
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13
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Yokobori S, Mazzeo AT, Hosein K, Gajavelli S, Dietrich WD, Bullock MR. Preconditioning for traumatic brain injury. Transl Stroke Res 2012; 4:25-39. [PMID: 24323189 DOI: 10.1007/s12975-012-0226-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Revised: 10/23/2012] [Accepted: 10/29/2012] [Indexed: 12/22/2022]
Abstract
Traumatic brain injury (TBI) treatment is now focused on the prevention of primary injury and reduction of secondary injury. However, no single effective treatment is available as yet for the mitigation of traumatic brain damage in humans. Both chemical and environmental stresses applied before injury have been shown to induce consequent protection against post-TBI neuronal death. This concept termed "preconditioning" is achieved by exposure to different pre-injury stressors to achieve the induction of "tolerance" to the effect of the TBI. However, the precise mechanisms underlying this "tolerance" phenomenon are not fully understood in TBI, and therefore even less information is available about possible indications in clinical TBI patients. In this review, we will summarize TBI pathophysiology, and discuss existing animal studies demonstrating the efficacy of preconditioning in diffuse and focal type of TBI. We will also review other non-TBI preconditioning studies, including ischemic, environmental, and chemical preconditioning, which maybe relevant to TBI. To date, no clinical studies exist in this field, and we speculate on possible future clinical situations, in which pre-TBI preconditioning could be considered.
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Affiliation(s)
- Shoji Yokobori
- Department of Neurosurgery, Miami Project to Cure Paralysis, University of Miami, Miami, FL, USA,
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14
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Bahjat FR, Gesuete R, Stenzel-Poore MP. Steps to translate preconditioning from basic research to the clinic. Transl Stroke Res 2012; 4:89-103. [PMID: 23504609 DOI: 10.1007/s12975-012-0223-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Efforts to treat cardiovascular and cerebrovascular diseases often focus on the mitigation of ischemia-reperfusion (I/R) injury. Many treatments or "preconditioners" are known to provide substantial protection against the I/R injury when administered prior to the event. Brief periods of ischemia itself have been validated as a means to achieve neuroprotection in many experimental disease settings, in multiple organ systems, and in multiple species suggesting a common pathway leading to tolerance. In addition, pharmacological agents that act as potent preconditioners have been described. Experimental induction of neuroprotection using these various preconditioning paradigms has provided a unique window into the brain's endogenous protective mechanisms. Moreover, preconditioning agents themselves hold significant promise as clinical-stage therapies for prevention of I/R injury. The aim of this article is to explore several key steps involved in the preclinical validation of preconditioning agents prior to the conduct of clinical studies in humans. Drug development is difficult, expensive and relies on multi-factorial analysis of data from diverse disciplines. Importantly, there is no single path for the preclinical development of a novel therapeutic and no proven strategy to ensure success in clinical translation. Rather, the conduct of a diverse array of robust preclinical studies reduces the risk of clinical failure by varying degrees depending upon the relevance of preclinical models and drug pharmacology to humans. A strong sense of urgency and high tolerance of failure are often required to achieve success in the development of novel treatment paradigms for complex human conditions.
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Affiliation(s)
- Frances R Bahjat
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon
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15
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Shein SL, Bell MJ, Kochanek PM, Tyler-Kabara EC, Wisniewski SR, Feldman K, Makoroff K, Scribano PV, Berger RP. Risk factors for mortality in children with abusive head trauma. J Pediatr 2012; 161:716-722.e1. [PMID: 22578583 PMCID: PMC3437227 DOI: 10.1016/j.jpeds.2012.03.046] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Revised: 02/03/2012] [Accepted: 03/22/2012] [Indexed: 11/29/2022]
Abstract
OBJECTIVE We sought to identify risk factors for mortality in a large clinical cohort of children with abusive head trauma. STUDY DESIGN Bivariate analysis and multivariable logistic regression models identified demographic, physical examination, and radiologic findings associated with in-hospital mortality of children with abusive head trauma at 4 pediatric centers. An initial Glasgow Coma Scale (GCS) ≤ 8 defined severe abusive head trauma. Data are shown as OR (95% CI). RESULTS Analysis included 386 children with abusive head trauma. Multivariable analysis showed children with initial GCS either 3 or 4-5 had increased mortality vs children with GCS 12-15 (OR = 57.8; 95% CI, 12.1-277.6 and OR = 15.6; 95% CI, 2.6-95.1, respectively, P < .001). Additionally, retinal hemorrhage (RH), intraparenchymal hemorrhage, and cerebral edema were independently associated with mortality. In the subgroup with severe abusive head trauma and RH (n = 117), cerebral edema and initial GCS of 3 or 4-5 were independently associated with mortality. Chronic subdural hematoma was independently associated with survival. CONCLUSIONS Low initial GCS score, RH, intraparenchymal hemorrhage, and cerebral edema are independently associated with mortality in abusive head trauma. Knowledge of these risk factors may enable researchers and clinicians to improve the care of these vulnerable children.
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Affiliation(s)
- Steven L. Shein
- Department of Critical Care Medicine, Children’s Hospital of Pittsburgh of UPMC, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA
| | - Michael J. Bell
- Departments of Critical Care Medicine and Neurological Surgery, Children’s Hospital of Pittsburgh of UPMC, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA
| | - Patrick M. Kochanek
- Department of Critical Care Medicine, Children’s Hospital of Pittsburgh of UPMC, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA
| | - Elizabeth C. Tyler-Kabara
- Departments of Neurological Surgery and Physical Medicine and Rehabilitation, Children’s Hospital of Pittsburgh of UPMC, Department of Bioengineering and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA
| | | | - Kenneth Feldman
- Seattle Children’s Hospital/Harborview Medical Center, Seattle, WA
| | - Kathi Makoroff
- Cincinnati Children’s Hospital Medical Center. Cincinnati, OH
| | | | - Rachel P. Berger
- Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania
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16
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Longhi L, Gesuete R, Perego C, Ortolano F, Sacchi N, Villa P, Stocchetti N, De Simoni MG. Long-lasting protection in brain trauma by endotoxin preconditioning. J Cereb Blood Flow Metab 2011; 31:1919-29. [PMID: 21468087 PMCID: PMC3185879 DOI: 10.1038/jcbfm.2011.42] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
We investigated the occurrence of endotoxin (lipopolysaccharide, LPS) preconditioning in traumatic brain injury (TBI), evaluating the time window of LPS-induced protection, its persistence, and the associated molecular mechanisms. Mice received 0.1 mg/kg LPS or saline intraperitoneally and subsequently TBI (by controlled cortical impact brain injury) at various time intervals. Mice receiving LPS 3, 5, or 7 days before TBI showed attenuated motor deficits at 1 week after injury compared with mice receiving saline. Those receiving LPS 5 days before injury had also a reduced contusion volume (7.9±1.3 versus 12±2.3 mm(3)) and decreased cell death. One month after injury, the protective effect of LPS on contusion volume (14.5±1.2 versus 18.2±1.2 mm(3)) and neurologic function was still present. Traumatic brain injury increased glial fibrillary acidic protein, CD11b, CD68, tumor necrosis factor-α, interleukin (IL)-10, and IL-6 mRNA expression 24 hours after injury. Lipopolysaccharide administered 5 (but not 9) days before injury increased the expression of CD11b (233%) and of interferon β (500%) in uninjured mice, while it reduced the expression of CD68 (by 46%) and increased that of IL-6 (by 52%) in injured mice. Lipopolysaccharide preconditioning conferred a long-lasting neuroprotection after TBI, which was associated with a modulation of microglia/macrophages activity and cytokine production.
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Affiliation(s)
- Luca Longhi
- Department of Anesthesia and Critical Care Medicine, University of Milano, Neurosurgical Intensive Care Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milano, Italy
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17
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Abstract
Preconditioning (PC) describes a phenomenon whereby a sub-injury inducing stress can protect against a later injurious stress. Great strides have been made in identifying the mechanisms of PC-induced protection in animal models of brain injury. While these may help elucidate potential therapeutic targets, there are questions over the clinical utility of cerebral PC, primarily because of questions over the need to give the PC stimulus prior to the injury, narrow therapeutic windows and safety. The object of this review is to address the question of whether there may indeed be a clinical use for cerebral PC and to discuss the deficiencies in our knowledge of PC that may hamper such clinical translation.
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Affiliation(s)
- Richard F. Keep
- Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA
- Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Michael M. Wang
- Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
| | - Jianming Xiang
- Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Ya Hua
- Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Guohua Xi
- Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA
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18
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Gurkoff GG, Giza CC, Shin D, Auvin S, Sankar R, Hovda DA. Acute neuroprotection to pilocarpine-induced seizures is not sustained after traumatic brain injury in the developing rat. Neuroscience 2009; 164:862-76. [PMID: 19695311 PMCID: PMC2762013 DOI: 10.1016/j.neuroscience.2009.08.021] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2009] [Revised: 07/06/2009] [Accepted: 08/04/2009] [Indexed: 10/20/2022]
Abstract
Following CNS injury there is a period of vulnerability when cells will not easily tolerate a secondary insult. However recent studies have shown that following traumatic brain injury (TBI), as well as hypoxic-ischemic injuries, the CNS may experience a period of protection termed "preconditioning." While there is literature characterizing the properties of vulnerability and preconditioning in the adult rodent, there is an absence of comparable literature in the developing rat. To determine if there is a window of vulnerability in the developing rat, post-natal day 19 animals were subjected to a severe lateral fluid percussion injury followed by pilocarpine (Pc)-induced status epilepticus at 1, 6 or 24 h post TBI. During the first 24 h after TBI, the dorsal hippocampus exhibited less status epilepticus-induced cell death than that normally seen following Pc administration alone. Instead of producing a state of hippocampal vulnerability to activation, TBI produced a state of neuroprotection. However, in a second group of animals evaluated 20 weeks post injury, double-injured animals were statistically indistinguishable in terms of seizure threshold, mossy fiber sprouting and cell survival when compared to those treated with Pc alone. TBI, therefore, produced a temporary state of neuroprotection from seizure-induced cell death in the developing rat; however, this ultimately conferred no long-term protection from altered hippocampal circuit rearrangements, enhanced excitability or later convulsive seizures.
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Affiliation(s)
- Gene G. Gurkoff
- Department of Neurosurgery, David Geffen School of Medicine at UCLA
- Brain Research Institute, David Geffen School of Medicine at UCLA
- UCLA Brain Injury Research Center, David Geffen School of Medicine at UCLA
- Interdepartmental Program for Neuroscience, David Geffen School of Medicine at UCLA
| | - Christopher C. Giza
- Department of Neurosurgery, David Geffen School of Medicine at UCLA
- Division of Pediatric Neurology, Department of Pediatrics, David Geffen School of Medicine at UCLA
- Brain Research Institute, David Geffen School of Medicine at UCLA
- UCLA Brain Injury Research Center, David Geffen School of Medicine at UCLA
- Interdepartmental Program for Neuroscience, David Geffen School of Medicine at UCLA
- Interdepartmental Program in Biomedical Engineering, David Geffen School of Medicine at UCLA
| | - Don Shin
- Division of Pediatric Neurology, Department of Pediatrics, David Geffen School of Medicine at UCLA
| | - Stephane Auvin
- Division of Pediatric Neurology, Department of Pediatrics, David Geffen School of Medicine at UCLA
- Department of Pediatric Neurology, Hôpital Robert Debré Paris, France
| | - Raman Sankar
- Division of Pediatric Neurology, Department of Pediatrics, David Geffen School of Medicine at UCLA
- Brain Research Institute, David Geffen School of Medicine at UCLA
| | - David A. Hovda
- Department of Neurosurgery, David Geffen School of Medicine at UCLA
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA
- Brain Research Institute, David Geffen School of Medicine at UCLA
- UCLA Brain Injury Research Center, David Geffen School of Medicine at UCLA
- Interdepartmental Program for Neuroscience, David Geffen School of Medicine at UCLA
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19
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Abstract
Repetitive traumatic brain injury (TBI) occurs in a significant portion of trauma patients, especially in specific populations, such as child abuse victims or athletes involved in contact sports (e.g. boxing, football, hockey, and soccer). A continually emerging hypothesis is that repeated mild injuries may cause cumulative damage to the brain, resulting in long-term cognitive dysfunction. The growing attention to this hypothesis is reflected in several recent experimental studies of repeated mild TBI in vivo. These reports generally demonstrate cellular and cognitive dysfunction after repetitive injury using rodent TBI models. In some cases, data suggests that the effects of a second mild TBI may be synergistic, rather than additive. In addition, some studies have found increases in cellular markers associated with Alzheimer's disease after repeated mild injuries, which demonstrates a direct experimental link between repetitive TBI and neurodegenerative disease. To complement the findings from humans and in vivo experimentation, my laboratory group has investigated the effects of repeated trauma in cultured brain cells using a model of stretch-induced mechanical injury in vitro. In these studies, hippocampal cells exhibited cumulative damage when mild stretch injuries were repeated at either 1-h or 24-h intervals. Interestingly, the extent of damage to the cells was dependent on the time between repeated injuries. Also, a very low level of stretch, which produced no cell damage on its own, induced cell damage when it was repeated several times at a short interval (every 2 min). Although direct comparisons to the clinical situation are difficult, these types of repetitive, low-level, mechanical stresses may be similar to the insults received by certain athletes, such as boxers, or hockey and soccer players. This type of in vitro model could provide a reliable system in which to study the mechanisms underlying cellular dysfunction following repeated injuries. As this area of TBI research continues to evolve, it will be imperative that models of repetitive injury replicate injuries in humans as closely as possible. For example, it will be important to model appropriately concussive episodes versus even lower level injuries (such as those that might occur during boxing matches). Suitable inter-injury intervals will also be important parameters to incorporate into models. Additionally, it will be crucial to design and utilize proper controls, which can be more challenging than experimental approaches to single mild TBI. It will also be essential to combine, and compare, data derived from in vitro experiments with those conducted with animals in vivo. These issues, as well as a summary of findings from repeated TBI research, are discussed in this review.
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Affiliation(s)
- John T Weber
- Department of Neuroscience, Erasmus Medical Centre, Rotterdam, The Netherlands.
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20
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Steiger HJ, Hänggi D. Ischaemic preconditioning of the brain, mechanisms and applications. Acta Neurochir (Wien) 2007; 149:1-10. [PMID: 17151832 DOI: 10.1007/s00701-006-1057-1] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2006] [Accepted: 10/11/2006] [Indexed: 01/25/2023]
Abstract
BACKGROUND The concept of ischaemic preconditioning was introduced in the late 1980s. The concept emerged that a brief subcritical ischaemic challenge could mobilize intrinsic protective mechanisms that increased tolerance against subsequent critical ischaemia. Tissues with a high sensitivity against ischaemia, i.e. myocardium and central nervous system, present the most promising targets for therapeutic application of ischaemic preconditioning. During the last years the mechanisms of neuronal preconditioning were systematically studied and a number of molecular regulation pathways were discovered to participate in preconditioning. The purpose of the present review is to survey the actual knowledge on cerebral preconditioning, and to define the practical impact for neurosurgery. METHODS A systematic medline search for the terms preconditioning and postconditioning was filed. Publications related to the nervous system were selected and analysed. FINDINGS Preconditioning can be subdivided into early and late mechanisms, depending on whether the effect appears immediately after the nonlethal stress or with a delay of some hours or days. In general early effects can be linked to adaptation of membrane receptors whereas late effects are the result of gene up- or downregulation. Not only subcritical ischaemia can trigger preconditioning but also hypoxia, hyperthermia, isoflurane and other chemical substances. Although a vast amount of knowledge has been accumulated regarding neural preconditioning, it is unknown whether the effects can be potentiated by pharmacological or hypothermic neuroprotection during the critical ischaemia. Furthermore, although the practical importance of these findings is obvious, the resulting protective manipulations have so far not been transferred into clinical neurosurgery. Postconditioning and remote ischaemic preconditioning are additional emerging concepts. Postconditioning with a series of mechanical interruptions of reperfusion can apparently reduce ischaemic damage. Remote ischaemic preconditioning refers to the concept that transient ischaemia for example of a limb can lead to protection of the myocardium and possibly the brain. CONCLUSION Possible cumulative neuroprotection by preconditioning and pharmacological protection during critical ischaemia should be studied systematically. Easy to apply methods of preconditioning, such as the application of volatile anaesthetics or erythropoietin some hours or days prior to planned temporary ischaemia, should be introduced into the practice of operative neurosurgery.
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Affiliation(s)
- H-J Steiger
- Department of Neurosurgery, University Hospital, Heinrich-Heine University, Düsseldorf, Germany.
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21
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Lotocki G, de Rivero Vaccari JP, Perez ER, Alonso OF, Curbelo K, Keane RW, Dietrich WD. Therapeutic hypothermia modulates TNFR1 signaling in the traumatized brain via early transient activation of the JNK pathway and suppression of XIAP cleavage. Eur J Neurosci 2006; 24:2283-90. [PMID: 17074049 DOI: 10.1111/j.1460-9568.2006.05123.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Tumor necrosis factor (TNF) plays a critical role in pathomechanisms associated with secondary damage after traumatic brain injury (TBI). The TNF ligand-receptor system stimulates inflammation by activation of gene transcription through the IkappaB kinase (IKK)-NF-kappaB and c-Jun NH(2)-terminal kinase (JNK)-AP-1 signaling cascades. TNF signaling following TBI involves both cell survival and apoptotic pathways, but the mechanism that accounts for the dual role of TNF remains unclear. Multiple studies have reported hypothermia to be protective following TBI, but the precise mechanism has not been clearly defined. Here, TNFR1 signaling pathways were investigated in the cerebral cortex of adult male Sprague-Dawley rats subjected to moderate fluid-percussion TBI and of naïve controls. Another group was subjected to moderate TBI with 30 min of pre- and post-traumatic hypothermia (33 degrees C). Rapid and marked increases in protein expression of TNFR1 and signaling intermediates in both the IKK-NF-kappaB and JNK pathways were induced in traumatized cortices. Hypothermia decreased TNFR1 protein expression acutely in traumatized cortices and stimulated early activation of signaling intermediates in the JNK, but not the IKK-NF-kappaB, signaling pathways. Hypothermia promoted a rapid activation of caspase-3 acutely after injury but suppressed caspase-3 activation at later time points. Moreover, hypothermia treatment suppressed cleavage of X-linked inhibitor of apoptosis protein (XIAP) into fragments induced by TBI. These data suggest that hypothermia may regulate both the JNK signaling cascade via XIAP and the preconditioning pathways that activate caspases. Thus, hypothermia mediates TNFR1 responses via early activation of the JNK signaling pathway and caspase-3, leading to endogenous neuroprotective events.
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Affiliation(s)
- George Lotocki
- Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
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22
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Grasso G, Sfacteria A, Erbayraktar S, Passalacqua M, Meli F, Gokmen N, Yilmaz O, La Torre D, Buemi M, Iacopino DG, Coleman T, Cerami A, Brines M, Tomasello F. Amelioration of spinal cord compressive injury by pharmacological preconditioning with erythropoietin and a nonerythropoietic erythropoietin derivative. J Neurosurg Spine 2006; 4:310-8. [PMID: 16619678 DOI: 10.3171/spi.2006.4.4.310] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECT Spinal cord injury (SCI) is a devastating clinical syndrome for which no truly efficacious therapy has yet been identified. In preclinical studies, erythropoietin (EPO) and its nonerythropoietic derivatives asialoEPO and carbamylated EPO have markedly improved functional outcome when administered after compressive SCI. However, an optimum treatment paradigm is currently unknown. Because the uninjured spinal cord expresses a high density of EPO receptor (EPOR) in the basal state, signaling through these existing receptors in advance of injury (pharmacological preconditioning) might confer neuroprotection and therefore be potentially useful in situations of anticipated damage. METHODS The authors compared asialoEPO, a molecule that binds to the EPOR with high affinity but with a brief serum half-life (t1/2 < 2 minutes), to EPO to determine whether a single dose (10 microg/kg of body weight) administered by intravenous injection 24 hours before 1 minute of spinal cord compression provides benefit as determined by a 6-week assessment of neurological outcome and by histopathological analysis. Rats pretreated with asialoEPO or EPO and then subjected to a compressive injury exhibited improved motor function over 42 days, compared with animals treated with saline solution. However, pretreatment efficacy was substantially poorer than efficacy of treatment initiated at the time of injury. Serum samples drawn immediately before compression confirmed that no detectable asialoEPO remained within the systemic circulation. Western blot and immunohistochemical analyses performed using uninjured spinal cord 24 hours after a dose of asialoEPO exhibited a marked increase in glial fibrillary acidic protein, suggesting a glial response to EPO administration. CONCLUSIONS These results demonstrate that EPO and its analog do not need to be present at the time of injury to provide tissue protection and that tissue protection is markedly effective when either agent is administered immediately after injury. Furthermore, the findings suggest that asialoEPO is a useful reagent with which to study the dynamics of EPO-mediated neuroprotection. In addition, the findings support the concept of using a nonerythropoietic EPO derivative to provide tissue protection without activating the undesirable effects of EPO.
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23
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Morales DM, Marklund N, Lebold D, Thompson HJ, Pitkanen A, Maxwell WL, Longhi L, Laurer H, Maegele M, Neugebauer E, Graham DI, Stocchetti N, McIntosh TK. Experimental models of traumatic brain injury: do we really need to build a better mousetrap? Neuroscience 2005; 136:971-89. [PMID: 16242846 DOI: 10.1016/j.neuroscience.2005.08.030] [Citation(s) in RCA: 245] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2005] [Revised: 06/08/2005] [Accepted: 08/04/2005] [Indexed: 11/19/2022]
Abstract
Approximately 4000 human beings experience a traumatic brain injury each day in the United States ranging in severity from mild to fatal. Improvements in initial management, surgical treatment, and neurointensive care have resulted in a better prognosis for traumatic brain injury patients but, to date, there is no available pharmaceutical treatment with proven efficacy, and prevention is the major protective strategy. Many patients are left with disabling changes in cognition, motor function, and personality. Over the past two decades, a number of experimental laboratories have attempted to develop novel and innovative ways to replicate, in animal models, the different aspects of this heterogenous clinical paradigm to better understand and treat patients after traumatic brain injury. Although several clinically-relevant but different experimental models have been developed to reproduce specific characteristics of human traumatic brain injury, its heterogeneity does not allow one single model to reproduce the entire spectrum of events that may occur. The use of these models has resulted in an increased understanding of the pathophysiology of traumatic brain injury, including changes in molecular and cellular pathways and neurobehavioral outcomes. This review provides an up-to-date and critical analysis of the existing models of traumatic brain injury with a view toward guiding and improving future research endeavors.
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Affiliation(s)
- D M Morales
- Traumatic Brain Injury Laboratory, Department of Neurosurgery, University of Pennsylvania, 3320 Smith Walk, 105C Hayden Hall, Philadelphia, PA 19104, USA.
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24
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Thompson HJ, Lifshitz J, Marklund N, Grady MS, Graham DI, Hovda DA, McIntosh TK. Lateral fluid percussion brain injury: a 15-year review and evaluation. J Neurotrauma 2005; 22:42-75. [PMID: 15665602 DOI: 10.1089/neu.2005.22.42] [Citation(s) in RCA: 398] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
This article comprehensively reviews the lateral fluid percussion (LFP) model of traumatic brain injury (TBI) in small animal species with particular emphasis on its validity, clinical relevance and reliability. The LFP model, initially described in 1989, has become the most extensively utilized animal model of TBI (to date, 232 PubMed citations), producing both focal and diffuse (mixed) brain injury. Despite subtle variations in injury parameters between laboratories, universal findings are evident across studies, including histological, physiological, metabolic, and behavioral changes that serve to increase the reliability of the model. Moreover, demonstrable histological damage and severity-dependent behavioral deficits, which partially recover over time, validate LFP as a clinically-relevant model of human TBI. The LFP model, also has been used extensively to evaluate potential therapeutic interventions, including resuscitation, pharmacologic therapies, transplantation, and other neuroprotective and neuroregenerative strategies. Although a number of positive studies have identified promising therapies for moderate TBI, the predictive validity of the model may be compromised when findings are translated to severely injured patients. Recently, the clinical relevance of LFP has been enhanced by combining the injury with secondary insults, as well as broadening studies to incorporate issues of gender and age to better approximate the range of human TBI within study design. We conclude that the LFP brain injury model is an appropriate tool to study the cellular and mechanistic aspects of human TBI that cannot be addressed in the clinical setting, as well as for the development and characterization of novel therapeutic interventions. Continued translation of pre-clinical findings to human TBI will enhance the predictive validity of the LFP model, and allow novel neuroprotective and neuroregenerative treatment strategies developed in the laboratory to reach the appropriate TBI patients.
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Affiliation(s)
- Hilaire J Thompson
- Traumatic Brain Injury Laboratory, Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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25
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Orendácová J, Raceková E, Kuchárova K, Pousová B, Ondrejcák T, Martoncíková M, Daxnerová Z, Marsala J. Ependyma as a possible morphological basis of ischemic preconditioning tolerance in rat spinal cord ischemia model: nestin and Fluoro-Jade B observations. Cell Mol Neurobiol 2004; 24:477-89. [PMID: 15206826 PMCID: PMC11529954 DOI: 10.1023/b:cemn.0000022775.67975.ed] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
1. To test our hypothesis that a transient nonlethal ischemic insult benefits the lumbosacral spinal cord ischemic injury, nestin, the marker of proliferating cells, and Fluoro-Jade B, the marker of degenerating cells, were used in rats. Morphological outcome was evaluated after 12-min ischemia versus 12-min ischemia preconditioned by 3-min ischemic period and 30-min recirculation (IPC), in each group followed by 2, 3, and 4 days of posttreatment survival. 2. Twelve-minute ischemia, inducing nestin-positivity in ependyma and reactive astrocytes at the L(1-3) spinal cord segments, shows this region as the viable region of spinal cord in all postischemic survival periods. On the other hand, abundance of Fluoro-Jade B-positive cells, distributed throughout the dorsal horn and intermediate zone of L4-S2 segments, points out the most injured spinal cord region by ischemia. 3. After the same ischemic insult in IPC rats only a few nestin-positive ependymal cell and reactive astrocytes appeared beside the nestin-positive vessels in the lower lumbar and sacral spinal cord segments of all survival periods. The appearance of nestin-positive cells in the spinal cord segments, which "should have been affected" by ischemia indicates protection of this region by the IPC treatment. 4. The number and density evaluation of Fluoro-Jade B fluorescent cells of L4-S2 segments after ischemia and IPC confirmed that degenerating cells were significantly reduced in the IPC rats in all survival periods. 5. Our results showing the immunohistochemical response of epemdyma, committed to the presence of viable tissue, indicate that the ependymal cells may contribute to the ischemic resistance in the IPC rats.
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Affiliation(s)
- Judita Orendácová
- Institute of Neurobiology, Slovak Academy of Sciences, Kogice, Slovak Republic.
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26
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Ondrejcák T, Vanický I, Gálik J. Ischemic preconditioning does not improve neurological recovery after spinal cord compression injury in the rat. Brain Res 2004; 995:267-73. [PMID: 14672817 DOI: 10.1016/j.brainres.2003.10.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Ischemic preconditioning (IPC) has been defined as the endogenous cellular protective mechanism evoked by brief ischemic periods. IPC renders the tissue of the central nervous system more resistant to subsequent lethal ischemic insults, and similar protective effect of IPC has been observed after experimental traumatic brain injury. Spinal cord trauma differs from cerebral trauma in that the secondary processes are damaging mostly the white matter. In the present study, we have tested the hypothesis that a transient non-lethal ischemic insult would improve outcomes after subsequent traumatic spinal cord injury (SCI). In the IPC group, 5-min spinal cord ischemia has been induced by aortic occlusion combined with hypotension. Forty-eight hours after IPC, moderate spinal cord injury has been induced by epidural balloon inflation at T8 level. Control group underwent identical surgical procedures without ischemia followed by SCI after 48 h. During the 4-week survival, locomotor performance of all rats was repeatedly tested and evaluated according to BBB scale. After 4 weeks, the animals were perfusion-fixed for histopathology, and morphometric analyses were performed in order to quantify the extent of the spinal cord lesion. All animals were completely paraplegic after SCI, and showed partial neurological recovery during their survival period. No significant differences were detected either in neurological scores or in morphometric measurements after 4 weeks' survival. These results indicate that in contrary to cerebral trauma, IPC does not improve the outcome after SCI.
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Affiliation(s)
- Tomás Ondrejcák
- Institute of Neurobiology, Slovak Academy of Sciences, Soltésovej 4, 040 01 Kosice, Slovak Republic.
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27
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Butler TL, Kassed CA, Pennypacker KR. Signal transduction and neurosurvival in experimental models of brain injury. Brain Res Bull 2003; 59:339-51. [PMID: 12507684 DOI: 10.1016/s0361-9230(02)00926-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Brain injury and neurodegenerative disease are linked by their primary pathological consequence-death of neurons. Current approaches for the treatment of neurodegeneration are limited. In this review, we discuss animal models of human brain injury and molecular biological data that have been obtained from their analysis. In particular, signal transduction pathways that are associated with neurosurvival following injury to the brain are presented and discussed.
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Affiliation(s)
- T L Butler
- Department of Pharmacology and Therapeutics, College of Medicine, University of South Florida, Tampa, FL 33612, USA
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28
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Ruppel RA, Clark RSB, Bayir H, Satchell MA, Kochanek PM. Critical mechanisms of secondary damage after inflicted head injury in infants and children. Neurosurg Clin N Am 2002; 13:169-82, v. [PMID: 12391702 DOI: 10.1016/s1042-3680(01)00005-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
A number of critical mechanisms are involved in the pathophysiology of inflicted head injury. Excitotoxicity, oxidative stress, inflammation, programmed cell death, and mediators of blood flow and metabolism all contribute to secondary injury after abusive head trauma. These mechanisms are reviewed and the implications for clinical practice discussed.
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Affiliation(s)
- Randall A Ruppel
- Department of Anesthesiology and Critical Care Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
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29
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Mackay KB, Stiefel TH, Foster AC. Ischemic preconditioning reduces infarct volume after subdural hematoma in the rat. Brain Res 2002; 930:200-5. [PMID: 11879810 DOI: 10.1016/s0006-8993(01)03406-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The aim of the present study was to investigate the effects of ischemic preconditioning on infarct volume in a rat model of subdural hematoma (SDH). Ischemic preconditioning was induced by 15 min transient middle cerebral artery (MCA) occlusion followed 3 days later by the injection of 300 microl of autologous venous blood into the subdural space. Preconditioning significantly reduced the volume of cortical infarction (by 26%, P<0.001) 24 h after SDH induction, but not brain swelling (P>0.05) relative to sham-operated non-preconditioned animals. These data support the view that ischemic preconditioning reduces ischemic brain damage in this rat model of SDH.
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Affiliation(s)
- Kenneth B Mackay
- Neurocrine Biosciences Inc., 10555 Science Center Drive, San Diego, CA 92121-1102, USA.
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30
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Tauskela JS, Comas T, Hewitt K, Monette R, Paris J, Hogan M, Morley P. Cross-tolerance to otherwise lethal N-methyl-D-aspartate and oxygen-glucose deprivation in preconditioned cortical cultures. Neuroscience 2002; 107:571-84. [PMID: 11720781 DOI: 10.1016/s0306-4522(01)00381-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
In vitro ischemic preconditioning induced by subjecting rat cortical cultures to nonlethal oxygen-glucose deprivation protects against a subsequent exposure to otherwise lethal oxygen-glucose deprivation. We provide evidence that attenuation of the postsynaptic N-methyl-D-aspartate (NMDA) receptor- and Ca(2+)-dependent neurotoxicity underlies oxygen-glucose deprivation tolerance. It is demonstrated that extended tolerance to otherwise lethal NMDA or oxygen-glucose deprivation can be induced by either of their sublethal forms of preconditioning. These four pathways are linked, since NMDA receptor blockade during preconditioning by oxygen-glucose deprivation eliminates tolerance. These results suggest that NMDA tolerance, induced by nonlethal activation of these receptors during oxygen-glucose deprivation preconditioning, underlies oxygen-glucose deprivation tolerance. Several neurotoxic downstream Ca(2+)-dependent signaling events specifically linked to NMDA receptor activation are attenuated during otherwise lethal oxygen-glucose deprivation in preconditioned cultures. Specifically, calpain activation, as well as degradation of microtubule-associated protein-2 and postsynaptic density-95, are attenuated 2 h following otherwise lethal NMDA treatment alone or oxygen-glucose deprivation in preconditioned cultures. Formation of microtubule-associated protein-2-labeled dendritic varicosities is also attenuated in preconditioned cultures within 1 h of lethal oxygen-glucose deprivation or NMDA application. Intracellular Ca(2+) levels, measured using the high- or low-affinity dyes Fluo-4 (K(d) approximately equal 345 nM) or Fluo-4FF (K(d) approximately equal 9.7 microM) respectively, are markedly attenuated during lethal oxygen-glucose deprivation in preconditioned cultures.Collectively, the results suggest the attenuation of the postsynaptic NMDA-mediated component of otherwise lethal oxygen-glucose deprivation through the suppression of Ca(2+)-dependent neurotoxic signaling, a mechanism that is initially induced by transient nonlethal activation of this receptor during ischemic preconditioning.
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Affiliation(s)
- J S Tauskela
- National Research Council of Canada, Institute for Biological Sciences, Ottawa, ON, Canada.
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Ogawa T, Mimura Y, Kaminishi M. Renal denervation abolishes the protective effects of ischaemic preconditioning on function and haemodynamics in ischaemia-reperfused rat kidneys. ACTA PHYSIOLOGICA SCANDINAVICA 2002; 174:291-7. [PMID: 11906329 DOI: 10.1046/j.1365-201x.2002.00944.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Studies were conducted to investigate the role of renal sympathetic nerves in the process of acquiring ischaemic tolerance in ischaemic preconditioned ischaemia-reperfused rat kidneys. Two periods of 3-min occlusion of bilateral renal arteries was performed prior to 30-min bilateral ischaemia and 90-min reperfusion in acute renal denervated or innervated kidneys. The glomerular filtration rate (GFR), fractional excretion of sodium (FENa) and lithium (FELi), and renal blood flow (RBF) were assessed in reperfused kidneys. Ischaemic preconditioning significantly improved values for all these parameters as compared with no treated ischaemia-reperfused kidneys. Denervation caused slight increase in GFR, diuresis and natriuresis without improving RBF after reperfusion. However, protecting effects of ischaemic preconditioning on renal function were disappeared in denervated kidneys, while in innervated kidneys the effects of ischaemic preconditioning were maintained. These results clearly showed that ischaemic preconditioning pre-treatment protects kidneys against ischaemia-reperfusion injury, and the effects are, at least in part, mediated by sympathetic nerves, as the protective effects were abolished by denervation.
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Affiliation(s)
- T Ogawa
- Endocrine and Metabolic Unit, Department of Surgery, University of Tokyo, Tokyo, Japan
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Laurer HL, Bareyre FM, Lee VM, Trojanowski JQ, Longhi L, Hoover R, Saatman KE, Raghupathi R, Hoshino S, Grady MS, McIntosh TK. Mild head injury increasing the brain's vulnerability to a second concussive impact. J Neurosurg 2001; 95:859-70. [PMID: 11702878 DOI: 10.3171/jns.2001.95.5.0859] [Citation(s) in RCA: 239] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECT Mild, traumatic repetitive head injury (RHI) leads to neurobehavioral impairment and is associated with the early onset of neurodegenerative disease. The authors developed an animal model to investigate the behavioral and pathological changes associated with RHI. METHODS Adult male C57BL/6 mice were subjected to a single injury (43 mice), repetitive injury (two injuries 24 hours apart; 49 mice), or no impact (36 mice). Cognitive function was assessed using the Morris water maze test, and neurological motor function was evaluated using a battery of neuroscore, rotarod, and rotating pole tests. The animals were also evaluated for cardiovascular changes, blood-brain barrier (BBB) breakdown, traumatic axonal injury, and neurodegenerative and histopathological changes between 1 day and 56 days after brain trauma. No cognitive dysfunction was detected in any group. The single-impact group showed mild impairment according to the neuroscore test at only 3 days postinjury, whereas RHI caused pronounced deficits at 3 days and 7 days following the second injury. Moreover, RHI led to functional impairment during the rotarod and rotating pole tests that was not observed in any animal after a single impact. Small areas of cortical BBB breakdown and axonal injury. observed after a single brain injury, were profoundly exacerbated after RHI. Immunohistochemical staining for microtubule-associated protein-2 revealed marked regional loss of immunoreactivity only in animals subjected to RHI. No deposits of beta-amyloid or tau were observed in any brain-injured animal. CONCLUSIONS On the basis of their results, the authors suggest that the brain has an increased vulnerability to a second traumatic insult for at least 24 hours following an initial episode of mild brain trauma.
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Affiliation(s)
- H L Laurer
- The Head Injury Center, Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia 19104-6316, USA
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Ogawa T, Nussler AK, Tuzuner E, Neuhaus P, Kaminishi M, Mimura Y, Beger HG. Contribution of nitric oxide to the protective effects of ischemic preconditioning in ischemia-reperfused rat kidneys. THE JOURNAL OF LABORATORY AND CLINICAL MEDICINE 2001; 138:50-58. [PMID: 11433228 DOI: 10.1067/mlc.2001.115648] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We examined the contribution of nitric oxide (NO) to the effect of ischemic preconditioning (IP) on renal function and the hemodynamics in ischemia-reperfusion (I/R) mediated kidney injury. IP was performed by using 4 minutes of ischemia followed by a 30-minute reperfusion interval. I/R treatment consisted of a 30-minute ischemia and 60-minute reperfusion interval. We measured the glomerular filtration rate (GFR), the fractional excretion of sodium (FE(Na)), and the renal blood flow (RBF) in IP+I/R and I/R kidneys. Rats were pretreated with NaCl, N(G)-nitro-L-arginine methyl ester (L-NAME), or L-arginine. We found that IP significantly improved GFR and FE(Na) as compared with I/R treatment; however, this effect was completely abolished by L-NAME injection and enhanced by L-arginine treatment. L-NAME treatment significantly diminished RBF but did not alter nitrite/nitrate excretion. Furthermore, we found that IP alone does not lead to inducible NO synthase protein expression whereas I/R or IP+I/R treatment clearly did. Moreover, we observed an increased heme oxygenase-1 expression in IP+I/R kidneys as compared with I/R treated ones. Our results clearly showed that IP pretreatment protects kidneys from I/R mediated tissue injury and that these effects were partially mediated by NO.
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Affiliation(s)
- T Ogawa
- University of Ulm, Department of General Surgery, Humboldt University of Berlin, Campus Virchow, Berlin, Germany
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