Lovastatin improves histological and functional outcomes and reduces inflammation after experimental traumatic brain injury

Chen, Szu Fu; Hung, Tai-Ho; Chen, Chien Cheng; Lin, Kuei Han; Huang, Ya‐Fang; Tsai, Hung Chih; Wang, Jia Yi

doi:10.1016/j.lfs.2007.05.023

Cited by 111 publications

(85 citation statements)

References 66 publications

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“…TBI in rodents also increases levels of activated glial cells and proinflammatory cytokines, [34][35][36][37][38] and administration of these cytokines increases anxiety-like behaviors. [29][30][31][32] The aim of the present study was therefore to determine whether neuroinflammation is associated with the long-term maintenance of post-traumatic anxiety in an animal model.…”

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confidence: 99%

“…Peri-injury and immediate postinjury immunosuppression have been found to be neuroprotective after TBI in rodents, resulting in increased structural preservation and improved functional outcomes. 104 Early administration of the immunosuppressant drugs, minocycline, statins, cyclosporin A, and FK506, have been shown to exert anti-inflammatory effects through suppression of micro-and astroglial production of IL-1b, TNF-a, and IL-6, resulting in reduced functional deficits, cerebral edema, and brain lesion volumes, [35][36][37][38]66 improving mitochondrial preservation, reducing dendritic spine loss, and improving cognitive performance and functional motor recovery. 105,106 Our previous investigation found that peri-injury Ibudilast treatment attenuated glial cell activation at the time of injury, resulting in reduced anxiety-like behaviors and immunological impairments after LFPI.…”

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confidence: 99%

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Reversal of Established Traumatic Brain Injury-Induced, Anxiety-Like Behavior in Rats after Delayed, Post-Injury Neuroimmune Suppression

Rodgers

Deming

Bercum

et al. 2014

Journal of Neurotrauma

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Traumatic brain injury (TBI) increases the risk of neuropsychiatric disorders, particularly anxiety disorders. Yet, there are presently no therapeutic interventions to prevent the development of post-traumatic anxiety or effective treatments once it has developed. This is because, in large part, of a lack of understanding of the underlying pathophysiology. Recent research suggests that chronic neuroinflammatory responses to injury may play a role in the development of post-traumatic anxiety in rodent models. Acute peri-injury administration of immunosuppressive compounds, such as Ibudilast (MN166), have been shown to prevent reactive gliosis associated with immune responses to injury and also prevent lateral fluid percussion injury (LFPI)-induced anxiety-like behavior in rats. There is evidence in both human and rodent studies that post-traumatic anxiety, once developed, is a chronic, persistent, and drug-refractory condition. In the present study, we sought to determine whether neuroinflammation is associated with the long-term maintenance of post-traumatic anxiety. We examined the efficacy of an anti-inflammatory treatment in decreasing anxiety-like behavior and reactive gliosis when introduced at 1 month after injury. Delayed treatment substantially reduced established LFPI-induced freezing behavior and reactive gliosis in brain regions associated with anxiety and continued neuroprotective effects were evidenced 6 months post-treatment. These results support the conclusion that neuroinflammation may be involved in the development and maintenance of anxiety-like behaviors after TBI.

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confidence: 99%

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confidence: 99%

Reversal of Established Traumatic Brain Injury-Induced, Anxiety-Like Behavior in Rats after Delayed, Post-Injury Neuroimmune Suppression

Rodgers

Deming

Bercum

et al. 2014

Journal of Neurotrauma

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“…Glial activation is normally neuroprotective (26,32); however, the chronic inflammatory responses and exaggerated proinflammatory cytokine levels observed following injury initiate neurotoxic processes resulting in secondary tissue damage (20,(33)(34)(35), neuronal death (29,(36)(37)(38), secondary injury cascades (39)(40)(41)(42)(43) and neuronal hyperexcitability (28, 34, 38, 44). There is substantial support for chronic inflammation following TBI.…”

Section: Post-traumatic Anxiety Is a Leading And Devastating Consequementioning

confidence: 99%

Targeting Microglia to Prevent Post-Traumatic Epilepsy

Barth¹

2014

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE July 2014 REPORT TYPE PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)The Regents of the University of Colorado Boulder, CO 80303-1058 31 AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThe purpose of this research project is to explore anti-epileptogenic strategies in and animal model of post-traumatic epilepsy (PTE) using lateral fluid percussion injury (LFPI). Our focus is on attenuating damaging effects of hyperexcitability in the brain induced by inflammation resulting from glial cell immune responses to trauma. We are exploring two drugs, MN166 and SLC022, that are known to suppress post-traumatic glial activation and thus inflammation to evaluate their effectiveness in preventing epileptogenesis in the LFPI model of PTE. In the first project year we developed a high-speed video/EEG recording and analysis system for rapid quantification of chronically recorded epileptiform activity in multiple (24-32) subjects. With this system we became expert in identifying epileptiform versus normal video/EEG activity in the rodent and discovered an important source of artifact currently being interpreted in other published reports as seizure activity. We developed a pilocarpine model of temporal lobe epilepsy to explore the effectiveness of glial cell (neuroimmune) attenuation in preventing or limiting epileptogenesis (development of epilepsy) in this rapidly developing model. We explored numerous changes in the LFPI model to produce earlier developing signs of epilepsy, increasing the probability of succeeding in our long-term study of epileptogenesis following traumatic brain injury. Perhaps the most important outcome of this work was the negative finding that much published work concerning PTE with the LFPI model has not properly examined controls. Both injured and uninjured rats displ...

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“…For example, cortical contusional volume was decreased when rats were treated with lovastatin prior to experimental TBI, 9 although this result was not replicated with simvastatin or atorvastatin. 10 When animals were treated with statins post-injury, no…”

Section: Acute Lesional Effectsmentioning

confidence: 99%

“…In particular, tumor necrosis factor-␣ (TNF-␣), 9,15 interleukin-6 (IL)-6, 15 and IL-1␤ 9 are increased and associated with the loss of BBB integrity, likely contributing to cerebral edema. Recently, the toll-like receptor (TLR) 4 pathway has been proposed as the mechanism by which these mediators cause inflammation after TBI.…”

Section: Effects On Inflammation and Excitotoxicitymentioning

confidence: 99%

Statins in Traumatic Brain Injury

Wible

Laskowitz

2010

Neurotherapeutics

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Summary: Traumatic brain injury (TBI) is a common cause of long-term neurological morbidity, with devastating personal and societal consequences. At present, no pharmacological intervention clearly improves outcomes, and therefore a compelling unmet clinical need remains. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or "statins," offer a potential novel therapeutic strategy for TBI. Statins are well tolerated, easy to administer, and have a long clinical track record in critically ill patients. Their side effects are well defined and easily monitored. Preclinical studies have shown significant benefit of statins in models of TBI and related disease processes, including cerebral ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage. In fact, multiple mechanisms have been defined by which statins may exert benefit after acute brain injury. Statins are currently positioned to be translated into clinical trials in acute brain injury and have the potential to improve outcomes after TBI.

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Lovastatin improves histological and functional outcomes and reduces inflammation after experimental traumatic brain injury

Cited by 111 publications

References 66 publications

Reversal of Established Traumatic Brain Injury-Induced, Anxiety-Like Behavior in Rats after Delayed, Post-Injury Neuroimmune Suppression

Reversal of Established Traumatic Brain Injury-Induced, Anxiety-Like Behavior in Rats after Delayed, Post-Injury Neuroimmune Suppression

Targeting Microglia to Prevent Post-Traumatic Epilepsy

Statins in Traumatic Brain Injury

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