Simvastatin therapy prevents brain trauma‐induced increases in β‐amyloid peptide levels

Abrahamson, Eric E.; Ikonomović, Miloš D.; Dixon, C. Edward; DeKosky, Steven T.

doi:10.1002/ana.21731

Cited by 88 publications

(73 citation statements)

References 65 publications

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“…The probe trial is often highly sensitive to injury (Abrahamson et al, 2009;Lok et al, 2007), and in our case shows some level of functional impairment after CCI alone. It is also a task that is largely independent of swim speed.…”

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confidence: 57%

“…We noted a spectrum of functional deficits rarely seen when CCI is studied alone (Abrahamson et al, 2009;Smith et al, 1995;Tehranian et al, 2006Tehranian et al, ,2008Whalen et al, 1999aWhalen et al, ,1999bYou et al, 2008). We chose a mild to moderate CCI to limit functional deficits and neuropathology due to CCI alone, so that the full impact of secondary HS could be revealed.…”

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confidence: 99%

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Severe Brief Pressure-Controlled Hemorrhagic Shock after Traumatic Brain Injury Exacerbates Functional Deficits and Long-Term Neuropathological Damage in Mice

Hemerka

Dixon

et al. 2012

Journal of Neurotrauma

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Hypotension after traumatic brain injury (TBI) worsens outcome. We published the first report of TBI plus hemorrhagic shock (HS) in mice using a volume-controlled approach and noted increased neuronal death. To rigorously control blood pressure during HS, a pressure-controlled HS model is required. Our hypothesis was that a brief, severe period of pressure-controlled HS after TBI in mice will exacerbate functional deficits and neuropathology versus TBI or HS alone. C57BL6 male mice were randomized into four groups (n = 10/group): sham, HS, controlled cortical impact (CCI), and CCI + HS. We used a pressure-controlled shock phase (mean arterial pressure [MAP] = 25-27 mm Hg for 35 min) and its treatment after mild to moderate CCI including, a 90 min pre-hospital phase, during which lactated Ringer's solution was given to maintain MAP > 70 mm Hg, and a hospital phase, when the shed blood was re-infused. On days 14-20, the mice were evaluated in the Morris water maze (MWM, hidden platform paradigm). On day 21, the lesion and hemispheric volumes were quantified. Neuropathology and hippocampal neuron counts (hematoxylin and eosin [H&E], Fluoro-Jade B, and NeuN) were evaluated in the mice (n = 60) at 24 h, 7 days, or 21 days (n = 5/group/time point). HS reduced MAP during the shock phase in the HS and CCI + HS groups ( p < 0.05). Fluid requirements during the pre-hospital phase were greatest in the CCI + HS group ( p < 0.05), and were increased in HS versus sham and CCI animals ( p < 0.05). MWM latency was increased on days 14 and 15 after CCI + HS ( p < 0.05). Swim speed and visible platform latency were impaired in the CCI + HS group ( p < 0.05). CCI + HS animals had increased contusion volume versus the CCI group ( p < 0.05). Hemispheric volume loss was increased 33.3% in the CCI + HS versus CCI group ( p < 0.05). CA1 cell loss was seen in CCI + HS and CCI animals at 24 h and 7 days ( p < 0.05). CA3 cell loss was seen after CCI + HS ( p < 0.05 at 24 h and 7 days). CA1 cell loss at 21 days was seen only in CCI + HS animals ( p < 0.05). Brief, severe, pressure-controlled HS after CCI produces robust functional deficits and exacerbates neuropathology versus CCI or HS alone.

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confidence: 57%

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confidence: 99%

Severe Brief Pressure-Controlled Hemorrhagic Shock after Traumatic Brain Injury Exacerbates Functional Deficits and Long-Term Neuropathological Damage in Mice

Hemerka

Dixon

et al. 2012

Journal of Neurotrauma

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“…Both of these conditions in humans have been associated with delayed events including an increased risk of developing dementia (Burri et al, 2013;Ikonomovic et al, 2004;Vincent et al, 2014), and this is supported by data derived from animal studies (Uryu et al, 2002;Tran et al, 2011). The animal studies also suggest that anti-inflammatory and antioxidant compounds such as simvastatin, or the flavonoid, luteolin can blunt the effects of TBI (Abrahamson et al, 2009;Sawmiller et al, 2014).…”

Section: Oxidative Stress In Penetrating Tbimentioning

confidence: 82%

Common biochemical defects linkage between post-traumatic stress disorders, mild traumatic brain injury (TBI) and penetrating TBI

Prasad¹,

Bondy

2015

Brain Research

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AnxietyPsychological damage a b s t r a c t Post-traumatic stress disorder (PTSD) is a complex mental disorder with psychological and emotional components, caused by exposure to single or repeated extreme traumatic events found in war, terrorist attacks, natural or man-caused disasters, and by violent personal assaults and accidents. Mild traumatic brain injury (TBI) occurs when the brain is violently rocked back and forth within the skull following a blow to the head or neck as in contact sports, or when in close proximity to a blast pressure wave following detonation of explosives in the battlefield. Penetrating TBI occurs when an object penetrates the skull and damages the brain, and is caused by vehicle crashes, gunshot wound to the head, and exposure to solid fragments in the proximity of explosions, and other combat-related head injuries. Despite clinical studies and improved understanding of the mechanisms of cellular damage, prevention and treatment strategies for patients with PTSD and TBI remain unsatisfactory. To develop an improved plan for treating and impeding progression of PTSD and TBI, it is important to identify underlying biochemical changes that may play key role in the initiation and progression of these disorders. This review identifies three common biochemical events, namely oxidative stress, chronic inflammation and excitotoxicity that participate in the initiation and progression of these conditions. While these features are separately discussed, in many instances, they overlap. This review also addresses the goal of developing novel treatments and drug regimens, aimed at combating this triad of events common to, and underlying, injury to the brain.

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“…Total 44 100 P E R S P E C T I V E (27), and brain injury (28,29). A search of the literature reveals no systematic neuroPK studies in any mouse strain that would enable direct comparisons of CNS exposure across the various statins.…”

Section: Databases and Repurposingmentioning

confidence: 99%

Data gaps limit the translational potential of preclinical research

Kleiman

Ehlers

2016

Sci. Transl. Med.

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Simvastatin therapy prevents brain trauma‐induced increases in β‐amyloid peptide levels

Cited by 88 publications

References 65 publications

Severe Brief Pressure-Controlled Hemorrhagic Shock after Traumatic Brain Injury Exacerbates Functional Deficits and Long-Term Neuropathological Damage in Mice

Severe Brief Pressure-Controlled Hemorrhagic Shock after Traumatic Brain Injury Exacerbates Functional Deficits and Long-Term Neuropathological Damage in Mice

Common biochemical defects linkage between post-traumatic stress disorders, mild traumatic brain injury (TBI) and penetrating TBI

Data gaps limit the translational potential of preclinical research

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