Simvastatin and atorvastatin improve behavioral outcome, reduce hippocampal degeneration, and improve cerebral blood flow after experimental traumatic brain injury

Wang, Hai-Chen; Lynch, John; Song, Pingping; Yang, Hyuk Jun; Yates, Robert D.; Mace, Brian; Warner, David S.; Guyton, John R.; Laskowitz, Daniel T.

doi:10.1016/j.expneurol.2007.03.031

Cited by 166 publications

(124 citation statements)

References 40 publications

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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%

“…The administration of atorvastatin significantly decreased this response at all time points measured. 10 In addition to reducing oxidative stress via downregulation of microglial activity, statins decreased the production of other harmful oxygen free radicals, such as superoxide, when baseline inflammation was present. 21 Various statins have been shown in large clinical trials to decrease systemic markers of inflammation, such as high sensitivity C-reactive protein.…”

Section: Effects On Inflammation and Excitotoxicitymentioning

confidence: 99%

“…30 In laboratory studies, statins are associated with a reduction in post-traumatic hypoperfusion and rebound hyperemia. 10 Cerebral autoregulation is impaired after TBI, with the pial arterioles unable to respond to changes in PCO 2 and PO 2 . 31 The lack of normal vasomotor reactivity renders the already compromised brain exquisitely sensitive to modest hypoxemia or relative hypotension that would otherwise be well tolerated.…”

Section: Vascular and Endothelial Effectsmentioning

confidence: 99%

“…36 -39 However, the data is mixed, as decreased eNOS RNA levels were found in one murine model of TBI, and eNOS RNA levels were unchanged by statin treatment. 10 Therefore, the exact role of eNOS in TBI is unclear, although it remains possible that statins could affect the eNOS system downstream from transcription.…”

Section: Vascular and Endothelial Effectsmentioning

confidence: 99%

“…Various animal models have shown improvement of neuron survival in both areas with statin administration. 10,11,43,44 Neuronal loss may continue up to 35 days post-TBI, and statin treatment decreases the degree and rate of hippocampal neuron loss. 44 Statins suppress the activation of caspase-3, a key protease in the apoptotic pathway, as early as 1 day after statin treatment.…”

Section: Effects On Apoptosismentioning

confidence: 99%

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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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Section: Acute Lesional Effectsmentioning

confidence: 99%

Section: Effects On Inflammation and Excitotoxicitymentioning

confidence: 99%

Section: Vascular and Endothelial Effectsmentioning

confidence: 99%

Section: Vascular and Endothelial Effectsmentioning

confidence: 99%

Section: Effects On Apoptosismentioning

confidence: 99%

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Statins in Traumatic Brain Injury

Wible

Laskowitz

2010

Neurotherapeutics

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Approaches to Amyloid Therapies for the Treatment of Alzheimer's Disease

Robichaud

Kim

Jacobsen

2010

Burger's Medicinal Chemistry and Drug Discovery

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Recognized as the most common of the neurodegenerative disorders, Alzheimer's disease (AD) affects greater than 18 million people worldwide and is predicted to become the largest socioeconomic burden of the twenty‐first century. The underlying mechanism of Alzheimer's disease is as yet unknown, but the growing body of pathophysiologic evidence is beginning to point to two main causes, the formation of β‐amyloid plaques and neurofibrillary tangles. This review will cover approaches to disease modification that are based on the amyloid hypothesis; that being, the prevention of the accumulation, aggregation, and deposition of β‐amyloid peptide (Aβ) monomers, leading first to multiple oligomeric species and then to fibrils and ultimately senile plaques, is the center of focus for an approach to disease modification. There is a wealth of evidence to implicate this peptide and its subsequent aggregation in the etiology of the disease and approaches, both small molecule and biopharmaceutical, to prevent its accumulation have been the subject of much research. The vast majority of this research over the last decade has been, and continues to be, focused on these disease‐modifying, antiamyloidogenic approaches to AD. It is this subject, and the various approaches, past and present to amelioration of AD through the various agents being explored, that will be the focus of this chapter.

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

Abrahamson

Ikonomović

Dixon

et al. 2009

Annals of Neurology

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Elevations in beta-amyloid peptide (A beta) levels after traumatic brain injury (TBI) may confer risk for developing Alzheimer's disease in head trauma patients. We investigated the effects of simvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, on hippocampal A beta burden in a clinically relevant head injury/intervention model using mice expressing human A beta. Simvastatin therapy blunted TBI-induced increases in A beta, reduced hippocampal tissue damage and microglial activation, and improved behavioral outcome. The ability of statins to reduce post-injury A beta load and ameliorate pathological sequelae of brain injury makes them potentially effective in reducing the risk of developing Alzheimer's disease in TBI patients.

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Simvastatin and atorvastatin improve behavioral outcome, reduce hippocampal degeneration, and improve cerebral blood flow after experimental traumatic brain injury

Cited by 166 publications

References 40 publications

Statins in Traumatic Brain Injury

Statins in Traumatic Brain Injury

Approaches to Amyloid Therapies for the Treatment of Alzheimer's Disease

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

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