Acute lipophilicity-dependent effect of intravascular simvastatin in the early phase of focal cerebral ischemia

Beretta, Simone; Pastori, Chiara; Sala, Gessica; Piazza, Fabrizio; Ferrarese, Carlo; Cattalini, Alessandro; Curtis, Marco de; Librizzi, Laura

doi:10.1016/j.neuropharm.2011.01.003

Cited by 21 publications

(11 citation statements)

References 48 publications

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“…Activation of CREB has been associated with the MAPK/ERK and the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways, both implicated in LTP and memory processes (Davis et al, 2000;Jones et al, 2001;Bozon et al, 2003;Mizuno et al, 2003). Most relevant to the present findings, these pathways are activated by simvastatin (Li et al, 2006;Beretta et al, 2011), and a body of evidence has recently accumulated for a role of the PI3K pathway in the positive effect of simvastatin on memory. Particularly, chronic simvastatin treatment increased brain levels of total and phosphorylated Akt (P-Akt) in WT mice with enhanced learning and memory performance (Li et al, 2006).…”

Section: Discussionmentioning

confidence: 52%

Age-Dependent Rescue by Simvastatin of Alzheimer's Disease Cerebrovascular and Memory Deficits

Tong¹,

Lecrux²,

Hamel³

2012

J. Neurosci.

145

162

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Alzheimer's disease (AD) is now established as a progressive compromise not only of the neurons but also of the cerebral vasculature. Increasing evidence also indicates that cerebrovascular dysfunction may be a key or an aggravating pathogenic factor in AD, emphasizing the importance to properly control this deficit when aiming for effective therapy. Here, we report that simvastatin (3-6 months, 40 mg/kg/d) completely rescued cerebrovascular reactivity, basal endothelial nitric oxide synthesis, and activity-induced neurometabolic and neurovascular coupling in adult (6 months) and aged (12 months) transgenic mice overexpressing the Swedish and Indiana mutations of the human amyloid precursor protein (AD mice). Remarkably, simvastatin fully restored short-and long-term memory in adult, but not in aged AD mice. These beneficial effects occurred without any decreasing effect of simvastatin on brain amyloid-␤ (A␤) levels or plaque load. However, in AD mice with recovered memory, protein levels of the learning-and memory-related immediate early genes c-Fos and Egr-1 were normalized or upregulated in hippocampal CA1 neurons, indicative of restored neuronal function. In contrast, the levels of phospholipase A2, enkephalin, PSD-95, synaptophysin, or glutamate NMDA receptor subunit type 2B were either unaltered in AD mice or unaffected by treatment. These findings disclose new sites of action for statins against A␤-induced neuronal and cerebrovascular deficits that could be predictive of therapeutic benefit in AD patients. They further indicate that simvastatin and, possibly, other brain penetrant statins bear high therapeutic promise in early AD and in patients with vascular diseases who are at risk of developing AD.

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Section: Discussionmentioning

confidence: 52%

Age-Dependent Rescue by Simvastatin of Alzheimer's Disease Cerebrovascular and Memory Deficits

Tong¹,

Lecrux²,

Hamel³

2012

J. Neurosci.

145

162

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“…For instance, many antioxidants are reported to reduce ROS-mediated reactions and rescue hippocampal neurons from ischemia-reperfusion-induced neuronal loss in animal models of forebrain ischemia [14, 15, 35, 42, 43]. Additionally, statins protect against cerebral ischemia by limiting oxidative stress-induced damage [28–30]. …”

Section: Discussionmentioning

confidence: 99%

“…It protected rat heart against ischemia-reperfusion arrhythmias-induced cardiac damage [27]. Recently, it has been reported that other cholesterol lowering drugs such as simvastatin have been shown to be neuroprotective against cerebral ischemia-induced neuronal damage [28–31]. Although the therapeutic potential of probucol for the treatment of many forms of heart diseases, including myocardial ischemia reperfusion, is well documented, its direct role in forebrain ischemia-induced hippocampal damage has not been studied yet.…”

Section: Introductionmentioning

confidence: 99%

Probucol Attenuates Oxidative Stress, Energy Starvation, and Nitric Acid Production Following Transient Forebrain Ischemia in the Rat Hippocampus

Al-Majed

2011

Oxidative Medicine and Cellular Longevity

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Oxidative stress and energy depletion are believed to participate in hippocampal neuronal damage after forebrain ischemia. This study has been initiated to investigate the potential neuroprotective effects of probucol, a lipid-lowering drug with strong antioxidant properties, against transient forebrain ischemia-induced neuronal damage and biochemical abnormalities in rat hippocampal CA1 region. Adult male Wistar albino rats were subjected to forebrain ischemia and injected with probucol for the next 7 successive days, and compared to controls. Forebrain ischemia resulted in a significant decrease in the number of intact neurons (77%), glutathione (GSH), and adenosine triphosphate (ATP), and a significant increase in thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite, (NOx) production in hippocampal tissues. The administration of probucol attenuated forebrain ischemia-induced neuronal damage, manifested as a complete reversal of the decrease in the number of intact neurons, ATP and GSH and the increase in TBARS and NOx in hippocampal tissues. This study demonstrates that probucol treatment abates forebrain ischemia-induced hippocampal neuronal loss, energy depletion, and oxidative stress in hippocampal CA1 region. Thus, probucol could be a promising neuroprotective agent in the treatment of forebrain ischemia.

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“…In addition to natural extracts, studies have found that commonly used cardiovascular drugs such as simvastatin (transfusion of lipids) and trimetazidine (anti-angina drugs) have anti-CIRI effects, and that the mechanism involves anti-oxidative activity (Dhote and Balaraman, 2008;Beretta et al, 2011;Anthony Jalin et al, 2015). Lipophilic simvastatin can significantly improve the antioxidant capacity of ischemic brain tissue, while hydrophilic simvastatin has no obvious brain protection properties (Beretta et al, 2011), suggesting that increasing bloodcerebrospinal fluid barrier permeability could be an effective way to improve the treatment of CIRI with existing drugs. Edaravone, which is widely used in Asian countries, can improve mitochondrial edema, increase the expression of eNOS, reduce free radical formation, reduce cerebral infarction area, and prevent delayed neuronal damage (Fujiwara et al, 2016).…”

Section: Synthetic Antioxidantmentioning

confidence: 99%

Targeting Oxidative Stress and Inflammation to Prevent Ischemia-Reperfusion Injury

Xiong

et al. 2020

Front. Mol. Neurosci.

299

197

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The cerebral ischemia injury can result in neuronal death and/or functional impairment, which leads to further damage and dysfunction after recovery of blood supply. Cerebral ischemia/reperfusion injury (CIRI) often causes irreversible brain damage and neuronal injury and death, which involves many complex pathological processes including oxidative stress, amino acid toxicity, the release of endogenous substances, inflammation and apoptosis. Oxidative stress and inflammation are interactive and play critical roles in ischemia/reperfusion injury in the brain. Oxidative stress is important in the pathological process of ischemic stroke and is critical for the cascade development of ischemic injury. Oxidative stress is caused by reactive oxygen species (ROS) during cerebral ischemia and is more likely to lead to cell death and ultimately brain death after reperfusion. During reperfusion especially, superoxide anion free radicals, hydroxyl free radicals, and nitric oxide (NO) are produced, which can cause lipid peroxidation, inflammation and cell apoptosis. Inflammation alters the balance between pro-inflammatory and anti-inflammatory factors in cerebral ischemic injury. Inflammatory factors can therefore stimulate or exacerbate inflammation and aggravate ischemic injury. Neuroprotective therapies for various stages of the cerebral ischemia cascade response have received widespread attention. At present, neuroprotective drugs mainly include free radical scavengers, anti-inflammatory agents, and anti-apoptotic agents. However, the molecular mechanisms of the interaction between oxidative stress and inflammation, and their interplay with different types of programmed cell death in ischemia/reperfusion injury are unclear. The development of a suitable method for combination therapy has become a hot topic.

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Acute lipophilicity-dependent effect of intravascular simvastatin in the early phase of focal cerebral ischemia

Cited by 21 publications

References 48 publications

Age-Dependent Rescue by Simvastatin of Alzheimer's Disease Cerebrovascular and Memory Deficits

Age-Dependent Rescue by Simvastatin of Alzheimer's Disease Cerebrovascular and Memory Deficits

Probucol Attenuates Oxidative Stress, Energy Starvation, and Nitric Acid Production Following Transient Forebrain Ischemia in the Rat Hippocampus

Targeting Oxidative Stress and Inflammation to Prevent Ischemia-Reperfusion Injury

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