Statins in the Management of Aneurysmal Subarachnoid Hemorrhage: An Overview of Animal Research, Observational Studies, Randomized Controlled Trials and Meta-analyses

Kramer, Andreas H.

doi:10.1007/978-3-7091-0356-2_36

Cited by 7 publications

(7 citation statements)

References 59 publications

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“…166 Subsequent studies have yielded conflicting results, with high-dose statin treatment in animal models showing a definite neuroprotective effect, whereas studies in SAH patients remain inconclusive. 167, 168 In addition to its effects of endothelial function, statins also reduce blood viscosity by lowering blood lipid levels, and would therefore be expected to facilitate the capillary passage of blood and thus reduce CTH. The lipid-lowering effect of statins becomes significant 2 to 4 days after initiation of treatment in normocholesterolemic subjects, 169 and improved blood viscosity could therefore contribute to a protective effect in the days after SAH.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

The Role of the Microcirculation in Delayed Cerebral Ischemia and Chronic Degenerative Changes after Subarachnoid Hemorrhage

Østergaard

Aamand

Karabegovic

et al. 2013

J Cereb Blood Flow Metab

141

147

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The mortality after aneurysmal subarachnoid hemorrhage (SAH) is 50%, and most survivors suffer severe functional and cognitive deficits. Half of SAH patients deteriorate 5 to 14 days after the initial bleeding, so-called delayed cerebral ischemia (DCI). Although often attributed to vasospasms, DCI may develop in the absence of angiographic vasospasms, and therapeutic reversal of angiographic vasospasms fails to improve patient outcome. The etiology of chronic neurodegenerative changes after SAH remains poorly understood. Brain oxygenation depends on both cerebral blood flow (CBF) and its microscopic distribution, the so-called capillary transit time heterogeneity (CTH). In theory, increased CTH can therefore lead to tissue hypoxia in the absence of severe CBF reductions, whereas reductions in CBF, paradoxically, improve brain oxygenation if CTH is critically elevated. We review potential sources of elevated CTH after SAH. Pericyte constrictions in relation to the initial ischemic episode and subsequent oxidative stress, nitric oxide depletion during the pericapillary clearance of oxyhemoglobin, vasogenic edema, leukocytosis, and astrocytic endfeet swelling are identified as potential sources of elevated CTH, and hence of metabolic derangement, after SAH. Irreversible changes in capillary morphology and function are predicted to contribute to long-term relative tissue hypoxia, inflammation, and neurodegeneration. We discuss diagnostic and therapeutic implications of these predictions.

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Section: Therapeutic Implicationsmentioning

confidence: 99%

The Role of the Microcirculation in Delayed Cerebral Ischemia and Chronic Degenerative Changes after Subarachnoid Hemorrhage

Østergaard

Aamand

Karabegovic

et al. 2013

J Cereb Blood Flow Metab

141

147

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“…Keeping these adverse effects in mind, especially those of the single statin doses, and in light of the possibility of statin intolerance [ 16 , 17 ] reported clinically, further in-depth exploration of an animal model for single-dose statin intolerance is warranted. It is, however, difficult to directly extrapolate experimental animal-based data to humans because of species variation, and the drug dosages used clinically could vary considerably from those of the experimental studies in animals, in which doses of statins could be up to 80 times higher than those applied in human beings [ 1 , 2 , 25 , 29 ]. This is especially true when the endpoint effect is not the plasma cholesterol [ 14 , 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…It is, however, difficult to directly extrapolate experimental animal-based data to humans because of species variation, and the drug dosages used clinically could vary considerably from those of the experimental studies in animals, in which doses of statins could be up to 80 times higher than those applied in human beings [ 1 , 2 , 25 , 29 ]. This is especially true when the endpoint effect is not the plasma cholesterol [ 14 , 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress-Induced Adverse Effects of Three Statins Following Single or Repetitive Treatments in Mice

Al-Shalchi,

Mohammad

2024

Cureus

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Background and objective The hypolipidemic statins have been associated with various side effects, and in some cases, adverse reactions in humans and experimental animals, such as myotoxicity, neurobehavioral toxicity, as well as liver and kidney injuries. The purpose of the present study was to examine the possibility of the induction of oxidative stress in the brain and plasma of mice dosed with single or repetitive doses of three statins (atorvastatin, simvastatin, and rosuvastatin). Methods Male Swiss-origin mice were dosed orally with single doses of each of the three statins at 500 or 1000 mg/kg of body weight. Other groups of mice were dosed orally with repeated daily doses of each of the statins at 200 mg/kg of body weight/day for 14 or 28 consecutive days. These doses of statins were chosen to not produce overt toxicity in mice within the time frame allocated for each experiment. Brain and plasma glutathione (GSH) and malondialdehyde (MDA) levels, as well as liver enzymes activities alanine transaminase (ALT) and aspartate transaminase (AST), were determined using commercial kits. Results Single-dose treatments of the mice with the statins at either 500 or 1000 mg/kg significantly and dose-dependently (p < 0.05) reduced the GSH level in the plasma and the whole brain when compared with respective control values. Atorvastatin was the least effective statin, as only the high dose achieved a significant reduction in brain GSH level in comparison with the respective control value. Repetitive administration of the three statins at 200 mg/kg of body weight/day for 14 or 28 consecutive days significantly and time-dependently reduced plasma and brain GSH levels in comparison with respective control values. The oxidative stress biomarker MDA level significantly increased in the plasma and brain of mice following single or repetitive treatments with the three statins, and the most effective one was rosuvastatin. In association with these changes, activities of the liver enzymes ALT and AST were also increased in the plasma with single and repetitive statin treatments, and the most effective one was rosuvastatin. Conclusion The data suggest an association of high doses of three statins (atorvastatin, simvastatin, and rosuvastatin) with the induction of oxidative stress manifested as GSH reduction and MDA elevation as adverse effects in the brain and plasma of mice, which suffered from the additional burden of liver injury. These effects could be the basis of an in-depth exploration of statin adverse effects in experimental animals and to find an animal model, probably the mice, for the induction of adverse effects of statins that target the brain, as well as to shed light on potential statin intolerance outcomes following single-dose treatments in this species.

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“…Statins improve endothelial function and increase the mRNA and protein expression of eNOS, and enzymatic activity three-fold. The results of previous animal models of SAH suggest that statins may ameliorate cerebral vasospasm (38,39). It has been hypothesized that patients chronically treated with statins may exhibit a decreased risk of symptomatic vasospasm after SAH.…”

Section: Discussionmentioning

confidence: 99%

Effects of simvastatin and taurine on delayed cerebral vasospasm following subarachnoid hemorrhage in rabbits

Lin

Zhao

Wan

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The aim of the current study was to observe the effects of simvastatin and taurine on delayed cerebral vasospasm (DCVS) following experimental subarachnoid hemorrhage (SAH) in rabbits. A total of 48 New Zealand white rabbits were allocated at random into four groups (control, SAH, SAH + simvastatin and SAH + taurine groups; n=12 each). The rabbit model of DCVS was established using a double hemorrhage method, which involved injecting autologous arterial blood into the cisterna magna in the SAH groups. The SAH + simvastatin group was administered oral simvastatin (5 mg/kg) daily between days 0-6. The SAH + taurine group was administered oral taurine (50 mg/kg) daily between days 0-6. Starch (50 mg/kg) was administered orally to the animals in the other two groups (control and SAH groups). The control group were not subjected to any other injections or treatment. The internal diameter and internal diameter/wall thickness of the basilar artery (BA) were measured. The expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were determined using immunohistochemical and quantitative polymerase chain reaction methods following the sacrifice of all animals on day 7. The activity of nuclear factor (NF)-κB in the BA was also measured using an electrophoretic mobility shift assay. The BA walls in the SAH + simv astatin and SAH + taurine groups exhibited reduced narrowing and corrugation of the tunica elastica interna compared with the SAH group. At the protein and cDNA levels, it was found that cerebral vasospasm of the BA in the SAH + simvastatin and SAH + taurine groups was allevi ated, as indicated by the reduced expression of TNF-α, IL-1β, IL-6 and NF-κB compared with the SAH group (P<0.05). In conclusion, simvastatin and taurine reduced DCVS following SAH in rabbits, which suggests that these compounds may exert anti-inflammatory effects.

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Statins in the Management of Aneurysmal Subarachnoid Hemorrhage: An Overview of Animal Research, Observational Studies, Randomized Controlled Trials and Meta-analyses

Abstract: the role of statins in the management of patients with SAH remains unclear. Although promising, statins should not, at this time, be considered standard care.

Cited by 7 publications

References 59 publications

The Role of the Microcirculation in Delayed Cerebral Ischemia and Chronic Degenerative Changes after Subarachnoid Hemorrhage

The Role of the Microcirculation in Delayed Cerebral Ischemia and Chronic Degenerative Changes after Subarachnoid Hemorrhage

Oxidative Stress-Induced Adverse Effects of Three Statins Following Single or Repetitive Treatments in Mice

Effects of simvastatin and taurine on delayed cerebral vasospasm following subarachnoid hemorrhage in rabbits

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