Dose-Dependent Neuroprotection and Neurotoxicity of Simvastatin through Reduction of Farnesyl Pyrophosphate in Mice Treated with Intracerebroventricular Injection of Aβ 1-42

Jin, Huafeng; Chen, Tingting; Li, Guoxi; Wang, Conghui; Zhang, Baofeng; Cao, Xiufeng; Sha, Sha; Wan, Qi; Chen, Ling

doi:10.3233/jad-150782

Cited by 14 publications

(11 citation statements)

References 49 publications

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“…The dosage of statins seems to be important for their overall effect on neurons. Signs of dose‐dependent neuroprotection and neurotoxicity of simvastatin in a ‘U‐type’ manner were observed in a study on an AD mouse model . The production and release of Aβ observed with statin treatment was reduced in a dose‐dependent manner in two studies, but with contradictory findings.…”

Section: Medications With Potential Effects On the Brain Cholesterol mentioning

confidence: 99%

“… The isoprenoid effect has been attributed to intracellular levels of GGPP and FPP which exhibit opposing effects on cognition . The effect of statins on the isoprenoid levels seems to be dose‐dependent. Low doses of statins preferentially affected the isoprenoid synthesis in cell models , without change in intracellular cholesterol levels, which resulted in decreased Aβ production . The beneficial role of statins on cognition related to the isoprenoid levels has been suggested to be a result of preferentially lowering FPP levels . More specifically, a protective mechanism of statins against glutamate excitotoxicity has been shown to occur by diminishing FPP levels.…”

Section: Medications With Potential Effects On the Brain Cholesterol mentioning

confidence: 99%

“…More specifically, a protective mechanism of statins against glutamate excitotoxicity has been shown to occur by diminishing FPP levels. This resulted in disassociation of glutamate NMDA receptors and lipid rafts or increased phosphorylation of the NR2B subunit of the receptor . GGPP is required for learning and has a role in memory as it is essential for long‐term potentiation in the hippocampus and promotes neurite outgrowth . Additionally, GGPP has a beneficial role in amyloid processing by regulating the active γ‐secretase complex and membrane raft association .…”

Section: Medications With Potential Effects On the Brain Cholesterol mentioning

confidence: 99%

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Connecting the brain cholesterol and renin–angiotensin systems: potential role of statins and RAS‐modifying medications in dementia

et al. 2018

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Petek B, Sweden; S€ odersjukhuset, Stockholm, Sweden). Connecting the brain cholesterol and reninangiotensin systems: potential role of statins and RAS-modifying medications in dementia (Review). J Intern Med 2018;284: 620-642.Millions of people worldwide receive agents targeting the renin-angiotensin system (RAS) to treat hypertension or statins to lower cholesterol. The RAS and cholesterol metabolic pathways in the brain are autonomous from their systemic counterparts and are interrelated through the cholesterol metabolite 27-hydroxycholesterol (27-OHC). These systems contribute to memory and dementia pathogenesis through interference in the amyloid-beta cascade, vascular mechanisms, glucose metabolism, apoptosis, neuroinflammation and oxidative stress. Previous studies examining the relationship between these treatments and cognition and dementia risk have produced inconsistent results. Defining the blood-brain barrier penetration of these medications has been challenging, and the mechanisms of action on cognition are not clearly established. Potential biases are apparent in epidemiological and clinical studies, such as reverse epidemiology, indication bias, problems defining medication exposure, uncertain and changing doses, and inappropriate grouping of outcomes and medications. This review summarizes current knowledge of the brain cholesterol and RAS metabolism and the mechanisms by which these pathways affect neurodegeneration. The putative mechanisms of action of statins and medications inhibiting the RAS will be examined, together with prior clinical and animal studies on their effects on cognition. We review prior epidemiological studies, analysing their strengths and biases, and identify areas for future research. Understanding the pathophysiology of the brain cholesterol system and RAS and their links to neurodegeneration has enormous potential. In future, well-designed epidemiological studies could identify potential treatments for Alzheimer's disease (AD) amongst medications that are already in use for other indications.2 Promotion of oxidative stress by acting on LRX in astroglia [90,91].Brain cholesterol and RAS in dementia / B. Petek et al.

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Section: Medications With Potential Effects On the Brain Cholesterol mentioning

confidence: 99%

Section: Medications With Potential Effects On the Brain Cholesterol mentioning

confidence: 99%

Section: Medications With Potential Effects On the Brain Cholesterol mentioning

confidence: 99%

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Connecting the brain cholesterol and renin–angiotensin systems: potential role of statins and RAS‐modifying medications in dementia

et al. 2018

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“…CA/CPR-induced hypoxic brain injury and cholesterol-lowering action by lipophilic statins may be particularly harmful in this scenario. Indeed, it has been shown that neurotoxic effects of simvastatin in models of cognitive dysfunction could be rescued by the application of cholesterol synthesis intermediates (39) . However, we can only speculate about the actual brain injury as we refrained from systematic histological investigation or correlation of neurofunction with surrogate parameters of cerebral tissue injury.…”

Section: Discussionmentioning

confidence: 99%

Pravastatin But Not Simvastatin Improves Survival and Neurofunctional Outcome After Cardiac Arrest and Cardiopulmonary Resuscitation

Bergt

Grub

Wagner

et al. 2017

JACC: Basic to Translational Science

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“…Male mice (ICR, Xuzhou Medical University Animal Experiment Center), aged 3 months, were used in this study. The Aβ 1-42 -mice were obtained as previously described as AD model 19. The experimental programs were approved by the Ethics Committee of Animal Laboratory of Xuzhou Medical University and conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.…”

Section: Methodsmentioning

confidence: 99%

<p>Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer’s Disease</p>

Wang¹,

Wang²,

Zhu³

et al. 2019

DDDT

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BackgroundAlzheimer’s disease (AD), a leading cause of dementia, becomes a serious health issue for individuals and society around the world. AD is a neurodegenerative disease characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles (NFT) and the loss of large numbers of neurons. To date, there is no effective treatment for AD, and thus, to enhance neurogenesis in the AD brain may be a therapeutic strategy. RAS signaling pathway involves in synaptic plasticity and memory formation, which is overexpressed in brains with AD. This study used Aβ1-42-injected mice (Aβ1-42-mice) as the AD model to investigate the effects of S-trans, trans-farnesylthiosalicylic acid (FTS), a synthetic Ras inhibitor, on the impairment of neurogenesis and the spatial cognitive deﬁcits.Materials and methodsAD model mice were manufactured through intracerebroventricular injection of Aβ1-42. Morris water maze (MWM) was performed to evaluate the capacity of spatial memory, and Nissl staining was applied to assess neuronal damage in the hippocampus CA1. Immunohistochemistry of 5-bromo-2-deoxyuridine (BrdU), BrdU/neuronal nuclei (NeuN), and doublecortin (DCX) were used to detect progenitor cell proliferation, maturation, and neurite growth, respectively. And the expression levels of RAS, ERK/ERK phosphorylation (p-ERK) and CREB/CREB phosphorylation (p-CREB) were detected by Western blot.ResultsThe results demonstrated that FTS could prevent Aβ1-42 to impair survival and neurite growth of newborn neurons in the hippocampal dentate gyrus (DG) in Aβ1-42-mice. Furthermore, behavioral indexes and morphological findings showed that FTS improved the learning and spatial memory abilities of Aβ1-42-mice. In addition, FTS could inhibit the levels of hippocampal p-ERK and p-CREB activated by Aβ, which is the underlying molecular mechanism.ConclusionIn conclusion, these findings suggest that FTS as a RAS inhibitor could be a potential therapeutic agent for the treatment of AD.

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Dose-Dependent Neuroprotection and Neurotoxicity of Simvastatin through Reduction of Farnesyl Pyrophosphate in Mice Treated with Intracerebroventricular Injection of Aβ 1-42

Abstract: SV-treatment in Aβ1-42-mice exerts dose-dependent neuroprotection and neurotoxicity by reducing FPP to enhance the phosphorylation of NR2B and Akt.

Cited by 14 publications

References 49 publications

Connecting the brain cholesterol and renin–angiotensin systems: potential role of statins and RAS‐modifying medications in dementia

Connecting the brain cholesterol and renin–angiotensin systems: potential role of statins and RAS‐modifying medications in dementia

Pravastatin But Not Simvastatin Improves Survival and Neurofunctional Outcome After Cardiac Arrest and Cardiopulmonary Resuscitation

<p>Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer’s Disease</p>

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