Pravastatin acute neuroprotective effects depend on blood brain barrier integrity in experimental cerebral ischemia

Carone, Davide; Librizzi, Laura; Cattalini, Alessandro; Sala, Gessica; Conti, Elisa; Cuccione, Elisa; Versace, Alessandro; Cai, Ruiyao; Monza, L; Curtis, Marco de; Ferrarese, Carlo; Beretta, Simone

doi:10.1016/j.brainres.2015.04.025

Cited by 10 publications

(8 citation statements)

References 55 publications

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“…These points emphasize the need to advance neuroprotective therapies in ischemic stroke patients; however, many neuroprotectants have failed in clinical trials, in part due to poor BBB penetration (Xu and Pan, 2013). Interestingly, retrospective clinical studies have revealed that patients who were treated with statins both prior to onset of ischemic stroke or at the time of stroke onset have better outcomes (Ni Chroinin et al, 2013;Carone et al, 2015). While the benefits of statin therapy are generally accepted, the mechanisms used by these compounds to permeate the BBB are unclear.…”

Section: Discussionmentioning

confidence: 99%

Functional Expression of Organic Anion Transporting Polypeptide 1a4 Is Regulated by Transforming Growth Factor-β/Activin Receptor-like Kinase 1 Signaling at the Blood-Brain Barrier

et al. 2018

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Central nervous system (CNS) drug delivery can be achieved by targeting drug uptake transporters such as Oatp1a4. In fact, many drugs that can improve neurologic outcomes in CNS diseases [3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (i.e., statins)] are organic anion transporting polypeptide (OATP) transport substrates. To date, transport properties and regulatory mechanisms of Oatp1a4 at the blood-brain barrier (BBB) have not been rigorously studied. Such knowledge is critical to develop Oatp1a4 for optimization of CNS drug delivery and for improved treatment of neurological diseases. Our laboratory has demonstrated that the transforming growth factor-b (TGF-b)/activin receptor-like kinase 1 (ALK1) signaling agonist bone morphogenetic protein 9 (BMP-9) increases functional expression of Oatp1a4 in rat brain microvessels. Here, we expand on this work and show that BMP-9 treatment increases blood-to-brain transport and brain exposure of established OATP transport substrates (i.e., taurocholate, atorvastatin, and pravastatin). We also demonstrate that BMP-9 activates the TGF-b/ALK1 pathway in brain microvessels as indicated by increased nuclear translocation of specific Smad proteins associated with signaling mediated by the ALK1 receptor (i.e., pSmad1/5/8). Furthermore, we report that an activated Smad protein complex comprised of phosphorylated Smad1/5/8 and Smad4 is formed following BMP-9 treatment and binds to the promoter of the Slco1a4 gene (i.e., the gene that encodes Oatp1a4). This signaling mechanism causes increased expression of Slco1a4 mRNA. Overall, this study provides evidence that Oatp1a4 transport activity at the BBB is directly regulated by TGF-b/ALK1 signaling and indicates that this pathway can be targeted for control of CNS delivery of OATP substrate drugs.

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Section: Discussionmentioning

confidence: 99%

Functional Expression of Organic Anion Transporting Polypeptide 1a4 Is Regulated by Transforming Growth Factor-β/Activin Receptor-like Kinase 1 Signaling at the Blood-Brain Barrier

et al. 2018

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“…Similar conclusions were drawn in a recent study regarding the ability of statins to modulate membrane ion channel composition and exert anti-inflammatory effects in monocytes (31) . In this regard, it was shown that the ability of pravastatin, as a hydrophilic statin, to exert neuroprotective effects following cerebral ischemia depended on increased blood-brain barrier permeability (32) . In the pathophysiology of post-CA syndrome, post-CA brain injury is a key component closely linked to survival (7) .…”

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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“…Although amifostine cannot permeate the blood-brain barrier (BBB) [ 33 ] in physiological condition, in some pathological conditions, including brain ischemia/reperfusion injury, traumatic brain injury, and neurodegenerative diseases [ 34 – 36 ], the BBB may be destroyed; in this case, the drug may induce protections in neuronal cells. In addition, as some drugs or methods may open the BBB, such as mannitol, borneol, and ultrasound [ 37 – 39 ], combination of amifostine and these drugs or methods may induce significant neuroprotective effects.…”

Section: Discussionmentioning

confidence: 99%

SOD2 Mediates Amifostine‐Induced Protection against Glutamate in PC12 Cells

Jia

Zhang

Shi

et al. 2015

Oxidative Medicine and Cellular Longevity

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Background. Cytoprotectant amifostine attenuates radiation-induced oxidative injury by increasing intracellular manganese superoxide dismutase (SOD2) in peripheral tissue. However, whether amifostine could protect neuronal cells against oxidative injury has not been reported. The purpose of this study is to explore the protection of amifostine in PC12 cells. Methods. PC12 cells exposed to glutamate were used to mimic neuronal oxidative injury. SOD assay kit was taken to evaluate intracellular Cu/Zn SOD (SOD1) and SOD2 activities; western blot analysis and immunofluorescence staining were performed to investigate SOD2 protein expression; MTT, lactate dehydrogenase (LDH), release and cell morphology were used to evaluate cell injury degree, and apoptotic rate and cleaved caspase-3 expression were taken to assess apoptosis; mitochondrial superoxide production, intracellular reactive oxygen species (ROS), and glutathione (GSH) and catalase (CAT) levels were evaluated by reagent kits. Results. Amifostine increased SOD2 activity and expression, decreased cell injury and apoptosis, reduced mitochondrial superoxide production and intracellular ROS generation, and restored intracellular GSH and CAT levels in PC12 cells exposed to glutamate. SOD2-siRNA, however, significantly reversed the amifostine-induced cytoprotective and antioxidative actions. Conclusion. SOD2 mediates amifostine-induced protection in PC12 cells exposed to glutamate.

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Pravastatin acute neuroprotective effects depend on blood brain barrier integrity in experimental cerebral ischemia

Cited by 10 publications

References 55 publications

Functional Expression of Organic Anion Transporting Polypeptide 1a4 Is Regulated by Transforming Growth Factor-β/Activin Receptor-like Kinase 1 Signaling at the Blood-Brain Barrier

Functional Expression of Organic Anion Transporting Polypeptide 1a4 Is Regulated by Transforming Growth Factor-β/Activin Receptor-like Kinase 1 Signaling at the Blood-Brain Barrier

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

SOD2 Mediates Amifostine‐Induced Protection against Glutamate in PC12 Cells

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