Edaravone and cyclosporine A as neuroprotective agents for acute ischemic stroke

Matsumoto, Shohei; Murozono, Michihiro; Kanazawa, Masahiro; Nara, Takeshi; Ozawa, Takuro; Watanabe, Yasuo

doi:10.1002/ams2.343

Cited by 68 publications

(58 citation statements)

References 55 publications

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“…The excessive ROS generation can mediate inflammation and immune response by stimulating the expression of cytokines and adhesion molecules, ultimately causing further injury by inflammation, finally leading to ischemia-reperfusion injury (5,6). Edaravone-based neuroprotective therapy is the main strategy for the treatment of ischemic stroke by eliminating the free radicals and suppressing oxidative stress (7)(8)(9). However, its clinical application is limited by the low bioavailability, short half-life, inefficient penetration across the blood-brain barrier (BBB), and the side effects to kidney and liver functions.…”

Section: Introductionmentioning

confidence: 99%

Highly bioactive zeolitic imidazolate framework-8–capped nanotherapeutics for efficient reversal of reperfusion-induced injury in ischemic stroke

et al. 2020

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Rational design of potent antioxidative agent with high biocompatibility is urgently needed to treat ischemic reperfusion-induced ROS-mediated cerebrovascular and neural injury during ischemia strokes. Here, we demonstrate an in situ synthetic strategy of bioactive zeolitic imidazolate framework-8–capped ceria nanoparticles (CeO2@ZIF-8 NPs) to achieve enhanced catalytic and antioxidative activities and improved stroke therapeutic efficacy. This nanosystem exhibits prolonged blood circulation time, reduced clearance rate, improved BBB penetration ability, and enhanced brain accumulation, where it effectively inhibits the lipid peroxidation in brain tissues in middle cerebral artery occlusion mice and reduces the oxidative damage and apoptosis of neurons in brain tissue. CeO2@ZIF-8 also suppresses inflammation- and immune response–induced injury by suppressing the activation of astrocytes and secretion of proinflammatory cytokines, thus achieving satisfactory prevention and treatment in neuroprotective therapy. This study also sheds light on the neuroprotective action mechanisms of ZIF-8–capped nanomedicine against reperfusion-induced injury in ischemic stroke.

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Section: Introductionmentioning

confidence: 99%

Highly bioactive zeolitic imidazolate framework-8–capped nanotherapeutics for efficient reversal of reperfusion-induced injury in ischemic stroke

et al. 2020

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“…Therefore, combinatorial treatment with Dox and antioxidants has been proposed to eliminate cardiotoxicity and endotheliotoxicity (Soultati et al, 2012;Wang et al, 2015;Akolkar et al, 2017;Abdel-Daim et al, 2017;He et al, 2018). Edaravone (Eda), a free radical scavenger, is the only neuroprotective agent for acute ischemic stroke used in Japan (Matsumoto et al, 2018). It captures and reduces excessive ROS, preventing brain damage.…”

Section: Introductionmentioning

confidence: 99%

“…It captures and reduces excessive ROS, preventing brain damage. Studies have also confirmed that Eda inhibits ROS upstream, closes mitochondrial permeability transition pore (mPTP), prevents mitochondrial dysfunction, and in turn, potentially protects cells (Ikeda and Iwasaki, 2015;Matsumoto et al, 2018). Whether Eda can reduce the damage of VE caused by Dox toxicity is not clear.…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin Induces Endotheliotoxicity and Mitochondrial Dysfunction via ROS/eNOS/NO Pathway

Wang

Qiao

et al. 2020

Front. Pharmacol.

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Background: Doxorubicin (Dox) can induce endotheliotoxicity and damage the vascular endothelium (VE). The most principle mechanism might be excess reactive oxygen species (ROS) generation. Nevertheless, the characteristics of ROS generation, downstream mechanisms, and target organelles in Dox-induced endotheliotoxicity have yet to be elucidated. Methods and Results: In order to explore the related problems, the VE injury models were established in mice and human umbilical vein endothelial cells (HUVECs) by Dox-induced endotheliotoxicity. Results showed that the activities of lactate dehydrogenase (LDH) and creatine kinase of mice's serum increased after injected Dox. The thoracic aortic strips' endothelium-dependent dilation was significantly impaired, seen noticeable inflammatory changes, and brown TUNEL-positive staining in microscopy. After Dox-treated, HUVECs viability lowered, LDH and caspase-3 activities, and apoptotic cells increased. Both intracellular/mitochondrial ROS generation significantly increased, and intracellular ROS generation lagged behind mitochondria. HUVECs treated with Dox plus ciclosporin A (CsA) could basically terminate ROS burst, but plus edaravone (Eda) could only delay or inhibit, but could not completely cancel ROS burst. Meanwhile, the expression of endothelial nitric oxide synthase (eNOS) decreased, especially phosphorylation of eNOS significantly. Then nitric oxide content decreased, the mitochondrial function was impaired, mitochondrial membrane potential (MMP) impeded, mitochondrial swelled, mitochondrial permeability transition pore (mPTP) was opened, and cytochrome C was released from mitochondria into the cytosol. Conclusion: Dox produces excess ROS in the mitochondria, thereby weakens the MMP, opens mPTP, activates the ROS-induced ROS release mechanism, induces ROS burst, and leads to mitochondrial dysfunction, which in turn damages VE. Therefore, interrupting any step of the cycles, as mentioned above can end the related vicious cycle and prevent the occurrence and development of injury.

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“…The ability of cyclosporin and other PTP inhibitors to attenuate NLRP3 inflammasome activation provides a link between PTP and inflammation [ 219 , 220 ]. Several works reported that the inhibition of PTP by genetic or pharmacological approaches confers protection against ischemic damage [ 221 , 222 , 223 ]. Accordingly, it has been observed that ROS generation induced by rotenone injection, are mitigated by the inhibition of PTP or mitochondria ROS scavenger [ 224 ], indicating the important participation of PTP in the activation and sustainment of IS-induced inflammation.…”

Section: Ischemic Stroke and Mitochondrial Induced Neuroinflammatimentioning

confidence: 99%

The Dichotomous Role of Inflammation in the CNS: A Mitochondrial Point of View

et al. 2020

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Innate immune response is one of our primary defenses against pathogens infection, although, if dysregulated, it represents the leading cause of chronic tissue inflammation. This dualism is even more present in the central nervous system, where neuroinflammation is both important for the activation of reparatory mechanisms and, at the same time, leads to the release of detrimental factors that induce neurons loss. Key players in modulating the neuroinflammatory response are mitochondria. Indeed, they are responsible for a variety of cell mechanisms that control tissue homeostasis, such as autophagy, apoptosis, energy production, and also inflammation. Accordingly, it is widely recognized that mitochondria exert a pivotal role in the development of neurodegenerative diseases, such as multiple sclerosis, Parkinson’s and Alzheimer’s diseases, as well as in acute brain damage, such in ischemic stroke and epileptic seizures. In this review, we will describe the role of mitochondria molecular signaling in regulating neuroinflammation in central nervous system (CNS) diseases, by focusing on pattern recognition receptors (PRRs) signaling, reactive oxygen species (ROS) production, and mitophagy, giving a hint on the possible therapeutic approaches targeting mitochondrial pathways involved in inflammation.

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Edaravone and cyclosporine A as neuroprotective agents for acute ischemic stroke

Cited by 68 publications

References 55 publications

Highly bioactive zeolitic imidazolate framework-8–capped nanotherapeutics for efficient reversal of reperfusion-induced injury in ischemic stroke

Highly bioactive zeolitic imidazolate framework-8–capped nanotherapeutics for efficient reversal of reperfusion-induced injury in ischemic stroke

Doxorubicin Induces Endotheliotoxicity and Mitochondrial Dysfunction via ROS/eNOS/NO Pathway

The Dichotomous Role of Inflammation in the CNS: A Mitochondrial Point of View

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