scholarly journals Therapeutic Potential of Novel Twin Compounds Containing Tetramethylpyrazine and Carnitine Substructures in Experimental Ischemic Stroke

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Ziying Wang ◽  
Zhuanli Zhou ◽  
Xinbing Wei ◽  
Mingwei Wang ◽  
Bi-Ou Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Ischemia Reperfusion ◽  
The Novel ◽  
Neuroprotective Effects ◽  
Chemical Structures ◽  
Cerebral Ischemia Reperfusion Injury ◽  
Blood Brain Barrier Integrity

Although studies have seen dramatic advances in the understanding of the pathogenesis of stroke such as oxidative stress, inflammation, excitotoxicity, calcium overload and apoptosis, the delivery of stroke therapies is still a great challenge. In this study, we designed and synthesized a series of novel twin compounds containing tetramethylpyrazine and carnitine substructures and explored their therapeutic potential and mechanism in stroke-related neuronal injury. We first screened the neuroprotective effects of candidate compounds and found that among the tested compounds, LR134 and LR143 exhibited significant neuroprotection as evidenced by reducing cerebral infarct and edema, improving neurological function as well as blood-brain barrier integrity in rats after cerebral ischemia/reperfusion injury. We further demonstrated that the neuroprotective effects of compounds LR134 and LR143 were associated with the reduced inflammatory responses and NADPH oxidase- (NOX2-) mediated oxidative stress and the protection of mitochondria accompanied by the improvement of energy supply. In summary, this study provides direct evidence showing that the novel twin compounds containing tetramethylpyrazine and carnitine substructures have neuroprotective effects with multiple therapeutic targets, suggesting that modulation of these chemical structures may be an innovative therapeutic strategy for treating patients with stroke.

scholarly journals Effects of Alpha-Mangostin Encapsulated in Nanostructured Lipid Carriers in Mice with Cerebral Ischemia Reperfusion Injury

2021 ◽  
Vol 50 (7) ◽  
pp. 2007-2015
Author(s):  
Romgase Sakamula ◽  
Teerapong Yata ◽  
Wachiryah Thong-asa
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
Cerebral Infarction ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Nanostructured Lipid Carriers ◽  
Neuroprotective Effects ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion Injury

Cerebral ischemia reperfusion injury (CIRI) is a phenomenon in which the cerebral blood supply is restored after a period of ischemia, resulting in irreversible damage to brain tissue. Oxidative stress plays a crucial role in the development of CIRI, therefore, targeting oxidative stress might be an effective strategy for CIRI prevention and treatment. Many therapeutic substances possess antioxidant and protective properties against neurodegenerative disorders but lack of in vivo application due to their solubility, and bioavailability. We investigated the effects of alpha-mangostin (αM) encapsulated in nanostructured lipid carriers (αM-NLC) on CIRI in mice. Forty male ICR mice were randomly divided into four groups: Sham, ischemia reperfusion (IR), ischemia reperfusion with 25 mg/kg of αM (IR+αM), and ischemia reperfusion with 25 mg/kg of αM-NLC (IR+αM-NLC). After 6 days of oral administrations, IR was delivered using 30 min of bilateral common carotid artery occlusion, followed by 45 min of reperfusion. Cerebral infarction volume, hippocampal neuronal and corpus callosum (CC) white matter damage, malondialdehyde (MDA) level, and catalase (CAT) activity were evaluated. Our results indicated that αM and αM-NLC prevent lipid peroxidation as well as hippocampal CA1, CA3, and CC damage (p<0.05). Only αM-NLC prevented cerebral infarction and enhanced CAT activity (p<0.05). We therefore conclude that αM and αM-NLC have neuroprotective effects against CIRI, and NLC increases therapeutic efficacy of αM against CIRI.

scholarly journals A Hypothesis: Hydrogen Sulfide Might Be Neuroprotective against Subarachnoid Hemorrhage Induced Brain Injury

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Yong-Peng Yu ◽  
Xiang-Lin Chi ◽  
Li-Jun Liu
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Hydrogen Sulfide ◽  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
The Brain

Gases such as nitric oxide (NO) and carbon monoxide (CO) play important roles both in normal physiology and in disease. Recent studies have shown that hydrogen sulfide (H2S) protects neurons against oxidative stress and ischemia-reperfusion injury and attenuates lipopolysaccharides (LPS) induced neuroinflammation in microglia, exhibiting anti-inflammatory and antiapoptotic activities. The gas H2S is emerging as a novel regulator of important physiologic functions such as arterial diameter, blood flow, and leukocyte adhesion. It has been known that multiple factors, including oxidative stress, free radicals, and neuronal nitric oxide synthesis as well as abnormal inflammatory responses, are involved in the mechanism underlying the brain injury after subarachnoid hemorrhage (SAH). Based on the multiple physiologic functions of H2S, we speculate that it might be a promising, effective, and specific therapy for brain injury after SAH.

scholarly journals The Cardioprotective Effects of Hydrogen Sulfide in Heart Diseases: From Molecular Mechanisms to Therapeutic Potential

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Yaqi Shen ◽  
Zhuqing Shen ◽  
Shanshan Luo ◽  
Wei Guo ◽  
Yi Zhun Zhu
Keyword(s):  
Hydrogen Sulfide ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Cardiac Diseases ◽  
Mammalian Tissues ◽  
Antioxidative Action

Hydrogen sulfide (H2S) is now recognized as a third gaseous mediator along with nitric oxide (NO) and carbon monoxide (CO), though it was originally considered as a malodorous and toxic gas. H2S is produced endogenously from cysteine by three enzymes in mammalian tissues. An increasing body of evidence suggests the involvement of H2S in different physiological and pathological processes. Recent studies have shown that H2S has the potential to protect the heart against myocardial infarction, arrhythmia, hypertrophy, fibrosis, ischemia-reperfusion injury, and heart failure. Some mechanisms, such as antioxidative action, preservation of mitochondrial function, reduction of apoptosis, anti-inflammatory responses, angiogenic actions, regulation of ion channel, and interaction with NO, could be responsible for the cardioprotective effect of H2S. Although several mechanisms have been identified, there is a need for further research to identify the specific molecular mechanism of cardioprotection in different cardiac diseases. Therefore, insight into the molecular mechanisms underlying H2S action in the heart may promote the understanding of pathophysiology of cardiac diseases and lead to new therapeutic targets based on modulation of H2S production.

The Mechanism of Gastrodin Participating in Improving the Cerebral Ischemia-Reperfusion Injury Through Notch 1 and NF-κB Signaling Pathways

2021 ◽  
Vol 11 (2) ◽  
pp. 271-275
Author(s):  
Qing Hong ◽  
Junqiang Ye ◽  
Xijia Wang ◽  
Chao Zhang
Keyword(s):  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Signaling Pathways ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Brain Area ◽  
Notch 1 ◽  
Neuroprotective Effects ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion Injury

Background: The purpose of this study was to investigate whether Gastrodin can activate the Notch 1 signaling pathway in the ischemic brain area to produce neuroprotective effects against cerebral ischemia-reperfusion injury, and to elucidate the role of Notch 1 and NF-κB signaling pathways in the Gastrodin-induced cerebral ischemic tolerance. Material and methods: The focal cerebral ischemia reperfusion model of middle cerebral artery embolism was established. TTC staining was applied to detect cerebral infarction. Tunel/NeuN immunofluorescence double labeling was employed to detect apoptosis. WB was used to detect the expressions of proteins related to the Notch 1 and NF-κB pathways. Results: Gastrodin can reduce neuron apoptosis in hippocampus after MCAO/R injury. After DAPT blocked Notch 1 signaling, the neuroprotective effects of Gastrodin improving neural function score, reducing cerebral infarction volume, and inhibiting neuronal apoptosis, were all reversed. Compared with the MCAO/R group, DAPT blocking Notch 1 signaling can also improve the neurological score of rats after MCAO/R injury, reduce cerebral infarct volume, and reduce neuronal apoptosis. Gastrodin can activate Notch 1 and NF-κB signaling pathways in cerebral ischemic areas and increase the expression of related proteins. After DAPT inhibited the Notch 1 signaling in the ipsilateral brain region, the phosphorylation level was significantly decreased, indicating that the activity of the NF-κB pathway was regulated by the Notch 1 signaling. Conclusion: Gastrodin-mediated protection against cerebral ischemia-reperfusion injury is related to the activation of Notch 1 signaling and the up-regulation of NF-κB signaling pathway activity in neurons of ischemic brain area.

Calorie restriction attenuates inflammatory responses to myocardial ischemia-reperfusion injury

2001 ◽  
Vol 280 (5) ◽  
pp. H2094-H2102 ◽  
Author(s):  
B. Chandrasekar ◽  
J. F. Nelson ◽  
J. T. Colston ◽  
G. L. Freeman
Keyword(s):  
Oxidative Stress ◽  
Dna Binding ◽  
Antioxidant Enzyme ◽  
Calorie Restriction ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Binding Activity ◽  
Dna Binding Activity ◽  
Myocardial Oxidative Stress

The life-prolonging effects of calorie restriction (CR) may be due to reduced damage from cumulative oxidative stress. Our goal was to determine the long-term effects of moderate dietary CR on the myocardial response to reperfusion after a single episode of sublethal ischemia. Male Fisher 344 rats were fed either an ad libitum (AL) or CR (40% less calories) diet. At age 12 mo the animals were anaesthetized and subjected to thoracotomy and a 15-min left-anterior descending coronary artery occlusion. The hearts were reperfused for various periods. GSH and GSSG levels, nuclear factor-κB (NF-κB) DNA binding activity, cytokine, and antioxidant enzyme expression were assessed in the ischemic zones. Sham-operated animals served as controls. Compared with the AL diet, chronic CR limited oxidative stress as seen by rapid recovery in GSH levels in previously ischemic myocardium. CR reduced DNA binding activity of NF-κB. The κB-responsive cytokines interleukin-1β and tumor necrosis factor-α were transiently expressed in the CR group but persisted longer in the AL group. Furthermore, expression of manganese superoxide dismutase, a key antioxidant enzyme, was significantly delayed in the AL group. Collectively these data indicate that CR significantly attenuates myocardial oxidative stress and the postischemic inflammatory response.

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