scholarly journals Protective Effects of a New C-Jun N-terminal Kinase Inhibitor in the Model of Global Cerebral Ischemia in Rats

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1722 ◽  
Author(s):  
Mark B. Plotnikov ◽  
Galina A. Chernysheva ◽  
Oleg I. Aliev ◽  
Vera I. Smol’iakova ◽  
Tatiana I. Fomina ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cerebral Ischemia ◽  
Endothelial Dysfunction ◽  
Neurological Deficit ◽  
Neuroprotective Effect ◽  
Global Cerebral Ischemia ◽  
Hippocampal Ca1 ◽  
Hippocampal Ca1 Area ◽  
Ca1 Area ◽  
The Brain

c-Jun N-terminal kinase (JNK) is activated by various brain insults and is implicated in neuronal injury triggered by reperfusion-induced oxidative stress. Some JNK inhibitors demonstrated neuroprotective potential in various models, including cerebral ischemia/reperfusion injury. The objective of the present work was to study the neuroprotective activity of a new specific JNK inhibitor, IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt), in the model of global cerebral ischemia (GCI) in rats compared with citicoline (cytidine-5′-diphosphocholine), a drug approved for the treatment of acute ischemic stroke and to search for pleiotropic mechanisms of neuroprotective effects of IQ-1S. The experiments were performed in a rat model of ischemic stroke with three-vessel occlusion (model of 3VO) affecting the brachiocephalic artery, the left subclavian artery, and the left common carotid artery. After 7-min episode of GCI in rats, 25% of animals died, whereas survived animals had severe neurological deficit at days 1, 3, and 5 after GCI. At day 5 after GCI, we observing massive loss of pyramidal neurons in the hippocampal CA1 area, increase in lipid peroxidation products in the brain tissue, and decrease in local cerebral blood flow (LCBF) in the parietal cortex. Moreover, blood hyperviscosity syndrome and endothelial dysfunction were found after GCI. Administration of IQ-1S (intragastrically at a dose 50 mg/kg daily for 5 days) was associated with neuroprotective effect comparable with the effect of citicoline (intraperitoneal at a dose of 500 mg/kg, daily for 5 days).The neuroprotective effect was accompanied by a decrease in the number of animals with severe neurological deficit, an increase in the number of animals with moderate degree of neurological deficit compared with control GCI group, and an increase in the number of unaltered neurons in the hippocampal CA1 area along with a significant decrease in the number of neurons with irreversible morphological damage. In rats with IQ-1S administration, the LCBF was significantly higher (by 60%) compared with that in the GCI control. Treatment with IQ-1S also decreases blood viscosity and endothelial dysfunction. A concentration-dependent decrease (IC50 = 0.8 ± 0.3 μM) of tone in isolated carotid arterial rings constricted with phenylephrine was observed after IQ-1S application in vitro. We also found that IQ-1S decreased the intensity of the lipid peroxidation in the brain tissue in rats with GCI. 2.2-Diphenyl-1-picrylhydrazyl scavenging for IQ-1S in acetonitrile and acetone exceeded the corresponding values for ionol, a known antioxidant. Overall, these results suggest that the neuroprotective properties of IQ-1S may be mediated by improvement of cerebral microcirculation due to the enhanced vasorelaxation, beneficial effects on blood viscosity, attenuation of the endothelial dysfunction, and antioxidant/antiradical IQ-1S activity.

scholarly journals cGMP Imaging in Brain Slices Reveals Brain Region-Specific Activity of NO-Sensitive Guanylyl Cyclases (NO-GCs) and NO-GC Stimulators

2018 ◽  
Vol 19 (8) ◽  
pp. 2313 ◽  
Author(s):  
Stefanie Peters ◽  
Michael Paolillo ◽  
Evanthia Mergia ◽  
Doris Koesling ◽  
Lea Kennel ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Brain Region ◽  
Specific Activity ◽  
Brain Slices ◽  
Specific Effect ◽  
Hippocampal Ca1 ◽  
Hippocampal Ca1 Area ◽  
Cgmp Signaling ◽  
Ca1 Area ◽  
The Brain

Impaired NO-cGMP signaling has been linked to several neurological disorders. NO-sensitive guanylyl cyclase (NO-GC), of which two isoforms—NO-GC1 and NO-GC2—are known, represents a promising drug target to increase cGMP in the brain. Drug-like small molecules have been discovered that work synergistically with NO to stimulate NO-GC activity. However, the effects of NO-GC stimulators in the brain are not well understood. In the present study, we used Förster/fluorescence resonance energy transfer (FRET)-based real-time imaging of cGMP in acute brain slices and primary neurons of cGMP sensor mice to comparatively assess the activity of two structurally different NO-GC stimulators, IWP-051 and BAY 41-2272, in the cerebellum, striatum and hippocampus. BAY 41-2272 potentiated an elevation of cGMP induced by the NO donor DEA/NO in all tested brain regions. Interestingly, IWP-051 potentiated DEA/NO-induced cGMP increases in the cerebellum and striatum, but not in the hippocampal CA1 area or primary hippocampal neurons. The brain-region-selective activity of IWP-051 suggested that it might act in a NO-GC isoform-selective manner. Results of mRNA in situ hybridization indicated that the cerebellum and striatum express NO-GC1 and NO-GC2, while the hippocampal CA1 area expresses mainly NO-GC2. IWP-051-potentiated DEA/NO-induced cGMP signals in the striatum of NO-GC2 knockout mice but was ineffective in the striatum of NO-GC1 knockout mice. These results indicate that IWP-051 preferentially stimulates NO-GC1 signaling in brain slices. Interestingly, no evidence for an isoform-specific effect of IWP-051 was observed when the cGMP-forming activity of whole brain homogenates was measured. This apparent discrepancy suggests that the method and conditions of cGMP measurement can influence results with NO-GC stimulators. Nevertheless, it is clear that NO-GC stimulators enhance cGMP signaling in the brain and should be further developed for the treatment of neurological diseases.

scholarly journals Propolis inhibited Bax expression and increased neuronal count of hippocampal area CA1 in rats receiving sodium nitrite

2019 ◽  
Vol 38 (2) ◽  
pp. 73
Author(s):  
Kuswati Kuswati ◽  
Ety Sari Handayani ◽  
Zainuri Sabta Nugraha ◽  
Fishella Aprista Rahmanti ◽  
Zulfikar Loka Wicaksana ◽  
...  
Keyword(s):  
Sodium Nitrite ◽  
Neuronal Damage ◽  
Control Group ◽  
Wistar Strain ◽  
Hippocampal Ca1 ◽  
Hippocampal Ca1 Area ◽  
Hippocampal Area ◽  
Ca1 Area ◽  
The Brain ◽  
Antioxidant Effects

Background<br />Sodium nitrite induces hypoxia and oxidative stress in the hippocampus, decreasing the number of neurons in the hippocampus and cognitive function. Propolis contains chrysin that has antioxidant effects that are expected to inhibit neuronal damage in the hippocampus. This study aims to determine the effects of propolis on the expression Bcl-2-associated X protein (Bax) and the number of neurons in the rat hippocampus receiving sodium nitrite.<br /><br />Methods<br />This study of laboratory experimental design was conducted on 18 male Wistar strain rats (Rattus norvegicus), they were randomized into 3 groups: one control group (K) received sodium nitrite and two intervention groups  (P1 and P2) received sodium nitrite and propolis at doses of 100 and 200 mg/kgBW. Treatment with sodium nitrite and propolis were given for 60 days, followed by termination. The number of neurons and Bax expression in the hippocampal CA1 area were measured. One-way ANOVA was used to analyze the data.<br /><br />Results<br />There were significant differences in Bax expression between group K and groups P1 and P2 (p&lt;0.001). The lowest number of neurons in the hippocampal CA1 area was in the K group. There were significant differences in the number of neurons between control (K) group and groups P1 and P2 (p&lt;0.001).<br /><br />Conclusion<br />Propolis inhibited the expression of Bax and decreased the number of neurons in the hippocampal CA1 area of rats receiving sodium nitrite. This study provides information about the benefits of propolis as an antioxidant in the brain.

scholarly journals Head Mild Hypothermia Inhibits the Increase of Extracellular Glutamate Concentration by Upregulating Glial Glutamate Transporter 1 During Ischemia-reperfusion Injury

2019 ◽  
Author(s):  
Dongyang Ma ◽  
Qi An ◽  
Zhiqiang Zhang ◽  
Qinghu Bian ◽  
Yanan Li ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Mild Hypothermia ◽  
Ischemia Reperfusion ◽  
Extracellular Glutamate ◽  
Glutamate Concentration ◽  
Cerebral Ischemia Reperfusion ◽  
Hippocampal Ca1 ◽  
Hippocampal Ca1 Area ◽  
Ca1 Area

Abstract Background Stroke is characterized by high morbidity, high mortality and disability. Therefore, it is very important to illuminate the pathological mechanism and find effective treatment strategies. Hypothermia therapy is widely used in clinical as a neuroprotective strategy practice. However, the exact mechanism is not fully understood. Methods Four-vessel occlusion (4-VO) was used to establish animal models of global cerebral ischemia-reperfusion and nasopharyngeal cavity cooling method was used for hypothermia treatment. Extracellular fluid in hippocampal CA1 area was collected by microdialysis technology, and extracellular glutamate concentration ([Glu]e) was detected by high performance liquid chromatography (HPLC). The expression levels of glial glutamate transport-1(GLT-1), Bcl-2 and Bax at the determined time points in hippocampal CA1 area were detected by Western blotting and immunohistochemistry and histopathological evaluation was performed by thionin staining. Dihydrokainate (DHK), a GLT-1 specific inhibitor, was used to confirm the function of GLT-1 in cerebral ischemia-reperfusion injury. Results Cerebral brain ischemia-reperfusion caused the downregulation of GLT-1 and Bcl-2, the upregulation of Bax, and an increase in [Glu]e, and leaded to neuron loss. Head mild hypothermia (HMH) for 2 h applied 8min after ischemic insult attenuated the abovementioned effects of ischemia-reperfusion, while pretreatment with DHK by injection into the lateral ventricle inhibited this effect. Conclusion HMH can play a neuroprotective role by upregulating GLT-1 and reducing the excitotoxicity of Glutamate during ischemia-reperfusion insult in rats. Keywords Ischemia-reperfusion; Mild hypothermia; Glutamate transport; Neuroprotection

Effect of Polygala tenuifolia Root Extract on Cerebral Ischemia and Reperfusion

2006 ◽  
Vol 34 (01) ◽  
pp. 115-123 ◽  
Author(s):  
Jin-Hyuk Park ◽  
Jin Sook Kim ◽  
Dae Sik Jang ◽  
Sun-Mee Lee
Keyword(s):  
Lipid Peroxidation ◽  
Cerebral Ischemia ◽  
Ethanol Extract ◽  
Root Extract ◽  
Ischemia And Reperfusion ◽  
Butanol Fraction ◽  
Hippocampal Ca1 ◽  
Polygala Tenuifolia ◽  
The Brain ◽  
Hippocampal Ca1 Subfield

In this study, the effects of Polygala tenuifolia root extract on brain ischemia/reperfusion injury in Mongolian gerbils were investigated. The gerbils were administered ethanol extract of P. tenuifolia and its four sub-fractions orally 2 hours prior to ischemia, and were subjected to a 20-minute no-flow cerebral ischemia in vivo. Thirty minutes and 72 hours after reperfusion, the brain was removed and the ATP, lactate and lipid peroxide levels were determined, and the neurons in the hippocampal CA1 subfield were examined. In the vehicle-treated ischemic gerbils, the brain ATP levels decreased significantly, but this decrease was prevented by pre-treatment with an n-butanol fraction of P. tenuifolia. In contrast, both the lactate content and lipid peroxidation levels were elevated in the vehicle-treated ischemic animals, but this elevation was inhibited by ethanol extract and n-butanol fraction of P. tenuifolia, respectively. Both the ethanol extract and n-butanol fraction of P. tenuifolia attenuated post-ischemic neuronal necrosis in the hippocampal CA1 subfield. Our findings suggest that both ethanol extract and n-butanol fraction of P. tenuifolia root can reduce brain damage during ischemia and reperfusion, and prevent lipid peroxidation and preserve the energy metabolism.

Exploring the Role of Remote Ischemic Preconditioning In Long Term Cognitive Impairment after Global Ischemia-Reperfusion-Induced Vascular Dementia in Mice

2020 ◽  
Author(s):  
Amteshwar Singh Jaggi
Keyword(s):  
Cognitive Impairment ◽  
Cerebral Ischemia ◽  
Vascular Dementia ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion ◽  
Remote Ischemic Preconditioning ◽  
Global Cerebral Ischemia ◽  
Cerebral Ischemic ◽  
The Brain

Aim: The aim of the present study is to explore the neuroprotective effects of remote ischemic preconditioning in long term cognitive impairment after global cerebral ischemia induced-vascular dementia in mice. Material and methods: The mice were subjected to global cerebral ischemia by occluding the bilateral common carotid arteries for 12 minutes followed by the 24 hours of the reperfusion. The remote ischemic preconditioning stimulus was delivered in the form of 4 cycles of ischemia/reperfusion for 5 minutes each. The cerebral ischemic injury induced-long term cognitive impairment-related learning and memory alterations was assessed using morris water maze, the motor performances of the animals were evaluated using rota-rod test and neurological severity score. The cerebral infract size of the brain were quantified using triphenyltetrazolium chloride staining. Results: Global cerebral ischemia causes long term memory impairment, decreases motor performances and increases the brain infract size in animals. The delivery of remote ischemic preconditioning stimulus significantly abolished the long-term cognitive impairment and ameliorates the motor performances as well as cerebral infract size in brain. Conclusion: The remote ischemic preconditioning mediates neuro protection against global cerebral ischemic injury induced long-term cognitive impairment.

scholarly journals Zingiber officinaleMitigates Brain Damage and Improves Memory Impairment in Focal Cerebral Ischemic Rat

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Jintanaporn Wattanathorn ◽  
Jinatta Jittiwat ◽  
Terdthai Tongun ◽  
Supaporn Muchimapura ◽  
Kornkanok Ingkaninan
Keyword(s):  
Cognitive Function ◽  
Cerebral Ischemia ◽  
Brain Damage ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Morris Water Maze Test ◽  
Brain Infarct ◽  
Ginger Rhizome ◽  
The Brain

Cerebral ischemia is known to produce brain damage and related behavioral deficits including memory. Recently, accumulating lines of evidence showed that dietary enrichment with nutritional antioxidants could reduce brain damage and improve cognitive function. In this study, possible protective effect ofZingiber officinale, a medicinal plant reputed for neuroprotective effect against oxidative stress-related brain damage, on brain damage and memory deficit induced by focal cerebral ischemia was elucidated. Male adult Wistar rats were administrated an alcoholic extract of ginger rhizome orally 14 days before and 21 days after the permanent occlusion of right middle cerebral artery (MCAO). Cognitive function assessment was performed at 7, 14, and 21 days after MCAO using the Morris water maze test. The brain infarct volume and density of neurons in hippocampus were also determined. Furthermore, the level of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in cerebral cortex, striatum, and hippocampus was also quantified at the end of experiment. The results showed that cognitive function and neurons density in hippocampus of rats receiving ginger rhizome extract were improved while the brain infarct volume was decreased. The cognitive enhancing effect and neuroprotective effect occurred partly via the antioxidant activity of the extract. In conclusion, our study demonstrated the beneficial effect of ginger rhizome to protect against focal cerebral ischemia.

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