scholarly journals The Mechanisms of Cucurbitacin E as a Neuroprotective and Memory-Enhancing Agent in a Cerebral Hypoperfusion Rat Model: Attenuation of Oxidative Stress, Inflammation, and Excitotoxicity

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhiyong Liu ◽  
Manish Kumar ◽  
Sushma Devi ◽  
Atul Kabra
Keyword(s):  
Rat Model ◽  
Antioxidant Activities ◽  
Acetylcholinesterase Activity ◽  
Artery Occlusion ◽  
Cerebral Hypoperfusion ◽  
Protein Carbonyls ◽  
Myeloperoxidase Activity ◽  
Neuroprotective Effects ◽  
Memory Functions ◽  
Cucurbitacin E

Impaired cerebral hemodynamic autoregulation, vasoconstriction, and cardiovascular and metabolic dysfunctions cause cerebral hypoperfusion (CH) that triggers pro-oxidative and inflammatory events. The sequences linked to ion-channelopathies and calcium and glutamatergic excitotoxicity mechanisms resulting in widespread brain damage and neurobehavioral deficits, including memory, neurological, and sensorimotor functions. The vasodilatory, anti-inflammatory, and antioxidant activities of cucurbitacin E (CuE) can alleviate CH-induced neurobehavioral impairments. In the present study, the neuroprotective effects of CuE were explored in a rat model of CH. Wistar rats were subjected to permanent bilateral common carotid artery occlusion to induce CH on day 1 and administered CuE (0.25, 0.5 mg/kg) and/or Bay-K8644 (calcium agonist, 0.5 mg/kg) for 28 days. CH caused impairment of neurological, sensorimotor, and memory functions that were ameliorated by CuE. CuE attenuated CH-triggered lipid peroxidation, 8-hydroxy-2′-deoxyguanosine, protein carbonyls, tumor necrosis factor-α, nuclear factor-kappaB, myeloperoxidase activity, inducible nitric oxide synthase, and matrix metalloproteinase-9 levels in brain resulting in a decrease in cell death biomarkers (lactate dehydrogenase and caspase-3). CuE decreased acetylcholinesterase activity, glutamate, and increased γ-aminobutyric acid levels in the brain. An increase in brain antioxidants was observed in CuE-treated rats subjected to CH. CuE has the potential to alleviate pathogenesis of CH and protect neurological, sensorimotor, and memory functions against CH.

scholarly journals URB597 protects against NLRP3 inflammasome activation by inhibiting autophagy dysfunction in a rat model of chronic cerebral hypoperfusion

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Shao-Hua Su ◽  
Yi-Fang Wu ◽  
Qi Lin ◽  
Da-Peng Wang ◽  
Jian Hai
Keyword(s):  
Proinflammatory Cytokines ◽  
Rat Model ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Artery Occlusion ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Ultrastructural Changes ◽  
Inflammasome Activation ◽  
Related Proteins

Abstract Background Previous studies reported that URB597 (URB) had therapeutic potential for treating chronic cerebral hypoperfusion (CCH)-induced neuroinflammation and autophagy dysfunction. However, the interaction mechanisms underlying the CCH-induced abnormal excessive autophagy and neuroinflammation remain unknown. In this study, we investigated the roles of impaired autophagy in nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing (NLRP) 3 inflammasome activation in the rat hippocampus and the underlying mechanisms under the condition of induced CCH as well as the effect of URB treatment. Methods The CCH rat model was established by bilateral common carotid artery occlusion (BCCAo), and rats were randomly divided into 11 groups as follows: (1) sham-operated, (2) BCCAo; (3) BCCAo+autophagy inhibitor 3-methyladenine (3-MA), (4) BCCAo+lysosome inhibitor chloroquine (CQ), (5) BCCAo+microglial activation inhibitor minocycline, (6) BCCAo+ROS scavenger N-acetylcysteine (NAC), (7) BCCAo+URB, (8) BCCAo+URB+3-MA, (9) BCCAo+URB+CQ, (10) BCCAo+URB+minocycline, (11) BCCAo+URB+NAC. The cell localizations of LC3, p62, LAMP1, TOM20 and NLRP3 were assessed by immunofluorescence staining. The levels of autophagy-related proteins (LC3, p62, LAMP1, BNIP3 and parkin), NLRP3 inflammasome-related proteins (NLRP3, CASP1 and IL-1β), microglial marker (OX-42) and proinflammatory cytokines (iNOS and COX-2) were evaluated by western blotting, and proinflammatory cytokines (IL-1β and TNF-a) were determined by ELISA. Reactive oxygen species (ROS) were assessed by dihydroethidium staining. The mitochondrial ultrastructural changes were examined by electron microscopy. Results CCH induced microglial overactivation and ROS accumulation, promoting the activation of the NLRP3 inflammasome and the release of IL-1β. Blocked autophagy and mitophagy flux enhanced the activation of the NLRP3-CASP1 inflammasome pathway. However, URB alleviated impaired autophagy and mitophagy by decreasing mitochondrial ROS and microglial overactivation as well as restoring lysosomal function, which would further inhibit the activation of the NLRP3-CASP1 inflammasome pathway. Conclusion These findings extended previous studies indicating the function of URB in the mitigation of chronic ischemic injury of the brain.

scholarly journals Characterization of Tauopathy in a Rat Model of Post-Stroke Dementia Combining Acute Infarct and Chronic Cerebral Hypoperfusion

2020 ◽  
Vol 21 (18) ◽  
pp. 6929
Author(s):  
Dong Bin Back ◽  
Bo-Ryoung Choi ◽  
Jung-Soo Han ◽  
Kyoung Ja Kwon ◽  
Dong-Hee Choi ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cognitive Impairment ◽  
Acute Ischemic Stroke ◽  
Rat Model ◽  
Artery Occlusion ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Tau Hyperphosphorylation ◽  
Post Stroke

Post-stroke dementia (PSD) is a major neurodegenerative consequence of stroke. Tauopathy has been reported in diverse neurodegenerative diseases. We investigated the cognitive impairment and pathomechanism associated with tauopathy in a rat model of PSD by modeling acute ischemic stroke and underlying chronic cerebral hypoperfusion (CCH). We performed middle cerebral artery occlusion (MCAO) surgery in rats to mimic acute ischemic stroke, followed by bilateral common carotid artery occlusion (BCCAo) surgery to mimic CCH. We performed behavioral tests and focused on the characterization of tauopathy through histology. Parenchymal infiltration of cerebrospinal fluid (CSF) tracers after intracisternal injection was examined to evaluate glymphatic function. In an animal model of PSD, cognitive impairment was aggravated when BCCAo was combined with MCAO. Tauopathy, manifested by tau hyperphosphorylation, was prominent in the peri-infarct area when CCH was combined. Synergistic accentuation of tauopathy was evident in the white matter. Microtubules in the neuronal axon and myelin sheath showed partial colocalization with the hyperphosphorylated tau, whereas oligodendrocytes showed near-complete colocalization. Parenchymal infiltration of CSF tracers was attenuated in the PSD model. Our experimental results suggest a hypothesis that CCH may aggravate cognitive impairment and tau hyperphosphorylation in a rat model of PSD by interfering with tau clearance through the glymphatic system. Therapeutic strategies to improve the clearance of brain metabolic wastes, including tau, may be a promising approach to prevent PSD after stroke.

Abstract WP156: Characterization of Tauopathy in a Rat Model of Post-Stroke Dementia Combining Acute Infarct and Chronic Cerebral Hypoperfusion

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Hahn Young Kim ◽  
Pil-Wook Chung
Keyword(s):  
Ischemic Stroke ◽  
Cognitive Impairment ◽  
Acute Ischemic Stroke ◽  
Rat Model ◽  
Artery Occlusion ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Tau Hyperphosphorylation ◽  
Post Stroke

Post-stroke dementia (PSD) is a major neurodegenerative consequence of stroke. Tauopathy has been reported in diverse neurodegenerative diseases. We investigated cognitive impairments and pathomechanisms of tauopathy in a rat model of PSD by modeling acute ischemic stroke and underlying chronic cerebral hypoperfusion (CCH) in the same animal. We performed middle cerebral artery occlusion (MCAO) surgery in rats, to mimic acute ischemic stroke, followed by bilateral common carotid artery occlusion (BCCAo) surgery, to mimic CCH. We performed behavioral tests and focused on the characterization of tauopathy through histology. Parenchymal infiltration of cerebrospinal fluid (CSF) tracers after intracisternal injection was examined to evaluate glymphatic clearance. In an animal model of PSD, cognitive impairment was aggravated when BCCAo was superimposed on MCAO. Tauopathy, manifested by tau hyperphosphorylation, was prominent in the penumbra when CCH was combined with acute ischemic stroke. Synergistic accentuation of tauopathy was more evident in the white matter. Oligodendrocytes and some neurons were colocalized with tau hyperphosphorylation. Parenchymal infiltration of CSF tracers was attenuated in the PSD model. Our experimental results suggest that CCH may aggravate cognitive impairment and tau hyperphosphorylation in a rat model of PSD by interfering with tau clearance through glymphatic pathway. Therapeutic strategies to improve clearance of brain metabolic wastes, including tau, may be a promising approach to prevent PSD after stroke.

Tadalafil enhances the neuroprotective effects of ischemic postconditioning in mice, probably in a nitric oxide associated manner

2014 ◽  
Vol 92 (5) ◽  
pp. 418-426 ◽  
Author(s):  
Puja Gulati ◽  
Nirmal Singh
Keyword(s):  
Nitric Oxide ◽  
Carotid Artery ◽  
Infarct Size ◽  
Acetylcholinesterase Activity ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Cerebral Infarct ◽  
Ischemic Postconditioning ◽  
Neuroprotective Effects ◽  
Nitrite Nitrate

This study investigates the modulatory effect of tadalafil, a selective phosphodiesterase (PDE-5) inhibitor, on the neuroprotective effects of ischemic postconditioning (iPoCo) in mice. Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was employed to produce ischemia and reperfusion induced cerebral injury. Cerebral infarct size was measured using TTC staining. Memory was assessed using the Morris water maze test. Degree of motor incoordination was evaluated using inclined beam-walking, rota-rod, and lateral push tests. Brain nitrite/nitrate, acetylcholinesterase activity, TBARS, and glutathione levels were also estimated. BCAO followed by reperfusion produced a significant increase in cerebral infarct size, brain nitrite/nitrate and TBARS levels, and acetylcholinesterase activity along with a reduction in glutathione. Marked impairment of memory and motor coordination was also noted. iPoCo consisting of 3 episodes of 10 s carotid artery occlusion and reperfusion instituted immediately after BCAO significantly decreased infarct size, memory impairment, motor incoordination, and altered biochemistry. Pretreatment with tadalafil mimicked the neuroprotective effects of iPoCo. The tadalafil-induced neuroprotective effects were significantly attenuated by l-NAME, a nonselective NOS inhibitor. We concluded that tadalafil mimics the neuroprotective effects of iPoCo, probably through a nitric oxide dependent pathway, and PDE-5 could be a target of interest with respect to the neuroprotective mechanism of iPoCo.

Acetylcholinesterase Inhibitory Potential and Antioxidant Activities of Five Cultivars of Rosa Damascena Mill. From Isparta, Turkey

2020 ◽  
Vol 18 (4) ◽  
pp. 354-359
Author(s):  
Shirin Tarbiat ◽  
Azize Simay Türütoğlu ◽  
Merve Ekingen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radical ◽  
Neurodegenerative Disorder ◽  
Antioxidant Activities ◽  
Radical Scavenging ◽  
Acetylcholinesterase Activity ◽  
Rosa Damascena ◽  
Free Radical Damage

Alzheimer's disease is a neurodegenerative disorder characterized by memory loss and impairment of language. Alzheimer's disease is strongly associated with oxidative stress and impairment in the cholinergic pathway, which results in decreased levels of acetylcholine in certain areas of the brain. Hence, inhibition of acetylcholinesterase activity has been recognized as an acceptable treatment against Alzheimer's disease. Nature provides an array of bioactive compounds, which may protect against free radical damage and inhibit acetylcholinesterase activity. This study compares the in vitro antioxidant and anticholinesterase activities of hydroalcoholic extracts of five cultivars of Rosa Damascena Mill. petals (R. damascena 'Bulgarica', R. damascena 'Faik', R. damascena 'Iranica', R. damascena 'Complex-635' and R. damascena 'Complex-637') from Isparta, Turkey. The antioxidant activities of the hydroalcoholic extracts were tested for ferric ion reduction and DPPH radical scavenging activities. The anti-acetylcholinesterase activity was also evaluated. All rose cultivars showed a high potency for scavenging free radical and inhibiting acetylcholinesterase activity. There was a significant correlation between antioxidant and acetylcholinesterase inhibitory activity. Among cultivars, Complex-635 showed the highest inhibitory effect with an IC50 value of 3.92 µg/mL. Our results suggest that all these extracts may have the potential to treat Alzheimer's disease with Complex-635 showing more promise.

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