Ameliorative Effect of a Selective Endothelin ET<sub>A</sub>Receptor Antagonist in Rat Model of L-Methionine-induced Vascular Dementia

Mangat, Gautamjeet S; Jaggi, Amteshwar Singh; Singh, Nirmal

doi:10.4196/kjpp.2014.18.3.201

Cited by 14 publications

(9 citation statements)

References 54 publications

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“…Chronic L‐methionine administration is well reported to produce HHcy‐induced VCID [40]. Endothelial dysfunction, impairment of learning and memory, and neuropathological changes have been reported to be associated with HHcy [36,57]. HHcy is further known to cause severe oxidative stress and decrease antioxidant enzyme activities and produce deleterious effects on endothelial cells causing endothelial cell damage [58,59].…”

Section: Discussionmentioning

confidence: 99%

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Ameliorative effect of ozagrel, a thromboxane A2 synthase inhibitor, in hyperhomocysteinemia‐induced experimental vascular cognitive impairment and dementia

Bhatia

Singh

2020

Fundamemntal Clinical Pharma

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The present study investigates the effect of ozagrel, a selective thromboxane A2 (TXA2) inhibitor, in rat model of hyperhomocysteinemia (HHcy)‐induced vascular cognitive impairment and dementia (VCID). Wistar rats were administered L‐methionine (1.7 g/kg/day; p.o. × 8 weeks) to induce VCID. Morris water maze (MWM) test was employed to assess learning and memory. Endothelial dysfunction was assessed in the isolated aorta by observing endothelial‐dependent vasorelaxation and levels of serum nitrite. Various biochemical and histopathological estimations were also performed. L‐methionine produced significant impairment in endothelium‐dependent vasorelaxation and decreases serum nitrite levels indicating endothelial dysfunction. Further, these animals performed poorly on MWM, depicting impairment of learning and memory. Further, a significant rise in brain oxidative stress level (indicated by increase in brain thiobarbituric acid‐reactive species and decrease in reduced glutathione levels), brain acetylcholinesterase activity, brain myeloperoxidase activity, brain TNF‐α and IL‐6 levels, and brain leukocyte (neutrophil) infiltration was also observed. Treatment of ozagrel (10 and 20 mg/kg, p. o.)/donepezil (0.5 mg/kg, i.p., serving as standard) ameliorated L‐methionine‐induced endothelial dysfunction, memory deficits, and biochemical and histopathological changes. It may be concluded that ozagrel markedly improved endothelial dysfunction, learning and memory, and biochemical and histopathological alteration associated with L‐methionine‐induced VCID and that TXA2 can be considered as an important therapeutic target for the management of VCID.

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Section: Discussionmentioning

confidence: 99%

“…L‐methionine (1.7 g/kg/day, p.o.) was administered for 56 days (8 weeks) to produce HHcy‐induced vascular dementia in rats [36]. Rats were subjected to Morris water maze (MWM) test from 52 nd till 56 th day to assess learning and memory.…”

Section: Methodsmentioning

confidence: 99%

Ameliorative effect of ozagrel, a thromboxane A2 synthase inhibitor, in hyperhomocysteinemia‐induced experimental vascular cognitive impairment and dementia

Bhatia

Singh

2020

Fundamemntal Clinical Pharma

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“…Most recently, a nanobody was constructed that may be useful as a potential new ET B antagonist in the treatment of melanoma [214]. Further studies suggested beneficial effects of ERA treatment on cognitive function in experimental models of vascular dementia [215,216]. The therapeutic potential of ERAs in vascular dementia or in Alzheimer disease has not yet been studied in humans yet, but preclinical and pathology data offer hope.…”

Section: Discussionmentioning

confidence: 99%

Endothelin Receptor Antagonists: Status Quo and Future Perspectives for Targeted Therapy

Enevoldsen

Sahana

Wehland

et al. 2020

JCM

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The endothelin axis, recognized for its vasoconstrictive action, plays a central role in the pathology of pulmonary arterial hypertension (PAH). Treatment with approved endothelin receptor antagonists (ERAs), such as bosentan, ambrisentan, or macitentan, slow down PAH progression and relieves symptoms. Several findings have indicated that endothelin is further involved in the pathogenesis of certain other diseases, making ERAs potentially beneficial in the treatment of various conditions. In addition to PAH, this review summarizes the use and perspectives of ERAs in cancer, renal disease, fibrotic disorders, systemic scleroderma, vasospasm, and pain management. Bosentan has proven to be effective in systemic sclerosis PAH and in decreasing the development of vasospasm-related digital ulcers. The selective ERA clazosentan has been shown to be effective in preventing cerebral vasospasm and delaying ischemic neurological deficits and new infarcts. Furthermore, in the SONAR (Study Of Diabetic Nephropathy With Atrasentan) trial, the selective ERA atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease. These data suggest atrasentan as a new therapy in the treatment of diabetic nephropathy and possibly other renal diseases. Preclinical studies regarding heart failure, cancer, and fibrotic diseases have demonstrated promising effects, but clinical trials have not yet produced measurable results. Nevertheless, the potential benefits of ERAs may not be fully realized.

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“…Similarly, it also attenuates the hyperhomocysteinemia, β-amyloid and renovascular hypertension-induced vascular dementia in rats. Further, the administration of selective endothelin ET-A receptor antagonist i.e., ambrisentan attenuates the L-methionine-induced vascular dementia in rats [46]. ECEs inhibitors can control the accumulation of ET-1 peptide and activation of ET receptors.…”

Section: Endothelin-converting Enzymementioning

confidence: 94%

Recent Advance of Enzyme Targets for the Management of Vascular Dementia

Muthuraman¹,

Rishitha²,

Islam³

2019

Advances in Dementia Research

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The basic understanding of vascular dementia (VaD) and their molecular mechanisms are a too complex phenomenon. VaD associated neurodegeneration and cognitive impairment are due to multiple complications of the neurovascular system. The progress of VaD is due to the central and/or peripheral pathophysiological process of the neurovascular system. There are limited nootropic agents are employed for the treatment of VaD. Moreover, the explored nootropic agents act on multiple targets such as receptors, enzymes, ion channel, free radicals, cytokines, chemokines, and apoptotic proteins. However, the enzyme targets, especially acetylcholinesterase inhibitors played a crucial role in the management of cognitive disorders. The pathogenesis of VaD is involved in the vascular complication and neurodegenerative process. Hence, the enzymatic regulation of neurovascular complication is expected to prevent the VaD. The present chapter attempts to explore the recent advancement of enzyme targets for the management of VaD.

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Ameliorative Effect of a Selective Endothelin ET_AReceptor Antagonist in Rat Model of L-Methionine-induced Vascular Dementia

Cited by 14 publications

References 54 publications

Ameliorative effect of ozagrel, a thromboxane A2 synthase inhibitor, in hyperhomocysteinemia‐induced experimental vascular cognitive impairment and dementia

Ameliorative effect of ozagrel, a thromboxane A2 synthase inhibitor, in hyperhomocysteinemia‐induced experimental vascular cognitive impairment and dementia

Endothelin Receptor Antagonists: Status Quo and Future Perspectives for Targeted Therapy

Recent Advance of Enzyme Targets for the Management of Vascular Dementia

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Ameliorative Effect of a Selective Endothelin ETAReceptor Antagonist in Rat Model of L-Methionine-induced Vascular Dementia

Cited by 14 publications

References 54 publications

Ameliorative effect of ozagrel, a thromboxane A2 synthase inhibitor, in hyperhomocysteinemia‐induced experimental vascular cognitive impairment and dementia

Ameliorative effect of ozagrel, a thromboxane A2 synthase inhibitor, in hyperhomocysteinemia‐induced experimental vascular cognitive impairment and dementia

Endothelin Receptor Antagonists: Status Quo and Future Perspectives for Targeted Therapy

Recent Advance of Enzyme Targets for the Management of Vascular Dementia

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Ameliorative Effect of a Selective Endothelin ET_AReceptor Antagonist in Rat Model of L-Methionine-induced Vascular Dementia