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Discovery of 3-n-butyl-2,3-dihydro-1H-isoindol-1-one as a potential anti-ischemic stroke agent.

Lan Z, Xu X, Xu W, Li J, Liang Z, Zhang X, Lei M, Zhao C - Drug Des Devel Ther (2015)

Bottom Line: This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone.Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains.In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.

ABSTRACT
To develop novel anti-ischemic stroke agents with better therapeutic efficacy and bioavailability, we designed and synthesized a series of 3-alkyl-2,3-dihydro-1H-isoindol-1-ones compounds (3a-i) derivatives, one of which (3d) exhibited the strongest inhibitory activity for the adenosine diphosphate-induced and arachidonic acid-induced platelet aggregation. This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone. Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains. Results from transient middle cerebral artery occlusion and permanent middle cerebral artery occlusion model, indicated that 3d could significantly reduce infarct size, improve neurobehavioral deficits, and prominently decrease attenuation of cerebral damage. Most importantly, 3d possessed a very high absolute bioavailability and was rapidly distributed in brain tissue to keep high plasma drug concentration for the treatment of ischemic strokes. In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

No MeSH data available.


Related in: MedlinePlus

Protective effect of 3d on cerebral ischemia-induced neuronal injury in Sprague Dawley rats.Notes: The cerebral cortex was stained by hematoxylin and eosin (H&E) staining, and pictures were taken under a light microscope. The red arrows represented perikaya shrinkage, and the black arrows represented vacuoles; representative images are (magnification, ×100) from individual groups of rats (n=3).Abbreviations: Eda, edaravone; NBP, 3-n-butylphthalide; L-3d, low-dose(3d); M-3d, medium-dose(3d); H-3d, high-dose (3d).
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f7-dddt-9-3377: Protective effect of 3d on cerebral ischemia-induced neuronal injury in Sprague Dawley rats.Notes: The cerebral cortex was stained by hematoxylin and eosin (H&E) staining, and pictures were taken under a light microscope. The red arrows represented perikaya shrinkage, and the black arrows represented vacuoles; representative images are (magnification, ×100) from individual groups of rats (n=3).Abbreviations: Eda, edaravone; NBP, 3-n-butylphthalide; L-3d, low-dose(3d); M-3d, medium-dose(3d); H-3d, high-dose (3d).

Mentions: H&E staining analysis suggested that 3d could significantly attenuate cerebral damage. As shown in Figure 7, the H&E stain of the cerebral cortex in the model group showed a large area of infarction in the cerebral cortex, neuronal perikarya shrinkage, and microglial cells, in addition to degeneration of a large number of nerve cells in the vacuoles. However, compared with that in the model group, drug-treated groups exhibited minor infarction of cerebral cortex, and less neuronal perikarya shrinkage in the brains, particularly in those exposed to the highest dose of 3d.


Discovery of 3-n-butyl-2,3-dihydro-1H-isoindol-1-one as a potential anti-ischemic stroke agent.

Lan Z, Xu X, Xu W, Li J, Liang Z, Zhang X, Lei M, Zhao C - Drug Des Devel Ther (2015)

Protective effect of 3d on cerebral ischemia-induced neuronal injury in Sprague Dawley rats.Notes: The cerebral cortex was stained by hematoxylin and eosin (H&E) staining, and pictures were taken under a light microscope. The red arrows represented perikaya shrinkage, and the black arrows represented vacuoles; representative images are (magnification, ×100) from individual groups of rats (n=3).Abbreviations: Eda, edaravone; NBP, 3-n-butylphthalide; L-3d, low-dose(3d); M-3d, medium-dose(3d); H-3d, high-dose (3d).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492651&req=5

f7-dddt-9-3377: Protective effect of 3d on cerebral ischemia-induced neuronal injury in Sprague Dawley rats.Notes: The cerebral cortex was stained by hematoxylin and eosin (H&E) staining, and pictures were taken under a light microscope. The red arrows represented perikaya shrinkage, and the black arrows represented vacuoles; representative images are (magnification, ×100) from individual groups of rats (n=3).Abbreviations: Eda, edaravone; NBP, 3-n-butylphthalide; L-3d, low-dose(3d); M-3d, medium-dose(3d); H-3d, high-dose (3d).
Mentions: H&E staining analysis suggested that 3d could significantly attenuate cerebral damage. As shown in Figure 7, the H&E stain of the cerebral cortex in the model group showed a large area of infarction in the cerebral cortex, neuronal perikarya shrinkage, and microglial cells, in addition to degeneration of a large number of nerve cells in the vacuoles. However, compared with that in the model group, drug-treated groups exhibited minor infarction of cerebral cortex, and less neuronal perikarya shrinkage in the brains, particularly in those exposed to the highest dose of 3d.

Bottom Line: This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone.Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains.In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.

ABSTRACT
To develop novel anti-ischemic stroke agents with better therapeutic efficacy and bioavailability, we designed and synthesized a series of 3-alkyl-2,3-dihydro-1H-isoindol-1-ones compounds (3a-i) derivatives, one of which (3d) exhibited the strongest inhibitory activity for the adenosine diphosphate-induced and arachidonic acid-induced platelet aggregation. This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone. Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains. Results from transient middle cerebral artery occlusion and permanent middle cerebral artery occlusion model, indicated that 3d could significantly reduce infarct size, improve neurobehavioral deficits, and prominently decrease attenuation of cerebral damage. Most importantly, 3d possessed a very high absolute bioavailability and was rapidly distributed in brain tissue to keep high plasma drug concentration for the treatment of ischemic strokes. In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

No MeSH data available.


Related in: MedlinePlus