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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

Radical-scavenging activity of 3d in vivo after I/R in ischemic cerebral cortex.Notes: Effect of 3d on the activities of brain T-SOD (A) and GSH-Px (B); the levels of MDA (C) and NO (D) in MCAO Sprague Dawley rats after I/R in ischemic cerebral cortex. Data were expressed as the mean ± SD (n=10) and analyzed by one-way analysis of variance (ANOVA) followed by Newman–Keuls test to determine statistical significance. **P<0.01 vs the sham-operated group, and ***P<0.001 vs the sham-operated group; #P<0.05, ##P<0.01, and ###P<0.001 vs the model group.Abbreviations: Eda, edaravone; GSH-Px, glutathione peroxidase; I/R, ischemia/reperfusion; MCAO, middle cerebral artery occlusion; MDA, malondialdehyde; NBP, 3-n-butylphthalide; NO, nitric oxide; SD, standard deviation; T-SOD, total superoxide dismutase; L-3d, low-dose(3d); M-3d, medium-dose(3d); H-3d, high-dose (3d).
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f9-dddt-9-3377: Radical-scavenging activity of 3d in vivo after I/R in ischemic cerebral cortex.Notes: Effect of 3d on the activities of brain T-SOD (A) and GSH-Px (B); the levels of MDA (C) and NO (D) in MCAO Sprague Dawley rats after I/R in ischemic cerebral cortex. Data were expressed as the mean ± SD (n=10) and analyzed by one-way analysis of variance (ANOVA) followed by Newman–Keuls test to determine statistical significance. **P<0.01 vs the sham-operated group, and ***P<0.001 vs the sham-operated group; #P<0.05, ##P<0.01, and ###P<0.001 vs the model group.Abbreviations: Eda, edaravone; GSH-Px, glutathione peroxidase; I/R, ischemia/reperfusion; MCAO, middle cerebral artery occlusion; MDA, malondialdehyde; NBP, 3-n-butylphthalide; NO, nitric oxide; SD, standard deviation; T-SOD, total superoxide dismutase; L-3d, low-dose(3d); M-3d, medium-dose(3d); H-3d, high-dose (3d).

Mentions: Postischemic reperfusion could enhance the formation of ROS in brain tissue,52–55 whereas endogenous antioxidants, including SOD, GSH-Px, and catalase, could scavenge ROS. Thus, to evaluate radical-scavenging activity of 3d in ischemic stroke rats, we evaluated the levels of GSH-Px, SOD, and the content of MDA (an indicator of lipid peroxidation) and NO in the brain tissues. Compared with the sham group, the content of SOD in the model group was decreased by 26.22% (from 88.66 to 65.41 U/mg), whereas the content of SOD in the 3d-treated group (10, 20, and 50 mg/kg), NBP-treated group, and Eda-treated group increased in comparison with the model group (Figure 9A). The GSH-Px activity in the ischemic core of rats in the model group was significantly decreased by 27.12% (from 30.17 to 21.98 nmol/mg), as shown in Figure 9B, compared with that in the sham group. However, the levels of GSH-Px activity in 3d-treated group (50 mg/kg) and Eda-treated group (3 mg/kg) were significantly higher than that in the model animals. Meanwhile, we measured the tissue content of MDA and the activity level of NO and found that these were significantly higher in the model group than in the sham group, whereas 3d treatment attenuated the increase in MDA and NO levels after reperfusion. Treatment with 3d (50 mg/kg) decreased the content of the cerebral cortex MDA by 26.16% (from 3.02 to 2.23 nmol/mg) and NO by 52.32% (from 1.51 to 0.72 U/mg), compared with that in the model group (as shown in Figure 9C and D). In addition, the effect of 3d on the brain MDA and NO levels was much stronger with the increase in dosage. The NO activity of the 20 mg/kg 3d-treated rats (1.01 U/mg) was comparable with that of the 20 mg/kg NBP-treated group (0.92 U/mg). Interestingly, after treatment with 3d in ischemic reperfusion rats, the levels of GSH-Px and SOD activity in ischemia penumbra were recovered to near the nonischemic control level and the content of MDA and NO activity remarkably decreased.


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)

Radical-scavenging activity of 3d in vivo after I/R in ischemic cerebral cortex.Notes: Effect of 3d on the activities of brain T-SOD (A) and GSH-Px (B); the levels of MDA (C) and NO (D) in MCAO Sprague Dawley rats after I/R in ischemic cerebral cortex. Data were expressed as the mean ± SD (n=10) and analyzed by one-way analysis of variance (ANOVA) followed by Newman–Keuls test to determine statistical significance. **P<0.01 vs the sham-operated group, and ***P<0.001 vs the sham-operated group; #P<0.05, ##P<0.01, and ###P<0.001 vs the model group.Abbreviations: Eda, edaravone; GSH-Px, glutathione peroxidase; I/R, ischemia/reperfusion; MCAO, middle cerebral artery occlusion; MDA, malondialdehyde; NBP, 3-n-butylphthalide; NO, nitric oxide; SD, standard deviation; T-SOD, total superoxide dismutase; L-3d, low-dose(3d); M-3d, medium-dose(3d); H-3d, high-dose (3d).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4492651&req=5

f9-dddt-9-3377: Radical-scavenging activity of 3d in vivo after I/R in ischemic cerebral cortex.Notes: Effect of 3d on the activities of brain T-SOD (A) and GSH-Px (B); the levels of MDA (C) and NO (D) in MCAO Sprague Dawley rats after I/R in ischemic cerebral cortex. Data were expressed as the mean ± SD (n=10) and analyzed by one-way analysis of variance (ANOVA) followed by Newman–Keuls test to determine statistical significance. **P<0.01 vs the sham-operated group, and ***P<0.001 vs the sham-operated group; #P<0.05, ##P<0.01, and ###P<0.001 vs the model group.Abbreviations: Eda, edaravone; GSH-Px, glutathione peroxidase; I/R, ischemia/reperfusion; MCAO, middle cerebral artery occlusion; MDA, malondialdehyde; NBP, 3-n-butylphthalide; NO, nitric oxide; SD, standard deviation; T-SOD, total superoxide dismutase; L-3d, low-dose(3d); M-3d, medium-dose(3d); H-3d, high-dose (3d).
Mentions: Postischemic reperfusion could enhance the formation of ROS in brain tissue,52–55 whereas endogenous antioxidants, including SOD, GSH-Px, and catalase, could scavenge ROS. Thus, to evaluate radical-scavenging activity of 3d in ischemic stroke rats, we evaluated the levels of GSH-Px, SOD, and the content of MDA (an indicator of lipid peroxidation) and NO in the brain tissues. Compared with the sham group, the content of SOD in the model group was decreased by 26.22% (from 88.66 to 65.41 U/mg), whereas the content of SOD in the 3d-treated group (10, 20, and 50 mg/kg), NBP-treated group, and Eda-treated group increased in comparison with the model group (Figure 9A). The GSH-Px activity in the ischemic core of rats in the model group was significantly decreased by 27.12% (from 30.17 to 21.98 nmol/mg), as shown in Figure 9B, compared with that in the sham group. However, the levels of GSH-Px activity in 3d-treated group (50 mg/kg) and Eda-treated group (3 mg/kg) were significantly higher than that in the model animals. Meanwhile, we measured the tissue content of MDA and the activity level of NO and found that these were significantly higher in the model group than in the sham group, whereas 3d treatment attenuated the increase in MDA and NO levels after reperfusion. Treatment with 3d (50 mg/kg) decreased the content of the cerebral cortex MDA by 26.16% (from 3.02 to 2.23 nmol/mg) and NO by 52.32% (from 1.51 to 0.72 U/mg), compared with that in the model group (as shown in Figure 9C and D). In addition, the effect of 3d on the brain MDA and NO levels was much stronger with the increase in dosage. The NO activity of the 20 mg/kg 3d-treated rats (1.01 U/mg) was comparable with that of the 20 mg/kg NBP-treated group (0.92 U/mg). Interestingly, after treatment with 3d in ischemic reperfusion rats, the levels of GSH-Px and SOD activity in ischemia penumbra were recovered to near the nonischemic control level and the content of MDA and NO activity remarkably decreased.

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