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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

Effect of 3d on the neurological deficit score at 24 hours after reperfusion and pMCAO.Notes: (A) Effect of 3d on the neurological deficit score in the rats subjected to I/R. (B) Effect of 3d on the neurological deficit score in the rats subjected to pMCAO (n=9). Data were expressed as the mean ± SD of individual groups of rats and were analyzed by one-way analysis of variance (ANOVA) followed by Newman-keuls test: ***P<0.001 vs the sham group; #P<0.05 vs the model group. ##P<0.01 and ###P<0.001 vs the model group. Triangle represents one rat.Abbreviations: Eda, edaravone; I/R, ischemia/reperfusion; NBP, 3-n-butylphthalide; pMCAO, permanent middle cerebral artery occlusion; SD, standard deviation; L-3d, low-dose(3d); M-3d, medium-dose(3d); H-3d, high-dose (3d).
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f5-dddt-9-3377: Effect of 3d on the neurological deficit score at 24 hours after reperfusion and pMCAO.Notes: (A) Effect of 3d on the neurological deficit score in the rats subjected to I/R. (B) Effect of 3d on the neurological deficit score in the rats subjected to pMCAO (n=9). Data were expressed as the mean ± SD of individual groups of rats and were analyzed by one-way analysis of variance (ANOVA) followed by Newman-keuls test: ***P<0.001 vs the sham group; #P<0.05 vs the model group. ##P<0.01 and ###P<0.001 vs the model group. Triangle represents one rat.Abbreviations: Eda, edaravone; I/R, ischemia/reperfusion; NBP, 3-n-butylphthalide; pMCAO, permanent middle cerebral artery occlusion; SD, standard deviation; L-3d, low-dose(3d); M-3d, medium-dose(3d); H-3d, high-dose (3d).

Mentions: The most common cause of ischemic strokes is occlusion of the MCA. Hence, we observed the effect of treatment with 3d on ischemic stroke injury by occlusion of MCAO for 2 hours followed by recirculation.43 Sprague Dawley rats were randomly divided into seven groups as follows: sham-operated group (just separated blood vessels), soybean oil group (negative control), NBP group (20 mg/kg), Eda group (3.0 mg/kg), and 3d group (10, 20, and 50 mg/kg). Fifteen minutes after the onset of MCAO, drugs or vehicle was administered to rats by ip injection, and the neurological deficits cores in rats were evaluated by Longa’s method 24 hours after reperfusion. The experiment result showed no obvious neurological deficit in the sham-operated group. However, the neurological deficit score in the group of soybean oil-treated rats significantly increased 24 hours after reperfusion. On the contrary, the neurobehavioral function score with 3d (10, 20, and 50 mg/kg) treatment significantly decreased, comparable with Eda-treated group, and treatment with 3d dose improved the neurological score 24 hours after ischemia in a dose-dependent manner in Figure 5. Meanwhile, we also observed the effect of treatment with 3d on ischemic stroke injury by occlusion of MCAO for 24 hours. Sprague Dawley rats were randomly divided into five groups as follows: sham-operated group (just separated blood vessels), 50% propanediol group (negative control), NBP group (50 mg/kg), Eda group (3.0 mg/kg), and 3d group (50 mg/kg). Two hours after the onset of MCAO, drugs or vehicle was administered to rats by ip injection, and the neurobehavioral function score with 3d (50 mg/kg) treatment also decreased (Figure 5).


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)

Effect of 3d on the neurological deficit score at 24 hours after reperfusion and pMCAO.Notes: (A) Effect of 3d on the neurological deficit score in the rats subjected to I/R. (B) Effect of 3d on the neurological deficit score in the rats subjected to pMCAO (n=9). Data were expressed as the mean ± SD of individual groups of rats and were analyzed by one-way analysis of variance (ANOVA) followed by Newman-keuls test: ***P<0.001 vs the sham group; #P<0.05 vs the model group. ##P<0.01 and ###P<0.001 vs the model group. Triangle represents one rat.Abbreviations: Eda, edaravone; I/R, ischemia/reperfusion; NBP, 3-n-butylphthalide; pMCAO, permanent middle cerebral artery occlusion; SD, standard deviation; L-3d, low-dose(3d); M-3d, medium-dose(3d); H-3d, high-dose (3d).
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f5-dddt-9-3377: Effect of 3d on the neurological deficit score at 24 hours after reperfusion and pMCAO.Notes: (A) Effect of 3d on the neurological deficit score in the rats subjected to I/R. (B) Effect of 3d on the neurological deficit score in the rats subjected to pMCAO (n=9). Data were expressed as the mean ± SD of individual groups of rats and were analyzed by one-way analysis of variance (ANOVA) followed by Newman-keuls test: ***P<0.001 vs the sham group; #P<0.05 vs the model group. ##P<0.01 and ###P<0.001 vs the model group. Triangle represents one rat.Abbreviations: Eda, edaravone; I/R, ischemia/reperfusion; NBP, 3-n-butylphthalide; pMCAO, permanent middle cerebral artery occlusion; SD, standard deviation; L-3d, low-dose(3d); M-3d, medium-dose(3d); H-3d, high-dose (3d).
Mentions: The most common cause of ischemic strokes is occlusion of the MCA. Hence, we observed the effect of treatment with 3d on ischemic stroke injury by occlusion of MCAO for 2 hours followed by recirculation.43 Sprague Dawley rats were randomly divided into seven groups as follows: sham-operated group (just separated blood vessels), soybean oil group (negative control), NBP group (20 mg/kg), Eda group (3.0 mg/kg), and 3d group (10, 20, and 50 mg/kg). Fifteen minutes after the onset of MCAO, drugs or vehicle was administered to rats by ip injection, and the neurological deficits cores in rats were evaluated by Longa’s method 24 hours after reperfusion. The experiment result showed no obvious neurological deficit in the sham-operated group. However, the neurological deficit score in the group of soybean oil-treated rats significantly increased 24 hours after reperfusion. On the contrary, the neurobehavioral function score with 3d (10, 20, and 50 mg/kg) treatment significantly decreased, comparable with Eda-treated group, and treatment with 3d dose improved the neurological score 24 hours after ischemia in a dose-dependent manner in Figure 5. Meanwhile, we also observed the effect of treatment with 3d on ischemic stroke injury by occlusion of MCAO for 24 hours. Sprague Dawley rats were randomly divided into five groups as follows: sham-operated group (just separated blood vessels), 50% propanediol group (negative control), NBP group (50 mg/kg), Eda group (3.0 mg/kg), and 3d group (50 mg/kg). Two hours after the onset of MCAO, drugs or vehicle was administered to rats by ip injection, and the neurobehavioral function score with 3d (50 mg/kg) treatment also decreased (Figure 5).

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