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Carvacrol, a food-additive, provides neuroprotection on focal cerebral ischemia/reperfusion injury in mice.

Yu H, Zhang ZL, Chen J, Pei A, Hua F, Qian X, He J, Liu CF, Xu X - PLoS ONE (2012)

Bottom Line: In this study, we investigated the protective effects of CAR on cerebral ischemia/reperfusion injury in a middle cerebral artery occlusion mouse model.These findings indicated that CAR has an extended therapeutic window, but delivery strategies may affect the protective effects of CAR.Further, we found that CAR significantly decreased the level of cleaved caspase-3, a marker of apoptosis, suggesting the anti-apoptotic activity of CAR.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, People's Republic of China.

ABSTRACT
Carvacrol (CAR), a naturally occurring monoterpenic phenol and food additive, has been shown to have antimicrobials, antitumor, and antidepressant-like activities. A previous study demonstrated that CAR has the ability to protect liver against ischemia/reperfusion injury in rats. In this study, we investigated the protective effects of CAR on cerebral ischemia/reperfusion injury in a middle cerebral artery occlusion mouse model. We found that CAR (50 mg/kg) significantly reduced infarct volume and improved neurological deficits after 75 min of ischemia and 24 h of reperfusion. This neuroprotection was in a dose-dependent manner. Post-treatment with CAR still provided protection on infarct volume when it was administered intraperitoneally at 2 h after reperfusion; however, intracerebroventricular post-treatment reduced infarct volume even when the mice were treated with CAR at 6 h after reperfusion. These findings indicated that CAR has an extended therapeutic window, but delivery strategies may affect the protective effects of CAR. Further, we found that CAR significantly decreased the level of cleaved caspase-3, a marker of apoptosis, suggesting the anti-apoptotic activity of CAR. Finally, our data indicated that CAR treatment increased the level of phosphorylated Akt and the neuroprotection of CAR was reversed by a PI3K inhibitor LY-294002, demonstrating the involvement of the PI3K/Akt pathway in the anti-apoptotic mechanisms of CAR. Due to its safety and wide use in the food industry, CAR is a promising agent to be translated into clinical trials.

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A PI3K inhibitor LY-294002 blocked the neuroprotection of CAR on cerebral I/R injury.Mice were treated with CAR (50 mg/kg, i.p.) or saline 2 h before ischemia and 5 µl LY-294002 (10 mM) was administered (i.c.v.) at 15 min before ischemia. (A) After 30 min of ischemia and 6 h reperfusion, brain tissues were collected and p-Akt and t-Akt levels were determined by Western blot. The photographs show that LY-294002 treatment inhibited the activation of Akt by CAR. (B) After 75 min of ischemia and 24 h of reperfusion, cerebral infarct volume was determined by TTC staining. The representative TTC-stained coronal sections demonstrate that LY-294002 treatment abolished the protection of CAR on infarct volume. (C) Statistical analysis of cerebral infarct volume shows that PI3K inhibitor LY-294002 blocked the protective effects of CAR. I/R+CAR+LY: CAR and LY-294002-treated I/R group. Bars represent mean ± SEM of 6–9 brains. *, P<0.05 versus vehicle-treated I/R group.
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pone-0033584-g006: A PI3K inhibitor LY-294002 blocked the neuroprotection of CAR on cerebral I/R injury.Mice were treated with CAR (50 mg/kg, i.p.) or saline 2 h before ischemia and 5 µl LY-294002 (10 mM) was administered (i.c.v.) at 15 min before ischemia. (A) After 30 min of ischemia and 6 h reperfusion, brain tissues were collected and p-Akt and t-Akt levels were determined by Western blot. The photographs show that LY-294002 treatment inhibited the activation of Akt by CAR. (B) After 75 min of ischemia and 24 h of reperfusion, cerebral infarct volume was determined by TTC staining. The representative TTC-stained coronal sections demonstrate that LY-294002 treatment abolished the protection of CAR on infarct volume. (C) Statistical analysis of cerebral infarct volume shows that PI3K inhibitor LY-294002 blocked the protective effects of CAR. I/R+CAR+LY: CAR and LY-294002-treated I/R group. Bars represent mean ± SEM of 6–9 brains. *, P<0.05 versus vehicle-treated I/R group.

Mentions: To further investigate whether the PI3K/Akt pathway mediates the neuroprotection of CAR in cerebral I/R injury, we treated the mice with a PI3K inhibitor LY-294002 (i.c.v., 5 µl 10 mM LY-294002 dissolved in 3% DMSO) at 15 min before ischemia. Western blot analysis showed that the PI3K inhibitor LY-294002 inhibited the increase of p-Akt level induced by CAR treatment and almost restored p-Akt level to basal level (Figure 6A). TTC staining was performed after the treatment with LY-294002 to evaluate its effects on infarct volume. As expected, LY-294002 treatment almost abolished the protection of CAR (Figure 6B). The quantitative analysis of infarct volumes indicated the inhibition of the PI3K/Akt pathway was able to reverse the neuroprotective effect by CAR treatment after MCAO (P<0.05, Figure 6C), demonstrating that the PI3K/Akt pathway mediates the neuroprotection of CAR after cerebral I/R injury.


Carvacrol, a food-additive, provides neuroprotection on focal cerebral ischemia/reperfusion injury in mice.

Yu H, Zhang ZL, Chen J, Pei A, Hua F, Qian X, He J, Liu CF, Xu X - PLoS ONE (2012)

A PI3K inhibitor LY-294002 blocked the neuroprotection of CAR on cerebral I/R injury.Mice were treated with CAR (50 mg/kg, i.p.) or saline 2 h before ischemia and 5 µl LY-294002 (10 mM) was administered (i.c.v.) at 15 min before ischemia. (A) After 30 min of ischemia and 6 h reperfusion, brain tissues were collected and p-Akt and t-Akt levels were determined by Western blot. The photographs show that LY-294002 treatment inhibited the activation of Akt by CAR. (B) After 75 min of ischemia and 24 h of reperfusion, cerebral infarct volume was determined by TTC staining. The representative TTC-stained coronal sections demonstrate that LY-294002 treatment abolished the protection of CAR on infarct volume. (C) Statistical analysis of cerebral infarct volume shows that PI3K inhibitor LY-294002 blocked the protective effects of CAR. I/R+CAR+LY: CAR and LY-294002-treated I/R group. Bars represent mean ± SEM of 6–9 brains. *, P<0.05 versus vehicle-treated I/R group.
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Related In: Results  -  Collection

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pone-0033584-g006: A PI3K inhibitor LY-294002 blocked the neuroprotection of CAR on cerebral I/R injury.Mice were treated with CAR (50 mg/kg, i.p.) or saline 2 h before ischemia and 5 µl LY-294002 (10 mM) was administered (i.c.v.) at 15 min before ischemia. (A) After 30 min of ischemia and 6 h reperfusion, brain tissues were collected and p-Akt and t-Akt levels were determined by Western blot. The photographs show that LY-294002 treatment inhibited the activation of Akt by CAR. (B) After 75 min of ischemia and 24 h of reperfusion, cerebral infarct volume was determined by TTC staining. The representative TTC-stained coronal sections demonstrate that LY-294002 treatment abolished the protection of CAR on infarct volume. (C) Statistical analysis of cerebral infarct volume shows that PI3K inhibitor LY-294002 blocked the protective effects of CAR. I/R+CAR+LY: CAR and LY-294002-treated I/R group. Bars represent mean ± SEM of 6–9 brains. *, P<0.05 versus vehicle-treated I/R group.
Mentions: To further investigate whether the PI3K/Akt pathway mediates the neuroprotection of CAR in cerebral I/R injury, we treated the mice with a PI3K inhibitor LY-294002 (i.c.v., 5 µl 10 mM LY-294002 dissolved in 3% DMSO) at 15 min before ischemia. Western blot analysis showed that the PI3K inhibitor LY-294002 inhibited the increase of p-Akt level induced by CAR treatment and almost restored p-Akt level to basal level (Figure 6A). TTC staining was performed after the treatment with LY-294002 to evaluate its effects on infarct volume. As expected, LY-294002 treatment almost abolished the protection of CAR (Figure 6B). The quantitative analysis of infarct volumes indicated the inhibition of the PI3K/Akt pathway was able to reverse the neuroprotective effect by CAR treatment after MCAO (P<0.05, Figure 6C), demonstrating that the PI3K/Akt pathway mediates the neuroprotection of CAR after cerebral I/R injury.

Bottom Line: In this study, we investigated the protective effects of CAR on cerebral ischemia/reperfusion injury in a middle cerebral artery occlusion mouse model.These findings indicated that CAR has an extended therapeutic window, but delivery strategies may affect the protective effects of CAR.Further, we found that CAR significantly decreased the level of cleaved caspase-3, a marker of apoptosis, suggesting the anti-apoptotic activity of CAR.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, People's Republic of China.

ABSTRACT
Carvacrol (CAR), a naturally occurring monoterpenic phenol and food additive, has been shown to have antimicrobials, antitumor, and antidepressant-like activities. A previous study demonstrated that CAR has the ability to protect liver against ischemia/reperfusion injury in rats. In this study, we investigated the protective effects of CAR on cerebral ischemia/reperfusion injury in a middle cerebral artery occlusion mouse model. We found that CAR (50 mg/kg) significantly reduced infarct volume and improved neurological deficits after 75 min of ischemia and 24 h of reperfusion. This neuroprotection was in a dose-dependent manner. Post-treatment with CAR still provided protection on infarct volume when it was administered intraperitoneally at 2 h after reperfusion; however, intracerebroventricular post-treatment reduced infarct volume even when the mice were treated with CAR at 6 h after reperfusion. These findings indicated that CAR has an extended therapeutic window, but delivery strategies may affect the protective effects of CAR. Further, we found that CAR significantly decreased the level of cleaved caspase-3, a marker of apoptosis, suggesting the anti-apoptotic activity of CAR. Finally, our data indicated that CAR treatment increased the level of phosphorylated Akt and the neuroprotection of CAR was reversed by a PI3K inhibitor LY-294002, demonstrating the involvement of the PI3K/Akt pathway in the anti-apoptotic mechanisms of CAR. Due to its safety and wide use in the food industry, CAR is a promising agent to be translated into clinical trials.

Show MeSH
Related in: MedlinePlus