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Male-Specific Alleviation of Iron-Induced Striatal Injury by Inhibition of Autophagy.

Wang LF, Yokoyama KK, Chen TY, Hsiao HW, Chiang PC, Hsieh YC, Lo S, Hsu C - PLoS ONE (2015)

Bottom Line: Pre-treatment of FC-infused females with rapamycin increased the FC-induced behavioral deficit and DRD2 neuron death.These results suggest that autophagy in FC-infusion males is overactive with maladaptive consequences and inhibition of autophagy decreases the severity of FC-induced striatal injury in males.These findings present prospects for male-specific therapeutic strategy that targets autophagy in patients suffering from iron overload.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.

ABSTRACT
Men exhibit a worse survival rate than premenopausal women after intracerebral hemorrhage (ICH), however, no sex-specific management has been concerned. In a rat model involving infusion of ferrous citrate (FC) that simulates iron accumulation after hemorrhage, a higher degree of autophagy associated with higher injury severity was observed in striatum of males than in females. Since the imbalance between the levels of autophagy and energy demand may lead to cell death, we proposed that FC-induced autophagy is detrimental in a male specific manner and autophagy modulation affects injury severity in a sex-dependent manner. Rapamycin, an autophagy inducer, and conditional knockout gene of autophagy-related protein 7 (Atg7) in dopamine receptor D2 (DRD2) neurons were used to test our hypothesis using a mouse model with striatal FC infusion. The result showed that the levels of autophagic cell death and injury severity were higher in male than in female mice. Pre-treatment of FC-infused females with rapamycin increased the FC-induced behavioral deficit and DRD2 neuron death. However, DRD2 neuron-specific knockout of Atg7 decreased FC-induced injury severity and the number of TUNEL(+) DRD2 neurons in males. These results suggest that autophagy in FC-infusion males is overactive with maladaptive consequences and inhibition of autophagy decreases the severity of FC-induced striatal injury in males. These findings present prospects for male-specific therapeutic strategy that targets autophagy in patients suffering from iron overload.

No MeSH data available.


Related in: MedlinePlus

Atg7 KO mice exhibited a male-specific benefit in FC-induced DNA fragmentation in the DRD2 neurons in the striatum.(A) Representative images of the TUNEL(+) DRD2 neurons. The bright green-yellow dots depict DRD2 neurons with DNA fragmentation, as indicated by the arrows. Quantitative results of the percentages of DRD2 neurons (B), TUNEL(+) cells (C), and TUNEL(+) DRD2 neurons (D). The data are expressed as the means ± SDs (n = 6). **p<0.01, Atg7F/F female vs. Atg7F/F male; ##p<0.01 Atg7F/F vs. Atg7+/-Drd2-Cre.
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pone.0131224.g007: Atg7 KO mice exhibited a male-specific benefit in FC-induced DNA fragmentation in the DRD2 neurons in the striatum.(A) Representative images of the TUNEL(+) DRD2 neurons. The bright green-yellow dots depict DRD2 neurons with DNA fragmentation, as indicated by the arrows. Quantitative results of the percentages of DRD2 neurons (B), TUNEL(+) cells (C), and TUNEL(+) DRD2 neurons (D). The data are expressed as the means ± SDs (n = 6). **p<0.01, Atg7F/F female vs. Atg7F/F male; ##p<0.01 Atg7F/F vs. Atg7+/-Drd2-Cre.

Mentions: Moreover, the results from TissueQuest analysis showed that no significant sex differences in the numbers of DRD2 neurons were found between the Atg7F/F and Atg7+/-Drd2-Cre mice (Fig 7A & 7B). FC infusion caused a significantly higher level of DNA fragmentation in male than in the female Atg7F/F mice. Interestingly, in males, Atg7 knockout decreased the percentages of TUNEL(+) cells and TUNEL(+) DRD2 neurons by 70% and 69%, respectively, following FC infusion. By contrast, no significant differences in the percentages of TUNEL(+) cells or TUNEL(+) DRD2 neurons between the Atg7+/-Drd2-Cre and Atg7F/F females following FC infusion were observed (Fig 7C and 7D).


Male-Specific Alleviation of Iron-Induced Striatal Injury by Inhibition of Autophagy.

Wang LF, Yokoyama KK, Chen TY, Hsiao HW, Chiang PC, Hsieh YC, Lo S, Hsu C - PLoS ONE (2015)

Atg7 KO mice exhibited a male-specific benefit in FC-induced DNA fragmentation in the DRD2 neurons in the striatum.(A) Representative images of the TUNEL(+) DRD2 neurons. The bright green-yellow dots depict DRD2 neurons with DNA fragmentation, as indicated by the arrows. Quantitative results of the percentages of DRD2 neurons (B), TUNEL(+) cells (C), and TUNEL(+) DRD2 neurons (D). The data are expressed as the means ± SDs (n = 6). **p<0.01, Atg7F/F female vs. Atg7F/F male; ##p<0.01 Atg7F/F vs. Atg7+/-Drd2-Cre.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4492841&req=5

pone.0131224.g007: Atg7 KO mice exhibited a male-specific benefit in FC-induced DNA fragmentation in the DRD2 neurons in the striatum.(A) Representative images of the TUNEL(+) DRD2 neurons. The bright green-yellow dots depict DRD2 neurons with DNA fragmentation, as indicated by the arrows. Quantitative results of the percentages of DRD2 neurons (B), TUNEL(+) cells (C), and TUNEL(+) DRD2 neurons (D). The data are expressed as the means ± SDs (n = 6). **p<0.01, Atg7F/F female vs. Atg7F/F male; ##p<0.01 Atg7F/F vs. Atg7+/-Drd2-Cre.
Mentions: Moreover, the results from TissueQuest analysis showed that no significant sex differences in the numbers of DRD2 neurons were found between the Atg7F/F and Atg7+/-Drd2-Cre mice (Fig 7A & 7B). FC infusion caused a significantly higher level of DNA fragmentation in male than in the female Atg7F/F mice. Interestingly, in males, Atg7 knockout decreased the percentages of TUNEL(+) cells and TUNEL(+) DRD2 neurons by 70% and 69%, respectively, following FC infusion. By contrast, no significant differences in the percentages of TUNEL(+) cells or TUNEL(+) DRD2 neurons between the Atg7+/-Drd2-Cre and Atg7F/F females following FC infusion were observed (Fig 7C and 7D).

Bottom Line: Pre-treatment of FC-infused females with rapamycin increased the FC-induced behavioral deficit and DRD2 neuron death.These results suggest that autophagy in FC-infusion males is overactive with maladaptive consequences and inhibition of autophagy decreases the severity of FC-induced striatal injury in males.These findings present prospects for male-specific therapeutic strategy that targets autophagy in patients suffering from iron overload.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.

ABSTRACT
Men exhibit a worse survival rate than premenopausal women after intracerebral hemorrhage (ICH), however, no sex-specific management has been concerned. In a rat model involving infusion of ferrous citrate (FC) that simulates iron accumulation after hemorrhage, a higher degree of autophagy associated with higher injury severity was observed in striatum of males than in females. Since the imbalance between the levels of autophagy and energy demand may lead to cell death, we proposed that FC-induced autophagy is detrimental in a male specific manner and autophagy modulation affects injury severity in a sex-dependent manner. Rapamycin, an autophagy inducer, and conditional knockout gene of autophagy-related protein 7 (Atg7) in dopamine receptor D2 (DRD2) neurons were used to test our hypothesis using a mouse model with striatal FC infusion. The result showed that the levels of autophagic cell death and injury severity were higher in male than in female mice. Pre-treatment of FC-infused females with rapamycin increased the FC-induced behavioral deficit and DRD2 neuron death. However, DRD2 neuron-specific knockout of Atg7 decreased FC-induced injury severity and the number of TUNEL(+) DRD2 neurons in males. These results suggest that autophagy in FC-infusion males is overactive with maladaptive consequences and inhibition of autophagy decreases the severity of FC-induced striatal injury in males. These findings present prospects for male-specific therapeutic strategy that targets autophagy in patients suffering from iron overload.

No MeSH data available.


Related in: MedlinePlus