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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

Knockout of Atg7 in DRD2 neurons decreased FC-induced striatal injury in male and female mice.(A) Atg7 KO decreased LC3 immunoreactivity in the DRD2 neurons. The images were captured using TissueFAXS. Arrows indicate LC3 immunoreactive DRD2 neurons. (B) Atg7 KO decreased FC-induced behavioral deficits in males but not in females. (C) Atg7 KO decreased the lesion ratios caused by FC infusion in males only. The data are expressed as the means ± SDs (n = 6). **p<0.01 compared with the sex-matched Atg7F/F groups; ##p<0.01 compared with the FC-infused Atg7F/F male mice. §§p<0.01 compared with the FC-infused Atg7F/F male mice.
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pone.0131224.g006: Knockout of Atg7 in DRD2 neurons decreased FC-induced striatal injury in male and female mice.(A) Atg7 KO decreased LC3 immunoreactivity in the DRD2 neurons. The images were captured using TissueFAXS. Arrows indicate LC3 immunoreactive DRD2 neurons. (B) Atg7 KO decreased FC-induced behavioral deficits in males but not in females. (C) Atg7 KO decreased the lesion ratios caused by FC infusion in males only. The data are expressed as the means ± SDs (n = 6). **p<0.01 compared with the sex-matched Atg7F/F groups; ##p<0.01 compared with the FC-infused Atg7F/F male mice. §§p<0.01 compared with the FC-infused Atg7F/F male mice.

Mentions: Both the male and female Atg7+/-Drd2-Cre mice exhibited lower levels of FC-induced LC3 aggregation in the striatum compared with the Atg7F/F mice (Fig 6A). In males, Atg7 knockout decreased both FC-induced behavioral deficits (Fig 6B) and histological lesions (Fig 6C) by 36% (p<0.01) and 36% (p<0.01), respectively. By contrast, in females, no significant effect of Atg7 KO on the FC-induced behavioral deficits and histological lesions was observed (Fig 6B and 6C).


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)

Knockout of Atg7 in DRD2 neurons decreased FC-induced striatal injury in male and female mice.(A) Atg7 KO decreased LC3 immunoreactivity in the DRD2 neurons. The images were captured using TissueFAXS. Arrows indicate LC3 immunoreactive DRD2 neurons. (B) Atg7 KO decreased FC-induced behavioral deficits in males but not in females. (C) Atg7 KO decreased the lesion ratios caused by FC infusion in males only. The data are expressed as the means ± SDs (n = 6). **p<0.01 compared with the sex-matched Atg7F/F groups; ##p<0.01 compared with the FC-infused Atg7F/F male mice. §§p<0.01 compared with the FC-infused Atg7F/F male mice.
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Related In: Results  -  Collection

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pone.0131224.g006: Knockout of Atg7 in DRD2 neurons decreased FC-induced striatal injury in male and female mice.(A) Atg7 KO decreased LC3 immunoreactivity in the DRD2 neurons. The images were captured using TissueFAXS. Arrows indicate LC3 immunoreactive DRD2 neurons. (B) Atg7 KO decreased FC-induced behavioral deficits in males but not in females. (C) Atg7 KO decreased the lesion ratios caused by FC infusion in males only. The data are expressed as the means ± SDs (n = 6). **p<0.01 compared with the sex-matched Atg7F/F groups; ##p<0.01 compared with the FC-infused Atg7F/F male mice. §§p<0.01 compared with the FC-infused Atg7F/F male mice.
Mentions: Both the male and female Atg7+/-Drd2-Cre mice exhibited lower levels of FC-induced LC3 aggregation in the striatum compared with the Atg7F/F mice (Fig 6A). In males, Atg7 knockout decreased both FC-induced behavioral deficits (Fig 6B) and histological lesions (Fig 6C) by 36% (p<0.01) and 36% (p<0.01), respectively. By contrast, in females, no significant effect of Atg7 KO on the FC-induced behavioral deficits and histological lesions was observed (Fig 6B and 6C).

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