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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

Rapamycin exaggerated FC-induced striatal injury in female mice.(A) Rapamycin (Rap) enhanced the LC3 immunoreactivity in DRD2 neurons of both male and female striatum. The pictures were captured under fluorescent microscope after immunostaining. Arrows indicated the merged nuclei surrounded by LC3 and DRD2 immunoreactivity depicted DRD2 neurons with autophagic features. (B) Rapamycin exaggerated FC-induced behavioral deficits in the female group. (C) Rapamycin increased the histological lesion ratio caused by FC infusion in the females. The data are expressed as the means ± SDs (n = 6). **p<0.01 compared with sex-matched saline-infusion control. ##p<0.01 compared with the FC-infusion males. §p<0.05, §§p<0.01 compared with the FC-infusion females.
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pone.0131224.g003: Rapamycin exaggerated FC-induced striatal injury in female mice.(A) Rapamycin (Rap) enhanced the LC3 immunoreactivity in DRD2 neurons of both male and female striatum. The pictures were captured under fluorescent microscope after immunostaining. Arrows indicated the merged nuclei surrounded by LC3 and DRD2 immunoreactivity depicted DRD2 neurons with autophagic features. (B) Rapamycin exaggerated FC-induced behavioral deficits in the female group. (C) Rapamycin increased the histological lesion ratio caused by FC infusion in the females. The data are expressed as the means ± SDs (n = 6). **p<0.01 compared with sex-matched saline-infusion control. ##p<0.01 compared with the FC-infusion males. §p<0.05, §§p<0.01 compared with the FC-infusion females.

Mentions: To examine whether autophagy induction affected FC-induced striatal injury in a sex-dependent manner, the effects of rapamycin on FC-induced injury, behavioral deficits, histological lesion, and the numbers of TUNEL(+) DRD2 neurons were compared between the intact male and female C57BL/6 mice. As shown in Fig 3A, immunoreactivity of LC3 was co-localized with the DRD2 neurons in both male and female mice with or without FC infusion. The histological changes after FC infusion and the images of brain sections after HE stain were showed in the S4 Fig. The quantitative result showed that rapamycin increased both the FC-induced forelimb use asymmetry scores and the lesion ratios by 63% (Fig 3B) and 33% (Fig 3C), respectively, in female mice but did not affect these measurements in the males.


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)

Rapamycin exaggerated FC-induced striatal injury in female mice.(A) Rapamycin (Rap) enhanced the LC3 immunoreactivity in DRD2 neurons of both male and female striatum. The pictures were captured under fluorescent microscope after immunostaining. Arrows indicated the merged nuclei surrounded by LC3 and DRD2 immunoreactivity depicted DRD2 neurons with autophagic features. (B) Rapamycin exaggerated FC-induced behavioral deficits in the female group. (C) Rapamycin increased the histological lesion ratio caused by FC infusion in the females. The data are expressed as the means ± SDs (n = 6). **p<0.01 compared with sex-matched saline-infusion control. ##p<0.01 compared with the FC-infusion males. §p<0.05, §§p<0.01 compared with the FC-infusion females.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131224.g003: Rapamycin exaggerated FC-induced striatal injury in female mice.(A) Rapamycin (Rap) enhanced the LC3 immunoreactivity in DRD2 neurons of both male and female striatum. The pictures were captured under fluorescent microscope after immunostaining. Arrows indicated the merged nuclei surrounded by LC3 and DRD2 immunoreactivity depicted DRD2 neurons with autophagic features. (B) Rapamycin exaggerated FC-induced behavioral deficits in the female group. (C) Rapamycin increased the histological lesion ratio caused by FC infusion in the females. The data are expressed as the means ± SDs (n = 6). **p<0.01 compared with sex-matched saline-infusion control. ##p<0.01 compared with the FC-infusion males. §p<0.05, §§p<0.01 compared with the FC-infusion females.
Mentions: To examine whether autophagy induction affected FC-induced striatal injury in a sex-dependent manner, the effects of rapamycin on FC-induced injury, behavioral deficits, histological lesion, and the numbers of TUNEL(+) DRD2 neurons were compared between the intact male and female C57BL/6 mice. As shown in Fig 3A, immunoreactivity of LC3 was co-localized with the DRD2 neurons in both male and female mice with or without FC infusion. The histological changes after FC infusion and the images of brain sections after HE stain were showed in the S4 Fig. The quantitative result showed that rapamycin increased both the FC-induced forelimb use asymmetry scores and the lesion ratios by 63% (Fig 3B) and 33% (Fig 3C), respectively, in female mice but did not affect these measurements in the males.

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