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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

FC induced higher levels of autophagy, autophagic cell death, and injury severity in males.(A) FC-induced LC3 lipidation. White column: male group; black column: female group. (B) Upper panel: Representative images of TUNEL(+) BECN1-immunoreactive cells. The yellow spots indicated by arrows depicted TUNEL(+) BECN1-immunoreactive cells with round (intact) nuclei, which were regarded as indicators of autophagic cell death. Lower panel: Numbers of DAPI-positive nuclei, TUNEL(+) nuclei, BECN1(+) cells, and TUNEL(+) BECN1-immunoreactive cells. The number of immunoreactive cells was counted in every fifteenth section of the striatum under fluorescent microscope. Five fields in each tissue section were randomly selected for counting. Male: white column; female: black column. Data are presented as the means ± SDs (6 mice in each group). (C) FC-induced injury severity. The ratio of SBDP 145/150 to spectrin depicts injury severity. Data are presented as the means ± SDs (n = 6), *p<0.05, **p<0.01 compared with sex-matched saline-infusion controls; #p<0.05 compared with the FC-infusion males.
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pone.0131224.g001: FC induced higher levels of autophagy, autophagic cell death, and injury severity in males.(A) FC-induced LC3 lipidation. White column: male group; black column: female group. (B) Upper panel: Representative images of TUNEL(+) BECN1-immunoreactive cells. The yellow spots indicated by arrows depicted TUNEL(+) BECN1-immunoreactive cells with round (intact) nuclei, which were regarded as indicators of autophagic cell death. Lower panel: Numbers of DAPI-positive nuclei, TUNEL(+) nuclei, BECN1(+) cells, and TUNEL(+) BECN1-immunoreactive cells. The number of immunoreactive cells was counted in every fifteenth section of the striatum under fluorescent microscope. Five fields in each tissue section were randomly selected for counting. Male: white column; female: black column. Data are presented as the means ± SDs (6 mice in each group). (C) FC-induced injury severity. The ratio of SBDP 145/150 to spectrin depicts injury severity. Data are presented as the means ± SDs (n = 6), *p<0.05, **p<0.01 compared with sex-matched saline-infusion controls; #p<0.05 compared with the FC-infusion males.

Mentions: To examine the sex differences in FC-induced autophagy and injury severity, the levels of LC3-II, autophagic cell death and SBDP 145/150 were detected in striatum of C57BL/6 mice after FC infusion. The results revealed that FC infusion caused increases of LC3-II (Fig 1A) and autophagic cell death, which is simultaneously TUNEL positive and BECN1 immunoreactive (Fig 1B), in male and female mice. After quantification, the numbers of nuclei in the striatums of both males and females were decreased following FC infusion (Fig 1). Additionally, FC infusion significantly increased the percentages of TUNEL(+) nuclei, BECN1(+) cells, and TUNEL(+) BECN1 immunoreactive cells by 32%, 27%, and 19% in males, respectively, and 22%, 19%, and 10% in females, respectively (Fig 1B). Moreover, FC infusion caused increases of 33% and 24% in the ratios of SBDP 145/150 to spectrin (Fig 1C) in male and female mice, respectively.


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)

FC induced higher levels of autophagy, autophagic cell death, and injury severity in males.(A) FC-induced LC3 lipidation. White column: male group; black column: female group. (B) Upper panel: Representative images of TUNEL(+) BECN1-immunoreactive cells. The yellow spots indicated by arrows depicted TUNEL(+) BECN1-immunoreactive cells with round (intact) nuclei, which were regarded as indicators of autophagic cell death. Lower panel: Numbers of DAPI-positive nuclei, TUNEL(+) nuclei, BECN1(+) cells, and TUNEL(+) BECN1-immunoreactive cells. The number of immunoreactive cells was counted in every fifteenth section of the striatum under fluorescent microscope. Five fields in each tissue section were randomly selected for counting. Male: white column; female: black column. Data are presented as the means ± SDs (6 mice in each group). (C) FC-induced injury severity. The ratio of SBDP 145/150 to spectrin depicts injury severity. Data are presented as the means ± SDs (n = 6), *p<0.05, **p<0.01 compared with sex-matched saline-infusion controls; #p<0.05 compared with the FC-infusion males.
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pone.0131224.g001: FC induced higher levels of autophagy, autophagic cell death, and injury severity in males.(A) FC-induced LC3 lipidation. White column: male group; black column: female group. (B) Upper panel: Representative images of TUNEL(+) BECN1-immunoreactive cells. The yellow spots indicated by arrows depicted TUNEL(+) BECN1-immunoreactive cells with round (intact) nuclei, which were regarded as indicators of autophagic cell death. Lower panel: Numbers of DAPI-positive nuclei, TUNEL(+) nuclei, BECN1(+) cells, and TUNEL(+) BECN1-immunoreactive cells. The number of immunoreactive cells was counted in every fifteenth section of the striatum under fluorescent microscope. Five fields in each tissue section were randomly selected for counting. Male: white column; female: black column. Data are presented as the means ± SDs (6 mice in each group). (C) FC-induced injury severity. The ratio of SBDP 145/150 to spectrin depicts injury severity. Data are presented as the means ± SDs (n = 6), *p<0.05, **p<0.01 compared with sex-matched saline-infusion controls; #p<0.05 compared with the FC-infusion males.
Mentions: To examine the sex differences in FC-induced autophagy and injury severity, the levels of LC3-II, autophagic cell death and SBDP 145/150 were detected in striatum of C57BL/6 mice after FC infusion. The results revealed that FC infusion caused increases of LC3-II (Fig 1A) and autophagic cell death, which is simultaneously TUNEL positive and BECN1 immunoreactive (Fig 1B), in male and female mice. After quantification, the numbers of nuclei in the striatums of both males and females were decreased following FC infusion (Fig 1). Additionally, FC infusion significantly increased the percentages of TUNEL(+) nuclei, BECN1(+) cells, and TUNEL(+) BECN1 immunoreactive cells by 32%, 27%, and 19% in males, respectively, and 22%, 19%, and 10% in females, respectively (Fig 1B). Moreover, FC infusion caused increases of 33% and 24% in the ratios of SBDP 145/150 to spectrin (Fig 1C) in male and female mice, respectively.

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