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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

E2 contributed to the sex differences in FC-induced autophagy and injury severity in the striatum.All of the mice in every groups were infused with 3 μL of FC (1 mmol/L) into the right striatum. (A) E2 reversed the increase of FC-induced LC3 lipidation by ovariectomy. (B) E2 decreased the ratios of SBDP 145/150 to spectrin in both sterilized female (♀ with a slash) and male (♂ with a slash) mice after FC infusion. The data are expressed as the means ± SDs (n = 6), *p<0.05 compared with intact males; #p<0.05 compared with intact females; §p<0.05 compared with ovariectomized females.
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pone.0131224.g002: E2 contributed to the sex differences in FC-induced autophagy and injury severity in the striatum.All of the mice in every groups were infused with 3 μL of FC (1 mmol/L) into the right striatum. (A) E2 reversed the increase of FC-induced LC3 lipidation by ovariectomy. (B) E2 decreased the ratios of SBDP 145/150 to spectrin in both sterilized female (♀ with a slash) and male (♂ with a slash) mice after FC infusion. The data are expressed as the means ± SDs (n = 6), *p<0.05 compared with intact males; #p<0.05 compared with intact females; §p<0.05 compared with ovariectomized females.

Mentions: To determine whether E2 contributed to the sex differences in FC-induced autophagy and injury severity in the striatum, both male and female C57BL/6 mice were sterilized prior to the implantation of E2 to exclude the influence of endogenous sex hormones. The results revealed that no significant effect of orchidectomy on FC-induced LC3 lipidation was observed, while ovariectomy increased the levels of FC-induced LC3 lipidation by 1.57-fold. Although E2 implantation slightly, but non-significantly, decreased the levels of FC-induced LC3 lipidation in the castrated male mice by 11%, the level of LC3-II in E2 implanted castrated males was lower than that of intact males by 25%. Moreover, E2 decreased FC-induced LC3 lipidation in the ovariectomized females by 39%, whereas no significant difference of the level of LC3-II between E2 implanted ovariectomized females and intact females was observed (Fig 2A). No significant effect of orchidectomy on FC-induced injury severity was observed in the male group, while ovariectomy markedly increased the FC-induced injury severity. E2 implantation decreased the ratios of SBDP 145/150 to spectrin in both sterilized male and female mice by 13% and 42%, respectively (Fig 2B).


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)

E2 contributed to the sex differences in FC-induced autophagy and injury severity in the striatum.All of the mice in every groups were infused with 3 μL of FC (1 mmol/L) into the right striatum. (A) E2 reversed the increase of FC-induced LC3 lipidation by ovariectomy. (B) E2 decreased the ratios of SBDP 145/150 to spectrin in both sterilized female (♀ with a slash) and male (♂ with a slash) mice after FC infusion. The data are expressed as the means ± SDs (n = 6), *p<0.05 compared with intact males; #p<0.05 compared with intact females; §p<0.05 compared with ovariectomized females.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4492841&req=5

pone.0131224.g002: E2 contributed to the sex differences in FC-induced autophagy and injury severity in the striatum.All of the mice in every groups were infused with 3 μL of FC (1 mmol/L) into the right striatum. (A) E2 reversed the increase of FC-induced LC3 lipidation by ovariectomy. (B) E2 decreased the ratios of SBDP 145/150 to spectrin in both sterilized female (♀ with a slash) and male (♂ with a slash) mice after FC infusion. The data are expressed as the means ± SDs (n = 6), *p<0.05 compared with intact males; #p<0.05 compared with intact females; §p<0.05 compared with ovariectomized females.
Mentions: To determine whether E2 contributed to the sex differences in FC-induced autophagy and injury severity in the striatum, both male and female C57BL/6 mice were sterilized prior to the implantation of E2 to exclude the influence of endogenous sex hormones. The results revealed that no significant effect of orchidectomy on FC-induced LC3 lipidation was observed, while ovariectomy increased the levels of FC-induced LC3 lipidation by 1.57-fold. Although E2 implantation slightly, but non-significantly, decreased the levels of FC-induced LC3 lipidation in the castrated male mice by 11%, the level of LC3-II in E2 implanted castrated males was lower than that of intact males by 25%. Moreover, E2 decreased FC-induced LC3 lipidation in the ovariectomized females by 39%, whereas no significant difference of the level of LC3-II between E2 implanted ovariectomized females and intact females was observed (Fig 2A). No significant effect of orchidectomy on FC-induced injury severity was observed in the male group, while ovariectomy markedly increased the FC-induced injury severity. E2 implantation decreased the ratios of SBDP 145/150 to spectrin in both sterilized male and female mice by 13% and 42%, respectively (Fig 2B).

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