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Combination treatment with ethyl pyruvate and IGF-I exerts neuroprotective effects against brain injury in a rat model of neonatal hypoxic-ischemic encephalopathy.

Rong Z, Pan R, Chang L, Lee W - Int. J. Mol. Med. (2015)

Bottom Line: Under conditions of OGD, the LDH levels increased and neuronal viability decreased.Treatment with 0.5 mM EP or 25 ng/ml IGF‑I protected the neurons (P<0.05), exerting additive effects.This effect may be the result of reduced neuronal injury, and enhanced neurogenesis and maturation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.

ABSTRACT
Neonatal hypoxic-ischemic (HI) brain injury causes severe brain damage in newborns. Following HI injury, rapidly accumulating oxidants injure neurons and interrupt ongoing developmental processes. The antioxidant, sodium pyruvate, has been shown to reduce neuronal injury in neonatal rats under conditions of oxygen glucose deprivation (OGD) and HI injury. In this study, we evaluated the effects of ethyl pyruvate (EP) and insulin‑like growth factor‑I (IGF‑I) alone or in combination in a similar setting. For this purpose, we used an in vitro model involving primary neonatal rat cortical neurons subjected to OGD for 2.5 h and an in vivo model involving unilateral carotid ligation in rats on post-natal day 7 with exposure to 8% hypoxia for 2.5 h. The cultured neurons were examined by lactate dehydrogenase (LDH) and cell viability assays. For the in vivo experiments, behavioral development was evaluated by the foot fault test at 4 weeks of recovery. 2,3,5‑Triphenyltetrazolium chloride monohydrate and cresyl violet staining were used to evaluate HI injury. The injured neurons were Fluoro‑Jade B-labeled, new neuroprecursors were double labeled with bromodeoxyuridine (BrdU) and doublecortin, new mature neurons were BrdU-labeled and neuronal nuclei were labeled by immunofluorescence. Under conditions of OGD, the LDH levels increased and neuronal viability decreased. Treatment with 0.5 mM EP or 25 ng/ml IGF‑I protected the neurons (P<0.05), exerting additive effects. Similarly, either the early administration of EP or delayed treatment with IGF‑I protected the neonatal rat brains against HI injury and improved neurological performance and these effects were also additive. This effect may be the result of reduced neuronal injury, and enhanced neurogenesis and maturation. On the whole, our findings demonstrate that the combination of the early administration of EP with delayed treatment with IGF‑I exerts neuroprotective effects against HI injury in neonatal rat brains.

No MeSH data available.


Related in: MedlinePlus

Hypoxic-ischemic (HI) injury promotes neuronal cell proliferation. (A) HI injury promoted cell proliferation in the hippocampus. Proliferating cells were identified by bromodeoxyuridine (BrdU) immunostaining (green) 72 h post-HI injury. The structure of the dentate nucleus is shown by the alignment of nuclei stained with 4′,6-diamidino-2-phenylindole (blue). (B) High magnification view of the square in (A) showing the distribution of proliferating cells. (C) Quantification of proliferating cells in the different subregions of the hippocampus. *P<0.05 compared with sham-operated group (sham; n=6). ML, molecular layer; GCL, granule cell layer; SGZ, subgranular zone.
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f5-ijmm-36-01-0195: Hypoxic-ischemic (HI) injury promotes neuronal cell proliferation. (A) HI injury promoted cell proliferation in the hippocampus. Proliferating cells were identified by bromodeoxyuridine (BrdU) immunostaining (green) 72 h post-HI injury. The structure of the dentate nucleus is shown by the alignment of nuclei stained with 4′,6-diamidino-2-phenylindole (blue). (B) High magnification view of the square in (A) showing the distribution of proliferating cells. (C) Quantification of proliferating cells in the different subregions of the hippocampus. *P<0.05 compared with sham-operated group (sham; n=6). ML, molecular layer; GCL, granule cell layer; SGZ, subgranular zone.

Mentions: To determine the effect of HI injury on neurogenesis, we labeled proliferating cells with BrdU during the first 7 days following HI injury. Within the hippocampus of the rats in the sham-operated group, the majority of BrdU+ cells was distributed in the subgranular zone (SGZ), where neural stem cells or immature neurons reside (Fig. 5). In comparison, the BrdU+ cells in the rats in the group subjected to HI injury were not confined to the SGZ, but were scattered around the entire DG, suggesting that newborn cells had migrated to other locations. Overall, the number of BrdU+ cells in the DG of the rats in the group subjected to HI injury was double that of the cells in the DG of rats in the sham-operated group (Fig. 5C).


Combination treatment with ethyl pyruvate and IGF-I exerts neuroprotective effects against brain injury in a rat model of neonatal hypoxic-ischemic encephalopathy.

Rong Z, Pan R, Chang L, Lee W - Int. J. Mol. Med. (2015)

Hypoxic-ischemic (HI) injury promotes neuronal cell proliferation. (A) HI injury promoted cell proliferation in the hippocampus. Proliferating cells were identified by bromodeoxyuridine (BrdU) immunostaining (green) 72 h post-HI injury. The structure of the dentate nucleus is shown by the alignment of nuclei stained with 4′,6-diamidino-2-phenylindole (blue). (B) High magnification view of the square in (A) showing the distribution of proliferating cells. (C) Quantification of proliferating cells in the different subregions of the hippocampus. *P<0.05 compared with sham-operated group (sham; n=6). ML, molecular layer; GCL, granule cell layer; SGZ, subgranular zone.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494588&req=5

f5-ijmm-36-01-0195: Hypoxic-ischemic (HI) injury promotes neuronal cell proliferation. (A) HI injury promoted cell proliferation in the hippocampus. Proliferating cells were identified by bromodeoxyuridine (BrdU) immunostaining (green) 72 h post-HI injury. The structure of the dentate nucleus is shown by the alignment of nuclei stained with 4′,6-diamidino-2-phenylindole (blue). (B) High magnification view of the square in (A) showing the distribution of proliferating cells. (C) Quantification of proliferating cells in the different subregions of the hippocampus. *P<0.05 compared with sham-operated group (sham; n=6). ML, molecular layer; GCL, granule cell layer; SGZ, subgranular zone.
Mentions: To determine the effect of HI injury on neurogenesis, we labeled proliferating cells with BrdU during the first 7 days following HI injury. Within the hippocampus of the rats in the sham-operated group, the majority of BrdU+ cells was distributed in the subgranular zone (SGZ), where neural stem cells or immature neurons reside (Fig. 5). In comparison, the BrdU+ cells in the rats in the group subjected to HI injury were not confined to the SGZ, but were scattered around the entire DG, suggesting that newborn cells had migrated to other locations. Overall, the number of BrdU+ cells in the DG of the rats in the group subjected to HI injury was double that of the cells in the DG of rats in the sham-operated group (Fig. 5C).

Bottom Line: Under conditions of OGD, the LDH levels increased and neuronal viability decreased.Treatment with 0.5 mM EP or 25 ng/ml IGF‑I protected the neurons (P<0.05), exerting additive effects.This effect may be the result of reduced neuronal injury, and enhanced neurogenesis and maturation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.

ABSTRACT
Neonatal hypoxic-ischemic (HI) brain injury causes severe brain damage in newborns. Following HI injury, rapidly accumulating oxidants injure neurons and interrupt ongoing developmental processes. The antioxidant, sodium pyruvate, has been shown to reduce neuronal injury in neonatal rats under conditions of oxygen glucose deprivation (OGD) and HI injury. In this study, we evaluated the effects of ethyl pyruvate (EP) and insulin‑like growth factor‑I (IGF‑I) alone or in combination in a similar setting. For this purpose, we used an in vitro model involving primary neonatal rat cortical neurons subjected to OGD for 2.5 h and an in vivo model involving unilateral carotid ligation in rats on post-natal day 7 with exposure to 8% hypoxia for 2.5 h. The cultured neurons were examined by lactate dehydrogenase (LDH) and cell viability assays. For the in vivo experiments, behavioral development was evaluated by the foot fault test at 4 weeks of recovery. 2,3,5‑Triphenyltetrazolium chloride monohydrate and cresyl violet staining were used to evaluate HI injury. The injured neurons were Fluoro‑Jade B-labeled, new neuroprecursors were double labeled with bromodeoxyuridine (BrdU) and doublecortin, new mature neurons were BrdU-labeled and neuronal nuclei were labeled by immunofluorescence. Under conditions of OGD, the LDH levels increased and neuronal viability decreased. Treatment with 0.5 mM EP or 25 ng/ml IGF‑I protected the neurons (P<0.05), exerting additive effects. Similarly, either the early administration of EP or delayed treatment with IGF‑I protected the neonatal rat brains against HI injury and improved neurological performance and these effects were also additive. This effect may be the result of reduced neuronal injury, and enhanced neurogenesis and maturation. On the whole, our findings demonstrate that the combination of the early administration of EP with delayed treatment with IGF‑I exerts neuroprotective effects against HI injury in neonatal rat brains.

No MeSH data available.


Related in: MedlinePlus