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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

Ethyl pyruvate (EP) and insulin-like growth factor-I (IGF-I) reduce hypoxic-ischemic (HI) injury to neonatal rat brains. (A) Representative 2,3,5-triphenyltetrazolium chloride-stained brain sections from 9-day-old rats (48 h after HI injury), treated with the vehicle, EP (25 mg/kg, 30 min post HI), IGF-I (3 mg/kg, 24 h post-HI injury) or a combination of the EP and IGF-I. (B) Quantification of the amount of surviving brain tissue following the different treatments. *P<0.05 as indicated (n=8). (C) Representative cresyl violet-stained sections from 14-day-old rats (7 days post-HI injury). (D) Quantification of the amount of surviving cortical or hippocampal tissue. *P<0.05 compared with the other 3 groups subjected to HI injury (n=8). L, left; R, right.
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f3-ijmm-36-01-0195: Ethyl pyruvate (EP) and insulin-like growth factor-I (IGF-I) reduce hypoxic-ischemic (HI) injury to neonatal rat brains. (A) Representative 2,3,5-triphenyltetrazolium chloride-stained brain sections from 9-day-old rats (48 h after HI injury), treated with the vehicle, EP (25 mg/kg, 30 min post HI), IGF-I (3 mg/kg, 24 h post-HI injury) or a combination of the EP and IGF-I. (B) Quantification of the amount of surviving brain tissue following the different treatments. *P<0.05 as indicated (n=8). (C) Representative cresyl violet-stained sections from 14-day-old rats (7 days post-HI injury). (D) Quantification of the amount of surviving cortical or hippocampal tissue. *P<0.05 compared with the other 3 groups subjected to HI injury (n=8). L, left; R, right.

Mentions: At 48 h of recovery, the amount of surviving brain tissue in the EP + IGF-I group was 84.2±9.0%, significantly higher than that with EP treatment alone (71.8±14.2%) or IGF-I treatment alone (68.8±10.3%). These neuroprotective effects were additive and not transient (Fig. 3A and B). At 7 days of recovery, the amount of surviving brain cortex tissue in the EP + IGF-I group was 89.7±6.8%, significantly higher than that with EP treatment alone (73.2±1.4%) or IGF-I treatment alone (70.0±8.6%). The amount of surviving tissue in the hippocampus in the EP + IGF-I group was 78.0±9.6%, significantly higher than that with EP treatment alone (58.3±1.2%) or IGF-I treatment alone (58.5±9.3%) (Fig. 3C and D). Therefore, treatment with EP (25 mg/g, 30 min post-HI injury) in combination with IGF-I (3 mg/kg, 24 h post-HI injury) exerted neuroprotective effects against HI injury, as indicated by the increase in the volume of surviving brain tissue at 48 h (Fig. 3A and B) and 7 days (Fig. 3C and D) of recovery.


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)

Ethyl pyruvate (EP) and insulin-like growth factor-I (IGF-I) reduce hypoxic-ischemic (HI) injury to neonatal rat brains. (A) Representative 2,3,5-triphenyltetrazolium chloride-stained brain sections from 9-day-old rats (48 h after HI injury), treated with the vehicle, EP (25 mg/kg, 30 min post HI), IGF-I (3 mg/kg, 24 h post-HI injury) or a combination of the EP and IGF-I. (B) Quantification of the amount of surviving brain tissue following the different treatments. *P<0.05 as indicated (n=8). (C) Representative cresyl violet-stained sections from 14-day-old rats (7 days post-HI injury). (D) Quantification of the amount of surviving cortical or hippocampal tissue. *P<0.05 compared with the other 3 groups subjected to HI injury (n=8). L, left; R, right.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3-ijmm-36-01-0195: Ethyl pyruvate (EP) and insulin-like growth factor-I (IGF-I) reduce hypoxic-ischemic (HI) injury to neonatal rat brains. (A) Representative 2,3,5-triphenyltetrazolium chloride-stained brain sections from 9-day-old rats (48 h after HI injury), treated with the vehicle, EP (25 mg/kg, 30 min post HI), IGF-I (3 mg/kg, 24 h post-HI injury) or a combination of the EP and IGF-I. (B) Quantification of the amount of surviving brain tissue following the different treatments. *P<0.05 as indicated (n=8). (C) Representative cresyl violet-stained sections from 14-day-old rats (7 days post-HI injury). (D) Quantification of the amount of surviving cortical or hippocampal tissue. *P<0.05 compared with the other 3 groups subjected to HI injury (n=8). L, left; R, right.
Mentions: At 48 h of recovery, the amount of surviving brain tissue in the EP + IGF-I group was 84.2±9.0%, significantly higher than that with EP treatment alone (71.8±14.2%) or IGF-I treatment alone (68.8±10.3%). These neuroprotective effects were additive and not transient (Fig. 3A and B). At 7 days of recovery, the amount of surviving brain cortex tissue in the EP + IGF-I group was 89.7±6.8%, significantly higher than that with EP treatment alone (73.2±1.4%) or IGF-I treatment alone (70.0±8.6%). The amount of surviving tissue in the hippocampus in the EP + IGF-I group was 78.0±9.6%, significantly higher than that with EP treatment alone (58.3±1.2%) or IGF-I treatment alone (58.5±9.3%) (Fig. 3C and D). Therefore, treatment with EP (25 mg/g, 30 min post-HI injury) in combination with IGF-I (3 mg/kg, 24 h post-HI injury) exerted neuroprotective effects against HI injury, as indicated by the increase in the volume of surviving brain tissue at 48 h (Fig. 3A and B) and 7 days (Fig. 3C and D) of recovery.

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