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. 2016 Aug:107:79-88.
doi: 10.1016/j.neuropharm.2016.03.009. Epub 2016 Mar 9.

Treatment with an activator of hypoxia-inducible factor 1, DMOG provides neuroprotection after traumatic brain injury

Tanusree Sen  1 , Nilkantha Sen  2
Affiliations

Treatment with an activator of hypoxia-inducible factor 1, DMOG provides neuroprotection after traumatic brain injury

Tanusree Sen et al. Neuropharmacology. 2016 Aug.

Erratum in

Abstract

Traumatic brain injury (TBI) is one of the major cause of morbidity and mortality and it affects more than 1.7 million people in the USA. A couple of regenerative pathways including activation of hypoxia-inducible transcription factor 1 alpha (HIF-1α) are initiated to reduce cellular damage following TBI; however endogenous activation of these pathways is not enough to provide neuroprotection after TBI. Thus we aimed to see whether sustained activation of HIF-1α can provide neuroprotection and neurorepair following TBI. We found that chronic treatment with dimethyloxaloylglycine (DMOG) markedly increases the expression level of HIF-1α and mRNA levels of its downstream proteins such as Vascular endothelial growth factor (VEGF), Phosphoinositide-dependent kinase-1 and 4 (PDK1, PDK4) and Erythropoietin (EPO). Treatment of DMOG activates a major cell survival protein kinase Akt and reduces both cell death and lesion volume following TBI. Moreover, administration of DMOG augments cluster of differentiation 31 (CD31) staining in pericontusional cortex after TBI, which suggests that DMOG stimulates angiogenesis after TBI. Treatment with DMOG also improves both memory and motor functions after TBI. Taken together our results suggest that sustained activation of HIF-1α provides significant neuroprotection following TBI.

Keywords: Angiogenesis; Cell death; DMOG; HIF-1α; Lesion volume; Traumatic brain injury.

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Figures

Fig. 1
Fig. 1. Treatment with DMOG activates HIF-1α
(A)Western blot analysis of the expression level of HIF-1α and interaction of HIF-1α and HIF-1β (A) in pericontusional cortex after TBI after treatment of DMOG in a dose-dependent manner.(B–C) Quantitation of the protein level of HIF-1α (B) and interaction of HIF-1α and HIF-1β in the pericontusional cortex (C) after treatment with DMOG as dose dependent manner (0–50 mg/kg). (D) Western blot analysis of the expression level of HIF-1α in pericontusional cortex after TBI after treatment of DMOG in a time-dependent manner (7–27 days).(E) Quantitation of the protein level of HIF-1α after treatment of DMOG in a time-dependent manner (7–27 days). (F–G) Western blot analysis of the expression level of HIF-1α (F) and quantitation of its level (G) with or without treatment of DMOG following TBI. (H–I) The interaction of HIF-1α and HIF-1β in the pericontusional cortex (H) and quantitation of its level (I) with or without treatment of DMOG following TBI. (J–K) The cytosolic and nuclear level of HIF-1α (J) and quantitation of its level (K) with or without treatment of DMOG following TBI. *P<0.01, n=5–7, one-way ANOVA, mean ± S.E.M.
Fig. 2
Fig. 2. Effect of DMOG treatment on mRNA levels of VEGF, EPO, PDK1, PDK4 and eNOS following TBI
quantitative RT-PCR analysis of mRNA level of VEGF (A), EPO (B), pdk1 (C), pdk4 (D) and eNOS (E) in the pericontusional cortex with or without treatment of DMOG in TBI mice. *P<0.01, n=5–7, one-way ANOVA, mean±S.E.M.
Fig. 3
Fig. 3. Influence of DMOG on Akt and CREB after TBI
(A–B) Western blot (A) and quantitative analysis (B) of Akt-phosphorylation at T308 residue (Akt-(P)) in the pericontusional cortex with or without treatment of DMOG in TBI mice. (C–D) Western blot (C) and quantitative analysis (D) of CREB-phosphorylation at S133 residue (CREB-(P)) in the pericontusional cortex with or without treatment of DMOG in TBI mice. *P<0.01, n=5–7, one-way ANOVA, mean ± S.E.M.
Fig. 4
Fig. 4. Effect of treatment of DMOG on cell death and lesion volume
(A–C) confocal microscopic analysis of (A) and quantitation (B–C) of TUNEL/NeuN positive cells (B) and total TUNEL positive cells (C) in the pericontusional cortex with or without treatment of DMOG after 2 and 22 days following TBI. (D–E) Measurement of (D) TUNEL/NeuN positive cells (E) and total TUNEL positive cells after administration of DMOG through intravenous route. (F) Mice were administered with DMOG after 1, 4,6,10 and 12 hours after TBI and continued up to 22 days following TBI. Total TUNEL positive cells were quantitated after 2 and 22 days after TBI. (G–H) Nissl staining (G) and quantitation of lesion volume (H) after treatment with DMOG for 2 and 22 days following TBI. *P<0.01, n=5–7, one-way ANOVA, mean ± S.E.M.
Fig. 5
Fig. 5. Effect of DMOG treatment on CD31 and ki67 positive cells
(A–C) Confocal microscopic analysis (A) and quantitative analysis (B) of CD31/Ki67 positive cells and a total number of CD31 positive cells (C) in the pericontusional cortex with or without treatment of DMOG in TBI mice. *P<0.01, n=5–7, one-way ANOVA, mean ± S.E.M.
Fig. 6
Fig. 6. Effect on DMOG on motor and memory functions
(A) The neurological severity score was calculated in TBI mice with or without treatment of DMOG. (B–C) latency to find the platform (B) and time spent in right quadrant (C) were measured in TBI mice with or without treatment of DMOG. A number of falls/min (D) and latency to first fall (E) were measured in both sham and TBI group of mice with or without treatment of DMOG. *P<0.01, n=10–12, mean ± S.E.M.
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