Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Pediatr Res. Author manuscript; available in PMC 2010 December 1.
Published in final edited form as:
PMCID: PMC2796291

Postnatal Age Influences Hypoglycemia-induced Poly(ADP-ribose) Polymerase-1 Activation in the Brain Regions of Rats


Poly(ADP-ribose) polymerase-1 (PARP-1) overactivation plays a significant role in hypoglycemia-induced brain injury in adult rats. To determine the influence of postnatal age on PARP-1 activation, developing and adult male rats were subjected to acute hypoglycemia of equivalent severity and duration. The expression of PARP-1 and its downstream effectors, apoptosis inducing factor (Aifm1), caspase 3 (Casp3), NF-κB (Nfkb1) and bcl-2 (Bcl2), and cellular poly(ADP-ribose) (PAR) polymer expression was assessed in the cerebral cortex, hippocampus, striatum and hypothalamus at 0 h and 24 h post-hypoglycemia. Compared with the control group, PARP-1 expression increased in the cerebral cortex of adult rats 24 h post-hypoglycemia, but not at 0 h, and was accompanied by increased number of PAR-positive cells. The expression was not altered in other brain regions. Aifm1, Nfkb1, Casp3, and Bcl2 expression also increased in the cerebral cortex of adult rats 24 h post-hypoglycemia. Conversely, hypoglycemia did not alter PARP-1 expression and its downstream effectors in any brain region in developing rats. These data parallel the previously demonstrated pattern of hypoglycemia-induced brain injury and suggest that PARP-1 overactivation may determine age- and region-specific vulnerability during hypoglycemia.

Hypoglycemia is a common metabolic problem in human newborn infants. Severe and recurrent hypoglycemia during the neonatal period is associated with brain injury (1). The effects of hypoglycemia of moderate severity on the developing brain are poorly understood.

We have recently demonstrated that the developing brain is less vulnerable than the mature brain to injury during moderate hypoglycemia in rats (2). Compared with the adult rats, neuronal injury was four fold less severe in postnatal day (P) 14 (i.e. developing) rats (2). This study and previous studies have also demonstrated that neuronal injury is primarily confined to the cerebral cortex in moderate hypoglycemia (24). The factors responsible for the age- and region-specific vulnerability are not well understood.

Activation of poly(ADP-ribose) polymerase-1 (PARP-1) is an important component of hypoglycemia-induced neuronal injury in adult rats (5). PARP-1 is a nuclear enzyme responsible for maintaining the genomic integrity and chromatin structure under basal conditions (69). Upon activation by DNA strand breaks, PARP-1 catalyzes the formation of poly(ADP-ribose) (PAR) polymers that bind to acceptor proteins near the site of DNA damage and facilitate its repair (Reviewed in 7,8). However, PARP-1 overactivation leads to cell death via depletion of cellular NAD+/ATP and release of apoptosis inducing factor (AIF) from the mitochondria (915). Although the trigger for AIF release during PARP-1 overactivation has yet to be conclusively established, loss of mitochondrial membrane potential and presence of PAR in the cytosol are considered major factors (13,14). AIF-mediated cell death is primarily caspase-independent, even though caspase activation may occur during the process (9,16,17). In addition, as a co-activator of nuclear factor kappa B (NF-κB), PARP-1 may potentiate injury by promoting the synthesis of pro-inflammatory mediators at the site (7,8,18,19).

The objective of the present study was to determine the influence of postnatal age on hypoglycemia-induced PARP-1 activation in the brain regions of rats. We evaluated PARP-1 expression in the cerebral cortex, hippocampus, striatum and hypothalamus because of their dissimilar vulnerability during hypoglycemia (25). To differentiate physiological upregulation from pathological overactivation, the expression of PARP-1 activation-dependent proapoptotic genes, AIF (Aifm1), caspase 3 (Casp3) and NF-κB (Nfkb1), and the antiapoptotic gene, bcl-2 (Bcl2) were assessed.


Animal preparation

P14 and P60 (adult) Sprague-Dawley rats (n = 76) were used. Only male rats were studied, based on the established gender-specific effects of PARP-1 in hypoxia-ischemia (12, 20). Pregnant rats were purchased (Harlan Sprague Dawley, Indianapolis, IN) and allowed to deliver spontaneously. The litter size was culled to 8–10 on P3 and pups were weaned on P21. Rats were maintained on a 12 h day-and-night cycle and allowed to feed and drink ad libitum. The Institutional Animal Care and Use Committee approved all experiments.

Induction of hypoglycemia

Acute hypoglycemia was induced as previously described (2). The target blood glucose concentration was <2.3 mmol/l (<40 mg/dl), a value conventionally used to define hypoglycemia in newborn infants (1). Briefly, after overnight fasting, human regular insulin (Novo Nordisk Inc., Clayton, NC) was injected in a dose of 6 IU/kg s.c. to half the number of rats in a litter (hypoglycemia group). The other half was injected with equivalent volume of 0.9% saline (control group). Ambient temperature was maintained at 34.0±1.0°C and fasting was continued for 240 min, based on previous studies (2,21). Blood glucose concentration was measured every 30 min using a glucometer (Roche Diagnostics, Indianapolis, IN). Hypoglycemia was terminated by injecting 10% dextrose, 200 mg/kg i.p., a dose that corrects brain glucose concentration in hypoglycemic newborn rats (22).

Tissue preparation

Rats were killed 24 h later (n = 8 per group) using sodium pentobarbital (100 mg/kg, i.p.). The brain was removed and the cerebral cortex, hippocampus, striatum, and hypothalamus were dissected on ice, flash-frozen in liquid nitrogen, and stored at −80°C. Some rats (n = 6 per group) were killed immediately after the termination of hypoglycemia (i.e. at 0 h) and their cerebral cortex was collected. Rats used for histochemistry (n = 4–6 per group) underwent in situ perfusion-fixation before removal of the brain (2). Serial 20 μm coronal sections were obtained from the brain using a cryostat.

Quantitative RT-PCR (qPCR)

Experiments were performed as previously described (23). Total RNA was isolated using RNA isolation kit (MO BIO Laboratories Inc., Carlsbad, CA) and cDNA was generated using 500 ng of RNA(Affinity Script, Stratagene, La Jolla, CA). The qPCR experiments were performed using 4 μl of diluted cDNA and 0.5 μl 20× primer/probes (TaqMan Gene Expression Assays; Applied Biosystems Inc., Foster City, CA) (Table S1, supplemental data online). Each sample was assayed in duplicate and normalized against ribosomal protein S18.

Western blot analysis

PARP protein was isolated using published methods (11,24). 20 μg of protein from the homogenized cerebral cortex was separated on 4–12% gradient SDS-PAGE gels (Invitrogen, Carlsbad, CA) and blotted onto nitrocellulose membranes. Following blocking in 10% non-fat powdered milk and 1% bovine serum albumin in Tris-buffered saline with 0.1% Tween-20 for 1 h at room temperature, the membranes were incubated with rabbit anti-PARP (1:1000; Abcam, Cambridge, MA) and mouse anti-β-actin (1:500; Sigma, St. Louis, MO) antibodies overnight at 4 C. After incubation with biotinylated goat anti-rabbit and anti-mouse antibodies (1:1000, each; Vector Laboratories, Burlingame, CA) for 30 min at room temperature, the bound antibodies were visualized (BCIP/NBT Substrate Kit; Vector Laboratories) and the intensity of PARP protein relative to β-actin was determined.

PAR immunohistochemistry

PAR immunohistochemistry was performed as previously described (11, 25). Brain sections were incubated with mouse monoclonal anti-rat PAR (1:100; Enzo Life Sciences International, Plymouth Meeting, PA) overnight, followed by incubation with anti-mouse biotinylated secondary antibody and avidin-horse radish peroxidase conjugate solution (Vector Elite ABC Kit; Vector Laboratories) for 30 min. The protein/antibody complex was visualized using a chromagen kit (Vector NovaRed; Vector Laboratories).

Double immunofluorescence staining was performed using primary antibodies (1:100 dilution) against PAR and AIF (Abcam, Cambridge, MA) and secondary antibodies conjugated with Alexa Fluor 555 or 488 (1:500 dilution) (Invitrogen, Eugene, OR), followed by Fluoro-Jade B (FJB; Chemicon, Temecula, CA) staining (2). Sections were cover-slipped using mounting medium containing 4′6-diamidino-2-phenylindole (DAPI).

PAR immunohistochemical analysis

Digital photomicrographs were collected and the brain regions were identified. Cells with intense cytosolic PAR were quantified using ImageJ program (Research Services Branch, National Institutes of Health, As nuclear PAR staining may represent PARP-1 mediated DNA repair, cells with staining confined to the nucleus were used to set threshold. All cells with staining intensity above this threshold inside 0.1 mm2 grids placed on the cerebral cortex, striatum and hippocampal subareas, CA1, CA3 and dentate gyrus were counted.

Statistical Analysis

The effects of age, brain region and hypoglycemia on Parp1 expression were determined using ANOVA. Inter- and intra-group differences were determined using unpaired t tests with Bonferroni correction when indicated. A software program was used for the analysis (SPSS version 15; SPSS, Chicago, IL). Data are presented as mean ± SEM. Significance was set at p < 0.05.


Blood glucose concentration

The target glucose concentration [<2.3 mmol/l (<40 mg/dl)] was achieved within 30 min of insulin administration and maintained until 240 min in both hypoglycemia groups. The blood glucose concentrations were similar in the two hypoglycemia groups: P14, 1.5±0.1 mmol/l (27.4±1.9 mg/dl) and P60, 1.7±0.1 mmol/l (30.2±1.3 mg/dl), p = 0.22. Rats were conscious and seizure-free during hypoglycemia. There was no mortality.

Parp1 expression under basal conditions

Parp1 expression in the brain regions differed between the two control groups. Compared with the P14, the expression was lower in the cerebral cortex (− 43%; p = 0.002) and hippocampus (− 33%; p = 0.05) in the P60 control group (Figure 1). Parp1 expressions in the striatum and hypothalamus were comparable in the two control groups.

Figure 1
Regional poly(ADP-ribose) polymerase-1 mRNA (Parp1) expression in the control group of postnatal day (P) 14 (An external file that holds a picture, illustration, etc.
Object name is nihms149425ig1.jpg) and P60 (□) rats. Values are mean ± SEM normalized to P14 control group; n = 8 per group. There was an effect of age and brain ...

PARP-1 expression post-hypoglycemia

Compared with the control group, Parp1 expression was increased 1.9 folds in the cerebral cortex in P60 hypoglycemia group at 24 h (p = 0.001; Figure 2A) with a corresponding 1.6 fold increase in PARP protein expression (Figure 2B). The expression was not altered in other brain regions. Hypoglycemia did not alter Parp1 expression in any brain region, and PARP protein levels in the cerebral cortex in the P14 hypoglycemia group at 24 h (Figure 2). There was no Parp1 upregulation at 0 h in either hypoglycemia group (Figure S1, supplemental data online).

Figure 2
Poly(ADP-ribose) polymerase-1 (PARP) mRNA (Parp1) (A) and PARP protein (B) expression in the cerebral cortex in control (■) and hypoglycemia (An external file that holds a picture, illustration, etc.
Object name is nihms149425ig1.jpg) groups of postnatal day (P) 14 and P60 rats 24 h post-hypoglycemia. Values are mean ± SEM normalized ...

Cellular PAR expression post-hypoglycemia

PAR-positive cells were absent in the control group and present in the hypoglycemia group of both ages. PAR-positive cells were primarily present in the cerebral cortex (Figure 3). Whereas nuclear PAR expression was predominantly seen in P14 group (Figure 3C and 3E), both nuclear and cytosolic staining was present in the P60 hypoglycemia group (Figure 3D and 3F). Few PAR-positive cells were present in the hippocampus and striatum. There was no difference among the hippocampal subareas. The hypothalamus was devoid of PAR-positive cells in both hypoglycemia groups. Compared with the P60 control and P14 hypoglycemia groups, there were more PAR-positive cells in the P60 hypoglycemia group (p < 0.02, each; Figure 3G). Cells expressing cytosolic PAR had condensed nucleus and labeled for AIF and FJB (Figures 3H and 3I).

Figure 3
Poly(ADP-ribose) (PAR) expressing cells in the cerebral cortex in control (■) and hypoglycemia (An external file that holds a picture, illustration, etc.
Object name is nihms149425ig1.jpg) groups of postnatal day (P) 14 and P60 rats 24 h post-hypoglycemia. Panels A, C and E are from P14 groups, and B, D and F from P60 groups. E and ...

PARP-1 activation-dependent downstream effectors

Similar to Parp1, the expression of Nfkb1, Bcl2, and Casp3 in the cerebral cortex differed in the two control groups. Compared with the P14 group, Nfkb1 and Casp3 levels were 45–75% lower, and Bcl2, 80% higher in the adult control group (p < 0.04, each; Figure S2, supplemental data online). There was a trend towards lower Aifm1 expression in the adult control group (p = 0.06). While none of the transcripts was upregulated in P14 rats (Figure 4A), the expression of all four transcripts increased between 1.9 and 2.3 folds in the cerebral cortex of P60 rats 24 h post-hypoglycemia (p < 0.02, each; Figure 4B).

Figure 4
The mRNA expression of apoptosis inducing factor (Aifm1), nuclear factor kappa B (Nfkb1), bcl-2 (Bcl2) and caspase 3 (Casp3) in the cerebral cortex in control (■) and hypoglycemia (An external file that holds a picture, illustration, etc.
Object name is nihms149425ig1.jpg) groups of postnatal day (P) 14 (A) and P60 (B) rats 24 h post-hypoglycemia. ...


In this comparative study of developing and adult rats, postnatal age influenced hypoglycemia-induced PARP-1 activation in the brain regions. PARP-1 expression increased in the cerebral cortex of adult rats with concurrent upregulation of cell death promoting genes. Conversely, no such induction was observed in the developing rats. These results parallel the pattern of regional injury previously reported in this model (2,4) and suggest that PARP-1 overactivation may underlie the regional vulnerability during hypoglycemia.

Among the control groups, Parp1 levels were higher in the cerebral cortex and hippocampus of P14 rats. This is consistent with previous studies in mice (26,27) and potentially reflects the neuroprotective role of PARP-1 during development (7,26,28). Unlike the striatum and hypothalamus, whose development is completed soon after birth, maturational changes continue in the cerebral cortex and hippocampus during the second postnatal week in rats (29). The potential risk of oxidant-mediated DNA damage, secondary to the increased metabolic demand in these regions (30), requires close genomic surveillance during this period. PARP-1 potentially serves this role, since inhibition of its activity leads to apoptosis and mutagenesis in developing cells (7,8,28,31).

PARP-1 expression increased in the adult hypoglycemia group, but not in the P14 group, suggesting that postnatal age influences hypoglycemia-induced PARP-1 activation in the brain. The lack of PARP-1 upregulation in P14 rats is consistent with the known resistance of the developing brain to injury during hypoglycemia of moderate severity (2,32). An inability to upregulate PARP-1 expression is unlikely to be responsible for our results, since PARP-1 overexpression has been reported in other injuries during development (11,12,24). It is possible that increasing the severity or duration of hypoglycemia will alter our results. NMDA receptor activation and oxidant stress that lead to PARP-1 activation in the hypoglycemic mature brain (33,34) are also observed in the developing brain during severe hypoglycemia (35,36). Alternately, the higher PARP-1 levels present during development may be adequate for repairing minor hypoglycemia-induced DNA damage at this age (7,27,28).

In the adult rats, hypoglycemia-induced PARP-1 upregulation was limited to the cerebral cortex, unlike a previous study that demonstrated parallel upregulation in the hippocampus (5). A lesser severity of hypoglycemia is potentially responsible for our results. Whereas extensive injury in the cerebral cortex, hippocampus and striatum is characteristic of the profound hypoglycemia induced in the previous study (5,37), neuronal injury is primarily confined to the cerebral cortex in moderate hypoglycemia produced in our study (24). Collectively, these studies suggest that PARP-1 expression reflects the regional vulnerability of the mature brain during hypoglycemia. The lack of Parp1 expression at 0 h suggests that PARP-1 activation is initiated after the resolution of hypoglycemia (5). This offers a therapeutic window for preventing hypoglycemia-induced injury in the mature brain using PARP-1 inhibitors (5,8,38).

Presence of cells with intense cytosolic PAR staining and upregulation of cell death promoters in the cerebral cortex of hypoglycemic adult rats further support PARP-1’s role in the pathogenesis of regional injury in hypoglycemia (5,6,11,14). Typically, PAR expression is restricted to the nucleus during PARP-1-mediated DNA repair and PAR entering the cytosol is rapidly degraded by the PAR glycohydrolase enzyme (6,14). Thus, the nuclear PAR expression seen in some hypoglycemic P14 rats may represent PARP-1-mediated DNA repair. Conversely, the increased cytosolic PAR staining in the adult hypoglycemia group likely represents excessive PAR synthesis and/or impaired degradation and potential for AIF-mediated cell death, as suggested by labeling of these cells with AIF and FJB (6,7,13,14) (Figure 5). Pro-inflammatory mediators may also be involved in this injury, since Nfkb1 was upregulated in these rats (8,18, 19,39,40). Conversely, despite Casp3 upregulation, cell death is likely to be caspase-independent, as the energy depleted state during PARP-1 overactivation is not conducive for caspase-dependent apoptosis (810,41). Similarly, even though the antiapoptotic Bcl2 was upregulated in the adult hypoglycemia group, potentially mediated by NF-κB (42), it is unlikely to prevent PARP-1-mediated cell death (15).

Figure 5
Proposed mechanism of poly(ADP-ribose) polymerase-1 (PARP-1) mediated neuronal injury during hypoglycemia in the mature rat brain. AIF, apoptosis inducing factor; Cyt c, cytochrome c; NF-κB, nuclear factor kappa B; PAR, poly(ADP-ribose) polymers. ...

The potential reasons for the age- and region-related variations in hypoglycemia-induced PARP-1 expression were not determined in the present study. Local energy demands, neuronal activity and the ability to transport and utilize glucose and non-glucose substrates determine the vulnerability of a brain region during hypoglycemia (32,4345). Variations in any of these factors among the developing and mature brain regions may be responsible for our results. Factors intrinsic to PARP-1-targeted genes probably had a minor role, since most were expressed higher in the developing brain under basal conditions. However, variations in factors that trigger the expression of these genes, such as cellular NAD+/ATP depletion, PAR degradation and mitochondrial depolarization (6,9), as well as posttranscriptional factors, such as the efficacy of protein synthesis during energy-depletion (46) may be responsible for the dissimilar effects in the developing and mature brains. As our assessment was limited to 0 h and 24 h, it is possible that we may have missed transient PARP-1 expression at an intermediate time, especially in the developing brain (11). Likewise, determining the cytosolic and nuclear protein levels of the target genes would have enhanced our results. Future studies are necessary to address these limitations and to determine gender-specific effects of PARP-1 in hypoglycemia (12,20).

In summary, the study demonstrates that postnatal age influences hypoglycemia-induced regional PARP-1 expression in the rat brain. The results also imply that PARP-1 overactivation potentially underlies regional vulnerability during hypoglycemia. The interspecies differences in neurodevelopment and substrate utilization (45) preclude extrapolation of these results to human infants and children without additional research. Nevertheless, the study may have clinical implications. The results emphasize the need for devising age-specific interventions for hypoglycemia. The lack of PARP-1 upregulation in the developing brain demonstrates the futility and potential harm of PARP inhibitors at this age (7,28,31). The relative resistance of the developing brain also argues against invasive diagnostic and therapeutic procedures for brief episodes of moderate hypoglycemia. Finally, understanding the neuroprotective factors in the developing brain may help in designing optimal preventive and therapeutic strategies for hypoglycemia-induced brain injury in the adult.

Supplementary Material


The authors thank Anirudh R. Rao for providing some tissue samples and Christopher Traudt, MD for statistical analysis and critical review of the manuscript.

Financial support: Supported by grants from NICHD (HD047276), Minnesota Medical Foundation, and Viking Children’s Fund.


apoptosis inducing factor
Fluoro-Jade B
poly(ADP-ribose) polymerase-1
postnatal day


Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (


1. Burns CM, Rutherford MA, Boardman JP, Cowan FM. Patterns of cerebral injury and neurodevelopmental outcomes after symptomatic neonatal hypoglycemia. Pediatrics. 2008;122:65–74. [PubMed]
2. Ennis K, Tran PV, Seaquist ER, Rao R. Postnatal age influences hypoglycemia-induced neuronal injury in the rat brain. Brain Res. 2008;1224:119–126. [PMC free article] [PubMed]
3. Yamada KA, Rensing N, Izumi Y, De Erausquin GA, Gazit V, Dorsey DA, Herrera DG. Repetitive hypoglycemia in young rats impairs hippocampal long-term potentiation. Pediatr Res. 2004;55:372–379. [PubMed]
4. Tkacs NC, Pan Y, Raghupathi R, Dunn-Meynell AA, Levin BE. Cortical Fluoro-Jade staining and blunted adrenomedullary response to hypoglycemia after noncoma hypoglycemia in rats. J Cereb Blood Flow Metab. 2005;25:1645–1655. [PubMed]
5. Suh SW, Aoyama K, Chen Y, Garnier P, Matsumori Y, Gum E, Liu J, Swanson RA. Hypoglycemic neuronal death and cognitive impairment are prevented by poly(ADP-ribose) polymerase inhibitors administered after hypoglycemia. J Neurosci. 2003;23:10681–10690. [PubMed]
6. David KK, Andrabi SA, Dawson TM, Dawson VL. Parthanatos, a messenger of death. Front Biosci. 2009;14:1116–1128. [PubMed]
7. Schreiber V, Dantzer F, Ame JC, de Murcia G. Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol. 2006;7:517–528. [PubMed]
8. Jagtap P, Szabo C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov. 2005;4:421–440. [PubMed]
9. Chiarugi A, Moskowitz MA. Cell biology. PARP-1--a perpetrator of apoptotic cell death? Science. 2002;297:200–201. [PubMed]
10. Formentini L, Macchiarulo A, Cipriani G, Camaioni E, Rapizzi E, Pellicciari R, Moroni F, Chiarugi A. Poly(ADP-ribose) catabolism triggers AMP-dependent mitochondrial energy failure. J Biol Chem. 2009;284:17668–17676. [PMC free article] [PubMed]
11. Martin SS, Perez-Polo JR, Noppens KM, Grafe MR. Biphasic changes in the levels of poly(ADP-ribose) polymerase-1 and caspase 3 in the immature brain following hypoxia-ischemia. Int J Dev Neurosci. 2005;23:673–686. [PubMed]
12. Hagberg H, Wilson MA, Matsushita H, Zhu C, Lange M, Gustavsson M, Poitras MF, Dawson TM, Dawson VL, Northington F, Johnston MV. PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury. J Neurochem. 2004;90:1068–1075. [PubMed]
13. Yu SW, Andrabi SA, Wang H, Kim NS, Poirier GG, Dawson TM, Dawson VL. Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Proc Natl Acad Sci USA. 2006;103:18314–18319. [PubMed]
14. Andrabi SA, Kim NS, Yu SW, Wang H, Koh DW, Sasaki M, Klaus JA, Otsuka T, Zhang Z, Koehler RC, Hurn PD, Poirier GG, Dawson VL, Dawson TM. Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci USA. 2006;103:18308–18313. [PubMed]
15. Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM, Dawson VL. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science. 2002;297:259–263. [PubMed]
16. Russo VC, Kobayashi K, Najdovska S, Baker NL, Werther GA. Neuronal protection from glucose deprivation via modulation of glucose transport and inhibition of apoptosis: a role for the insulin-like growth factor system. Brain Res. 2004;1009:40–53. [PubMed]
17. Beal MF. Mitochondria take center stage in aging and neurodegeneration. Ann Neurol. 2005;58:495–505. [PubMed]
18. Hassa PO, Buerki C, Lombardi C, Imhof R, Hottiger MO. Transcriptional coactivation of nuclear factor-kappaB-dependent gene expression by p300 is regulated by poly(ADP)-ribose polymerase-1. J Biol Chem. 2003;278:45145–45153. [PubMed]
19. Kauppinen TM, Swanson RA. Poly(ADP-ribose) polymerase-1 promotes microglial activation, proliferation, and matrix metalloproteinase-9-mediated neuron death. J Immunol. 2005;174:2288–2296. [PubMed]
20. McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD. Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab. 2005;25:502–512. [PubMed]
21. Kim M, Yu ZX, Fredholm BB, Rivkees SA. Susceptibility of the developing brain to acute hypoglycemia involving A1 adenosine receptor activation. Am J Physiol Endocrinol Metab. 2005;289:E562–E569. [PubMed]
22. Vannucci RC, Vannucci SJ. Cerebral carbohydrate metabolism during hypoglycemia and anoxia in newborn rats. Ann Neurol. 1978;4:73–79. [PubMed]
23. Tran PV, Fretham SJ, Carlson ES, Georgieff MK. Long-term reduction of hippocampal brain-derived neurotrophic factor activity following fetal-neonatal iron deficiency in adult rats. Pediatr Res. 2009;65:493–498. [PMC free article] [PubMed]
24. Williams BL, Hornig M, Yaddanapudi K, Lipkin WI. Hippocampal poly(ADP-Ribose) polymerase 1 and caspase 3 activation in neonatal bornavirus infection. J Virol. 2008;82:1748–1758. [PMC free article] [PubMed]
25. Joly LM, Benjelloun N, Plotkine M, Charriaut-Marlangue C. Distribution of Poly(ADP-ribosyl)ation and cell death after cerebral ischemia in the neonatal rat. Pediatr Res. 2003;53:776–782. [PubMed]
26. Hakme A, Huber A, Dolle P, Schreiber V. The macroPARP genes Parp-9 and Parp-14 are developmentally and differentially regulated in mouse tissues. Dev Dyn. 2008;237:209–215. [PubMed]
27. Schreiber V, Ame JC, Dolle P, Schultz I, Rinaldi B, Fraulob V, Menissier-de Murcia J, de Murcia G. Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem. 2002;277:23028–23036. [PubMed]
28. Visochek L, Steingart RA, Vulih-Shultzman I, Klein R, Priel E, Gozes I, Cohen-Armon M. PolyADP-ribosylation is involved in neurotrophic activity. J Neurosci. 2005;25:7420–7428. [PubMed]
29. Rice D, Barone S., Jr Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108:511–533. [PMC free article] [PubMed]
30. Slotkin TA, Oliver CA, Seidler FJ. Critical periods for the role of oxidative stress in the developmental neurotoxicity of chlorpyrifos and terbutaline, alone or in combination. Brain Res Dev Brain Res. 2005;157:172–180. [PubMed]
31. Dantzer F, de La Rubia G, Menissier-De Murcia J, Hostomsky Z, de Murcia G, Schreiber V. Base excision repair is impaired in mammalian cells lacking Poly(ADP-ribose) polymerase-1. Biochemistry. 2000;39:7559–7569. [PubMed]
32. Vannucci RC, Vannucci SJ. Hypoglycemic brain injury. Semin Neonatol. 2001;6:147–155. [PubMed]
33. Mandir AS, Poitras MF, Berliner AR, Herring WJ, Guastella DB, Feldman A, Poirier GG, Wang ZQ, Dawson TM, Dawson VL. NMDA but not non-NMDA excitotoxicity is mediated by Poly(ADP-ribose) polymerase. J Neurosci. 2000;20:8005–8011. [PubMed]
34. Suh SW, Hamby AM, Gum ET, Shin BS, Won SJ, Sheline CT, Chan PH, Swanson RA. Sequential release of nitric oxide, zinc, and superoxide in hypoglycemic neuronal death. J Cereb Blood Flow Metab. 2008;28:1697–1706. [PubMed]
35. McGowan JE, Chen L, Gao D, Trush M, Wei C. Increased mitochondrial reactive oxygen species production in newborn brain during hypoglycemia. Neurosci Lett. 2006;399:111–114. [PubMed]
36. McGowan JE, Haynes-Laing AG, Mishra OP, Delivoria-Papadopoulos M. The effect of acute hypoglycemia on the cerebral NMDA receptor in newborn piglets. Brain Res. 1995;670:283–288. [PubMed]
37. Auer RN, Wieloch T, Olsson Y, Siesjo BK. The distribution of hypoglycemic brain damage. Acta Neuropathol. 1984;64:177–191. [PubMed]
38. Suh SW, Gum ET, Hamby AM, Chan PH, Swanson RA. Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase. J Clin Invest. 2007;117:910–918. [PMC free article] [PubMed]
39. Chiarugi A, Moskowitz MA. Poly(ADP-ribose) polymerase-1 activity promotes NF-kappaB-driven transcription and microglial activation: implication for neurodegenerative disorders. J Neurochem. 2003;85:306–317. [PubMed]
40. Oliver FJ, Menissier-de Murcia J, Nacci C, Decker P, Andriantsitohaina R, Muller S, de la Rubia G, Stoclet JC, de Murcia G. Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP-ribose) polymerase-1 deficient mice. EMBO J. 1999;18:4446–4454. [PubMed]
41. Cipriani G, Rapizzi E, Vannacci A, Rizzuto R, Moroni F, Chiarugi A. Nuclear poly(ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction. J Biol Chem. 2005;280:17227–17234. [PubMed]
42. Tamatani M, Che YH, Matsuzaki H, Ogawa S, Okado H, Miyake S, Mizuno T, Tohyama M. Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFkappaB activation in primary hippocampal neurons. J Biol Chem. 1999;274:8531–8538. [PubMed]
43. Paschen W, Siesjo BK, Ingvar M, Hossmann KA. Regional differences in brain glucose content in graded hypoglycemia. Neurochem Pathol. 1986;5:131–142. [PubMed]
44. Sutherland GR, Tyson RL, Auer RN. Truncation of the krebs cycle during hypoglycemic coma. Med Chem. 2008;4:379–385. [PubMed]
45. Nehlig A. Cerebral energy metabolism, glucose transport and blood flow: changes with maturation and adaptation to hypoglycaemia. Diabetes Metab. 1997;23:18–29. [PubMed]
46. Hand SC, Menze MA. Mitochondria in energy-limited states: mechanisms that blunt the signaling of cell death. J Exp Biol. 2008;211:1829–1840. [PubMed]