Journal of Applied Physiology AJP: Endocrinology and Metabolism
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 89: 777-784, 2000;
8750-7587/00 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Najarian, T.
Right arrow Articles by Chemtob, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Najarian, T.
Right arrow Articles by Chemtob, S.
Vol. 89, Issue 2, 777-784, August 2000

Preservation of neural function in the perinate by high PGE2 levels acting via EP2 receptors

Taline Najarian1, Pierre Hardy3, Xin Hou3, Julie Lachapelle3, Anjali Doke2,3, Fernand Gobeil Jr.3, Marie-Sylvie Roy3, Pierre Lachapelle2, Daya R. Varma1, and Sylvain Chemtob1,3

1 Department of Pharmacology and Therapeutics and 2 Department of Ophthalmology and Laboratory of Visual Electrophysiology, McGill University, Montreal, Quebec H3G 1Y6; and 3 Departments of Pediatrics, Ophthalmology, and Pharmacology, Research Center of Hôpital Ste.-Justine, Montreal, Quebec, Canada H3T 1C5


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Despite increasingly frequent and longer lasting hypoxic episodes during progressive labor, the neonate is alert and vigorous at birth. We investigated whether high levels of PGs during the perinatal period assist in preserving neural function after such "stressful" hypoxic events. Visual evoked potentials (VEPs) and electroretinograms (ERGs) were recorded before and 45 min after mild moderate asphyxic hypoxia (two 4-min asphyxic-hypoxic periods induced by interrupting ventilation at 8-min intervals) in newborn piglets <12 h old treated or not treated with inhibitors of PG synthase (ibuprofen or diclofenac) with or without PG analogs. At 45 min after the hypoxic episode, P2 and b-wave amplitudes were slightly decreased and latencies were delayed. These changes in the VEP and ERG returned to near normal by 120 min. Ibuprofen and diclofenac decreased brain and retinal PG levels and markedly intensified 45 min after hypoxia-induced changes in VEP and ERG, but cerebral and retinal blood flows improved. Combined treatment with PG synthase inhibitor in combination with 16,16-dimethyl-PGE2 (a PGE2 analog), but not with PGI2 and PGF2alpha analogs, and in combination with the EP2 receptor agonist butaprost (but not EP1 or EP3 agonists), prevented ibuprofen- and diclofenac-aggravated postasphyxia electrophysiological changes. In conclusion, high levels of PGE2 in nervous tissue, via actions on EP2 receptors, seem to contribute to preservation of neural function in the perinate subjected to frequent hypoxic events.

prostaglandin E2; neuroprotection; newborn; visual evoked potential


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

AS LABOR PROGRESSES AND UTERINE contractions increase in frequency and intensity, a significant hypoxemia is observed as a result of placental and umbilical compression depriving the perinate of O2 intermittently; furthermore, the head of the perinate sustains considerable pressure, which may reduce O2 delivery to the brain (10, 12, 34, 35). Despite these apparent stresses, the neonate is normally vigorous and alert at birth. A number of hormones have been proposed to diminish the potentially adverse consequences of this stressful condition, such as perinatal surges in catecholamines, corticosteroids, and endorphins (19, 35, 61). PGs, mainly PGE2 and PGI2, but not thromboxane A2, also rise in the circulation and brain beginning with the onset of parturition, reaching their peak soon before birth (29), and abate after birth (29, 39, 44). However, the physiological significance of this transient rise in PGs in neural tissue of the perinate is not clear.

PGs also increase during hypoxic-asphyxic episodes (16, 54, 59); under these conditions, prostanoids affect cerebral vasomotor tone and participate in the hemodynamic response, facilitating O2 delivery to the brain (8, 17, 36, 53). In addition, prostanoids can exert important effects on the brain during development, maturation, and functioning (3, 18, 30, 33, 66).

Some prostanoids can produce deleterious effects, whereas others may afford protection (6, 24, 42, 43). For instance, thromboxane has largely been credited with hemodynamic compromising functions (42, 52); in contrast, PGE2 and PGI2 seem to protect neural tissue against toxicity and degeneration (1, 2, 6, 7, 14, 31, 40, 49, 51, 56, 60), although their physiological role in vivo, especially in the perinate, has never been demonstrated.

We therefore hypothesized that the high levels of PGs during the perinatal period may assist in preserving neural function after hypoxic events; if this is the case, a reduction in PG levels would enhance posthypoxic deterioration in neural function of the perinate. PG levels are still high in newborn pigs up to 12 h after birth (23, 29, 37, 39); we used this model to assess the effects of PG synthase inhibitors with or without PG analogs on electrophysiological brain function by recording visually evoked potentials (VEPs) before and after a hypoxic episode. In addition, retinal function (which is integral, although separate, from that of the central nervous system) was assessed by recording electroretinograms (ERGs). Our findings support our hypothesis, i.e., that high levels of PGs, specifically PGE2 acting apparently via EP2 receptors, preserve electrophysiological neural (brain and retina) function in the perinate subjected to hypoxic events; this effect of PGE2 is unrelated to improvements in cerebral and retinal blood flow (CBF and RBF, respectively).


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Preparation of animals for electrophysiological recordings and for blood flow measurements. Forty-five newborn pigs (<12 h old, 1.2-2.2 kg) were used in the study, which conformed to the guidelines of the Animal Care Committee of Ste. Justine Hospital Research Center. Vascular catheters were placed and tracheostomy was performed as previously described (9, 21) to prepare animals for electrophysiological recordings and for blood flow measurements. One group of piglets was anesthetized with 2.5% halothane for placement of a catheter (PE-50, Becton Dickinson, Parsippany, NJ) in the femoral artery for measurement of blood pressure (BP) and blood gases (model ABL-300, Radiometer, Copenhagen, Denmark) and another in the femoral vein for drug administration. VEP and ERG were recorded in separate groups of animals, because flash parameters to evoke these distinct signals differ (see below). A group of animals was also prepared for blood flow measurements, as previously described in detail (8, 9). Briefly, a polyethylene catheter was placed into the left ventricle via the right subclavian artery for the injection of radiolabeled microspheres, and another was placed in the proximal thoracic aorta via a femoral artery for continuous BP recording. The left subclavian artery was catheterized with a similar catheter for the withdrawal of blood samples including the reference samples and for measurements of blood gases. A small catheter was introduced into the femoral vein for administration of drugs. After catheterization, tracheostomy was performed on all animals, and the animals were ventilated with air by means of a small-animal respirator (Harvard, South Natick, MA). After surgery, halothane was discontinued and piglets were sedated intravenously with alpha -chloralose (50 mg/kg bolus followed by an infusion of 10 mg · kg-1 · h-1) and paralyzed with pancuronium (0.2 mg/kg iv). Animals were then placed under a radiant warmer to maintain their body temperature at 38°C and were allowed to recover from the surgery for 1.5 h before the start of the experiments.

Experimental protocol. Animals were randomly assigned to receive an intravenous injection of one of the following: saline (2 ml, n = 14); the PG synthase inhibitors ibuprofen (40 mg/kg, n = 5) or diclofenac (5 mg/kg, n = 9); a combination of ibuprofen or diclofenac and stable analogs of the major PGs, PGE2 (16,16-dimethyl-PGE2, 5 µg/kg, n = 17), PGI2 (carbaprostacyclin, 5 µg/kg, n = 10), and PGF2alpha (fenprostalene, 5 µg/kg, n = 10); or a combination of ibuprofen or diclofenac and a PGE2 receptor subtype agonist, 11-deoxy-PGE1 (an EP2, EP3, and EP4 agonist, 10 µg/kg, n = 6), 17-phenyl trinor-PGE2 (an EP1 agonist, 10 µg/kg, n = 6), butaprost (an EP2 agonist, 10 µg/kg, n = 6), and M & B-28767 (an EP3 agonist, 5 µg/kg, n = 6) (11), 30 min before the asphyxic-hypoxic episode. All doses are known to affect PG levels and to have effects on the piglet brain (21, 37, 39, 50).

Newborn piglets were subjected to two 4-min periods of asphyxic hypoxia 8 min apart by interruption of ventilation (9); the duration of these episodes approximates the progressively prolonged hypoxemia associated with increasing uterine contractions in labor (4) and, in other species, does not yield permanent neurofunctional changes (45, 55). VEP, ERG, CBF, and RBF were measured before and 45 min after the asphyxic-hypoxic episode; drugs had no effect on basal VEP and ERG (see RESULTS). VEP was also measured 120 min after the asphyxia to verify that the asphyxia did not yield permanent changes. At the end of the experiments (45 and 120 min after asphyxia), animals were killed with pentobarbital sodium (120 mg/kg), and neural tissues were obtained for PG measurements; some animals were killed before asphyxia for determination of basal PG levels.

VEP. VEP is a reliable and sensitive parameter by which to evaluate neurological functional alterations (46, 65). Flash VEPs in newborn pigs were recorded using a subdermal needle electrode (Grass Instruments, Quincy, MA) placed over the occipital region (3.5 mm right of midline) (58). The reference electrode was located on the right external ear, and the right paw served as the ground electrode. Electrode impedance was kept below 5 kOmega . The head of the animal was adjusted in the center of a Ganzfeld stimulator (LKC Technologies, Gaithersburg, MD), and one eye was kept open with use of a lid retractor. The intensity of the flash stimulus (Grass Instrument) was 3.65 cd · s · m-2 attenuated by 2 log units to enhance sensitivity and was delivered by the Ganzfeld stimulator. The VEP were recorded with a signal averager (sweep time 500 ms, recording bandwidth 1-100 Hz, rate 1.3/s; Epic 2000, LKC Technologies). At least two traces were recorded for each condition, and average latencies and amplitudes of P2 waves [from the first most-negative deflection (N1) to the first most-positive deflection] were determined; this wave is reliable and is always present in neonates (58) (P1 is small and at times difficult to detect). Control recordings in response to flash stimuli were also obtained by shielding the lamp.

ERG measurements. ERG were also recorded as previously described using corneal contact lens electrodes (ERG jet, Universo, La Chaux-De Fonds, Switzerland) filled with 2% hydroxypropylmethyl cellulose (21, 22). The reference electrode was placed on the forehead and the ground electrode on the right ear of the animal. The head of the animal was positioned in the center of a Ganzfeld stimulator. Scotopic ERGs were obtained after 40 min of dark adaptation. The intensity of the flash stimulus was adjusted at 3.65 cd · s · m-2. The ERG responses were amplified using an Epic 2000 electrodiagnostic instrument with a bandwidth of 0.3-500 Hz. A total of 10 responses per condition were averaged and stored on computer disks for subsequent analysis. The amplitude of the a-wave was calculated as the difference in voltage from the baseline to the most-negative deflection. The b-wave amplitude was measured from the most-negative deflection of the ERG to the peak of the positive deflection. ERG parameters were not altered by simple administration of drugs.

PGE2 measurements. PGE2 levels were measured in brain and retinal tissue of piglets treated with saline or ibuprofen and subjected to asphyxia. PGs were extracted on octadecylsilyl silica columns and determined by RIA, as described previously (9, 21, 22, 37).

Measurement of CBF and RBF. CBF and RBF were determined using the radionuclide-labeled microsphere technique (8, 9). Briefly, microspheres (~106, 15 µm diameter) labeled with 141Ce, 113Sn, or 85Sr were injected in a random sequence into the left ventricle. Withdrawal of reference blood samples from the left subclavian artery catheter was started 10 s before injection of each type of microsphere and was continued for 70 s at a rate of 2 ml/min with use of a Harvard infusion-withdrawal pump. After the experiment, animals were killed with excess pentobarbital sodium, the location of the catheters was verified, and the occipital brain cortex and retina were removed and weighed. Radioactivity in tissues and reference blood samples was counted in a gamma scintillation counter (Cobra II, Canberra Packard, Meridien, CT). Blood flow (ml · min-1 · 100 g-1) was calculated as (counts per minute per 100 g of tissue × reference blood withdrawal rate)/(counts per minute in reference blood) with use of the computer system on-line with the counter (PCGERDA, Charlottesville, VA).

Chemicals. Butaprost and M & B-28767 were gifts from Miles (West Haven, CT) and Rhône-Poulenc Rorer (Dagenham Essex, UK), respectively. The following agents were purchased: diclofenac, ibuprofen, alpha -chloralose, and pancuronium from Sigma Chemical (St. Louis, MO); 16,16-dimethyl-PGE2, carbaprostacyclin, 11-deoxy-PGE1, and 17-phenyl trinor-PGE2 from Cayman Chemical (Ann Arbor, MI); fenprostalene from Syntex (Mississauga, ON, Canada); RIA kits for PGE2 from Advanced Magnetics (Boston, MA); radiolabeled microspheres from DuPont-New England Nuclear (Boston, MA); and all other chemicals from Fisher Scientific (Montreal, PQ, Canada).

Statistical analysis. Data were analyzed by ANOVA with factoring for time and treatment group. Post hoc comparisons among means were done by the Tukey-Kramer method. Statistical significance was set at P <=  0.05. Values are means ±SE; n is the number of animals.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Arterial blood gases, pH, mean BP, and tissue PG levels. Asphyxia, as expected, decreased arterial blood PO2, pH, and mean BP and increased blood PCO2 in all groups of animals (Table 1); these parameters returned to preasphyxia levels 45 min after the end of asphyxic episodes. Baseline values and asphyxic changes were unaltered by ibuprofen or ibuprofen + 16,16-dimethyl-PGE2. PGE2 levels in brain and retina increased 45 min after the hypoxic-asphyxic episodes and approached basal values by 120 min; ibuprofen markedly reduced PGE2 concentrations (Fig. 1).

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Arterial blood gases, pH, and MBP before, during, and after asphyxic episodes



View larger version (12K):
[in this window]
[in a new window]
  		Fig. 1.   PGE2 levels in brain (A) and retina (B) before and after an asphyxic-hypoxic episode that was produced by interrupting ventilation. Values are means ± SE. * P < 0.05 compared with preasphyxia and 120-min postasphyxia values.

Effects of PGs and/or PG synthase inhibitors on VEP. The amplitude of the P2 wave was slightly decreased and latency was prolonged 45 min after asphyxic episodes. These changes were significantly intensified by pretreatment with ibuprofen (Fig. 2); ibuprofen did not alter basal VEP (Fig. 2, A and B). VEP parameters returned to near-basal values by 120 min. To further ascertain that PGs are involved in the aggravated postasphyxia VEP changes observed in ibuprofen-treated piglets, animals were treated with a combination of ibuprofen and stable analogs of major PGs, 16,16-dimethyl-PGE2 (a PGE2 analog), carbaprostacyclin (a PGI2 analog), and fenprostalene (a PGF2alpha analog); P2 amplitude and latency changes were diminished by the addition of PGs (Fig. 2).


View larger version (32K):
[in this window]
[in a new window]
  		Fig. 2.   Effects of ibuprofen and PGs on visual-evoked potential (VEP) before and after asphyxia. A: typical traces of VEP in 3 animals treated as indicated. Note reduction in P2 wave (1st major positive inflection) 45 min after the hypoxic-asphyxic episode, which is accentuated in ibuprofen-treated (40 mg/kg) animals; the latter is attenuated by injection (5 µg/kg iv) of analogs of major PGs [16,16-dimethyl-PGE2 (a PGE2 analog), carbaprostacyclin (carba-PGI2, a PGI2 analog), and fenprostalene (a PGF2alpha analog)]; animals were pretreated with drugs. Arrows, flash stimulus. B: amplitude and latency of P2 wave expressed in absolute values; note near normalization of values 120 min after asphyxia. * P < 0.05 compared with preasphyxia values (by ANOVA). C: amplitude and latency of P2 wave expressed as percent change from preasphyxic values. * P < 0.05 compared with corresponding value in saline-treated piglets.

Identification of PG type involved in preserving brain electrophysiological function. The type of major PG primarily responsible for the preservation of the VEP was investigated. Treatment of animals with 16,16-dimethyl-PGE2, but not with carbaprostacyclin or fenprostalene, significantly lessened postasphyxic effects of ibuprofen on P2 amplitude and latency (Fig. 3). Because PGE2 acts on four receptor subtypes (EP1, EP2, EP3, and EP4) (11), we conducted a study to determine on which of these receptors PGE2 acted to produce its effects on the VEP by using selective PGE2 receptor agonists. 11-Deoxy-PGE1 (an EP2, EP3, and EP4 agonist) and, more importantly, the selective EP2 agonist butaprost (11) were as effective as 16,16-dimethyl-PGE2 in diminishing ibuprofen-aggravated postasphyxic VEP changes (Fig. 3). The EP1 agonist 17-phenyl trinor-PGE2 and the EP3 agonist M & B-28767 did not modify ibuprofen-induced postasphyxic VEP changes; EP4 receptors are not detectable in piglet neural parenchyma (38, 38), and EP4 agonists are not available.


View larger version (27K):
[in this window]
[in a new window]
  		Fig. 3.   Effects of ibuprofen and PGs on the amplitude and latency of the VEP before and 45 min after asphyxia. 16,16-Dimethyl-PGE2, carbaprostacyclin, and fenprostalene were administered at 5 µg/kg iv and ibuprofen at 40 mg/kg iv. 11-Deoxy-PGE1 (an EP2, EP3, and EP4 agonist), 17 phenyl trinor-PGE2 (an EP1 agonist), and butaprost (an EP2 agonist) were injected at 10 µg/kg iv and M & B-28767 (a EP3 agonist) at 5 µg/kg iv. Values are means ± SE of P2 amplitudes (A) and latencies (B). * P < 0.05 compared with preasphyxic values; dagger  P < 0.05 compared with corresponding ibuprofen-treated value.

Effects of PG modulation on asphyxia-induced changes in the ERG. To further assess the role of PGs in diminishing asphyxic-hypoxia-induced deterioration in neural function, electrophysiological changes in the retina (ERG), a different neural tissue, were investigated. Furthermore, to ascertain the role of PGs on the neuroelectrophysiological findings, we used a PG synthase inhibitor molecularly distinct from ibuprofen, namely, diclofenac, which does not affect basal ERG (21). The results corroborated the VEP data. Asphyxic hypoxia caused a small decrease in amplitude and a delay in latency of the b-wave, which was augmented by diclofenac (Fig. 4); PGE2 levels in the retina were markedly reduced from 417 ± 84 to <190 pg/mg protein by diclofenac before and 45 min after asphyxia. Once again, 16,16-dimethyl-PGE2 and the selective EP2 agonist butaprost were the only PG agonists that significantly diminished the diclofenac-augmented postasphyxic changes in the ERG. Hence, PGE2 via EP2 receptors seems to preserve postasphyxic neural function in the perinate.


View larger version (25K):
[in this window]
[in a new window]
  		Fig. 4.   Effects of diclofenac and PGs on the electroretinogram (ERG) before and 45 min after asphyxia. A: typical traces of ERG. Note reduction in the b-wave amplitude (measured from the peak of the negative deflection to the peak of the largest positive inflection) after asphyxia that is further diminished by diclofenac (5 mg/kg iv); 16,16-dimethyl-PGE2 and the selective EP2 agonist butaprost markedly attenuated the aggravated postasphyxic changes induced by diclofenac. Arrows, flash stimulus. B: amplitude and latency of the b-wave; PG analog doses are presented in Fig. 3 legend. Values are means ± SE. * P < 0.05 compared with preasphyxia value; dagger  P < 0.05 compared with corresponding saline-treated value.

Effects of PG synthase inhibitor on postasphyxic changes in CBF and RBF. Early changes in posthypoxic neural function are often associated with compromised circulation (26, 41, 62). CBF and RBF decreased 45 min after asphyxic hypoxia in saline-treated animals; pretreatment with ibuprofen prevented this reduction in blood flow, and addition of 16,16-dimethyl-PGE2 did not cause further changes (Fig. 5). Thus a decrease in PG synthesis improves postasphyxic-hypoxia circulation but degrades neural function.


View larger version (12K):
[in this window]
[in a new window]
  		Fig. 5.   Cerebral (A) and retinal (B) blood flow before and 45 min after asphyxia in newborn piglets pretreated with saline, ibuprofen, and ibuprofen + 16,16-dimethyl-PGE2; drug doses are presented in Fig. 2 legend. Values are means ± SE. * P < 0.05 compared with preasphyxia.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

PG, especially PGE2, levels in neural tissue markedly rise during the perinatal period (29). The physiological reason for this rise remains unknown. The perinate encounters progressively more pronounced, frequent, and longer lasting hypoxemic events at the end of labor (4); despite such stresses, the neonate is vigorous and alert at birth. Some PGs, in particular PGE, exert cytoprotective actions (1, 2, 7, 14, 49, 60). Using a model of mild moderate asphyxic hypoxia (28, 45, 55), we hypothesized that high levels of PGs in the central nervous tissue of the perinate may contribute to preservation of neural function. Our findings support this hypothesis and reveal that these effects are mainly conferred by PGE2 through its actions on EP2 receptors.

The evidence to suggest a significant role for PGs in attenuating postasphyxic changes in central nervous system function is supported by data arising from two distinct evaluations, specifically in the brain by VEP and in the retina by ERG determinations. VEPs, as is the case for the ERGs, are reliable parameters to assess neural function (25, 46, 63, 65). A reduction in PG levels (Fig. 1) by treatment with molecularly unrelated cyclooxygenase inhibitors, ibuprofen and diclofenac, significantly worsened 45-min postasphyxic changes in VEP and ERG (Figs. 2 and 4). Addition of the PGE2 analog 16,16-dimethyl-PGE2 prevented such deterioration in VEP and ERG; in contrast, high doses (13, 39) of agonists of other major PGs, carbaprostacyclin and fenprostalene, were ineffective.

Cyclooxygenase inhibition in hypoxic-ischemic insults may be protective in the adult (9, 15, 20, 32, 57); this effect has mostly been attributed to inhibition of thromboxane generation (9, 27, 42). The consequences of increased thromboxane generation are mostly ascribed to circulatory compromise. In the present study, the immediate perinatal CBF and RBF also decreased 45 min after asphyxia (Fig. 5), and these changes, reported to be secondary to thromboxane formation (9), were prevented by ibuprofen. However, changes in circulation may not be associated with corresponding changes in function (41, 42). Indeed, we found that ibuprofen aggravated postasphyxic neural function in the perinate when PG, but not thromboxane, levels were very high (23, 29, 37, 39), and 16,16-dimethyl-PGE2 prevented the effects of cyclooxygenase inhibition (Figs. 2-4). Interestingly, administration of pharmacological doses of PGE to adult animals subjected to hypoxic-ischemic insults may also be neuroprotective (1); consistent with these in vivo data, PGE2 has been found to exert neuroprotective actions in vitro (1, 2, 6, 7, 14, 49, 60).

An important feature in this study is the identification of the PGE2 receptor EP2, which apparently confers the actions of PGE2. This inference is based on the effects of the selective EP2 agonist butaprost (11), which, in contrast to selective EP1 and EP3 agonists, reproduced actions of 16,16-dimethyl-PGE2; EP4 is not detected in newborn pig brain (38, 39). A similar role for the EP2 receptor has been reported in cultured neurons (2). The mechanism by which stimulation of EP2 leads to preservation of neural function is not clear from this study; however, certain speculations can be made. Stimulation of EP2 receptors is coupled to cAMP formation (11), which has been associated with cytoprotective actions (2, 56, 60). Activation of EP2 receptors may also lead to a reduction in influx of excess calcium (2), which in turn may likewise contribute to preservation of neural function (48, 64). In addition, a decrease in glutamate receptor activation by EP2 receptors may also be beneficial (2).

In conclusion, high levels of PGE2 in nervous tissue, through its actions on EP2 receptors, seem to contribute to preservation of neural function of the perinate subjected to frequent hypoxic events. During the progression of labor, as uterine contractions intensify [up to >2 min every 2 min (4)], so do the episodes of hypoxia (10, 12, 34, 35); commonly encountered mild moderate placental abruption can also further compromise fetal oxygenation (4). We speculate that, in addition to other purported factors, such as catecholamines, corticosteroids, and endorphins (19, 35, 60), the marked perinatal rise in PGE2 may assist in providing a neuroprotective mechanism that enables the neonate to manifest the needed vigor and alertness at birth, for instance, taking the first breath. In contrast, prolonged inhibition of PGs in perinates has been associated with neural injury (47).


    ACKNOWLEDGEMENTS

We thank Hensy Fernandez for technical assistance.


    FOOTNOTES

This work was supported by grants from the Medical Research Council of Canada, the Hospital for Sick Children Foundation, the March of Dimes Birth Defects Foundation, the Heart and Stroke Foundation of Quebec, and the Fonds de la Recherche en Santé du Québec. F. Gobeil, Jr., P. Hardy, and S. Chemtob are recipients of fellowship and scientist awards from the Medical Research Council of Canada.

Address for reprint requests and other correspondence: S. Chemtob, Research Center of Hôpital Ste. Justine, 3175 Côte Ste. Catherine, Montréal, PQ, Canada H3T 1C5 (E-mail: chemtobs{at}ere.umontreal.ca).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Received 29 October 1999; accepted in final form 24 March 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Abe, H, Sugino N, Matsuda T, Ueda Y, Mori H, and Aono M. Effects of prostaglandin E1 on transient forebrain ischemia, especially in hippocampal CA1 regions of the gerbil. Masui 45: 1216-1222, 1996[Medline].

2.   Akaike, A, Kaneko S, Tamura Y, Nakata N, Shiomi H, Ushikubi F, and Narumiya S. Prostaglandin E2 protects cultured cortical neurons against N-methyl-D-aspartate receptor-mediated glutamate cytotoxicity. Brain Res 663: 237-243, 1994[Web of Science][Medline].

3.   Al-Hader, AA, Lei ZM, and Rao CV. Novel expression of functional luteinizing hormone/chorionic gonadotropin receptors in cultured glial cells from neonatal rat brains. Biol Reprod 56: 501-507, 1997[Abstract].

4.   Beischer, NA, and Mackay EV. Obstetrics and the Newborn. Philadelphia, PA: Saunders, 1986, p. 158-162 and 346.

6.   Cazevieille, C, Muller A, and Bonne C. Prostacyclin (PGI2) protects rat cortical neurons in culture against hypoxia/reoxygenation and glutamate-induced injury. Neurosci Lett 160: 106-108, 1993[Web of Science][Medline].

7.   Cazevieille, C, Muller A, Meynier F, Dutrait N, and Bonne C. Protection by prostaglandins from glutamate toxicity in cortical neurons. Neurochem Int 24: 395-398, 1994[Web of Science][Medline].

8.   Chemtob, S, Beharry K, Rex J, Varma DR, and Aranda JV. Changes in cerebrovascular prostaglandins and thromboxane as a function of systemic blood pressure. Cerebral blood flow autoregulation of the newborn. Circ Res 67: 674-682, 1990[Abstract/Free Full Text].

9.   Chemtob, S, Hardy P, Abran D, Li DY, Peri KG, Cuzzani O, and Varma DR. Peroxide-cyclooxygenase interactions in postasphyxial changes in retinal and choroidal hemodynamics. J Appl Physiol 78: 2039-2046, 1995[Abstract/Free Full Text].

10.   Chua, S, Yeong SM, Razvi K, and Arulkumaran S. Fetal oxygen saturation during labour. Br J Obstet Gynaecol 104: 1080-1083, 1997[Web of Science][Medline].

11.   Coleman, RA, Smith WL, and Narumiya S. International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev 46: 205-229, 1994[Web of Science][Medline].

12.   Dildy, GA, Clark SL, and Loucks CA. Intrapartum fetal pulse oximetry: the effects of maternal hyperoxia on fetal arterial oxygen saturation. Am J Obstet Gynecol 171: 1120-1124, 1994[Web of Science][Medline].

13.   Dumont, I, Peri KG, Hardy P, Hou X, Martinez-Bermudez AK, Molotchnikoff S, Varma DR, and Chemtob S. PGE2, via EP3 receptors, regulates brain nitric oxide synthase in the perinatal period. Am J Physiol Regulatory Integrative Comp Physiol 275: R1812-R1821, 1998[Abstract/Free Full Text].

14.   Dymond, JB, and Kalmus GW. The cytoprotective properties of prostaglandin E2 against the toxic effects of actinomycin C on embryonic neural retina cells. Prostaglandins 44: 129-134, 1992[Web of Science][Medline].

15.   Furlow, TW, and Hallenbeck JM. Indomethacin prevents impaired perfusion of the dog's brain after global ischemia. Stroke 9: 591-594, 1978[Abstract/Free Full Text].

16.   Gaudet, RJ, Alam I, and Levine L. Accumulation of cyclooxygenase products of arachidonic acid metabolism in gerbil brain during reperfusion after bilateral common carotid artery occlusion. J Neurochem 35: 653-658, 1980[Web of Science][Medline].

17.   Goddard-Finegold, J, and Michael LH. Effects of prostaglandin E2 on cerebral blood flow in the newborn beagle. Ann Neurol 12: 222-223, 1982.

18.   Goldin, E, Harel S, Tomer A, and Yavin E. Arachidonic acid oxidation by brain and placenta preparations from normal and placental insufficient fetal rabbit. J Neurochem 54: 587-591, 1987[Web of Science][Medline].

19.   Gradert, Y, Hertel J, Lenstrup C, Bach FW, Christensen NJ, and Roseno H. Warm tub bath during labor. Effects on plasma catecholamine and beta -endorphin-like immunoreactivity concentrations in the infants at birth. Acta Obstet Gynecol Scand 66: 681-683, 1987[Web of Science][Medline].

20.   Hallenbeck, JM, Leitch DR, Dutka AJ, Greenbaum LJ, Jr, and McKee AE. Prostaglandin I2, indomethacin, and heparin promote post-ischemic neuronal recovery in dogs. Ann Neurol 12: 145-156, 1982[Web of Science][Medline].

21.   Hanna, N, Lachapelle P, Roy MS, Orquin J, Varma DR, and Chemtob S. Alterations in the electroretinogram of newborn piglets by propionic acid-derivative nonsteroidal anti-inflammatory drugs but not by indomethacin and diclofenac. Pediatr Res 37: 81-85, 1995[Web of Science][Medline].

22.   Hanna, N, Peri KG, Abran D, Hardy P, Doke A, Lachapelle P, Roy MS, Orquin J, Varma DR, and Chemtob S. Light induces peroxidation in retina by activating prostaglandin G/H synthase. Free Radic Biol Med 23: 885-897, 1997[Web of Science][Medline].

23.   Hardy, P, Bhattacharya M, Abran D, Peri KG, Asselin P, Varma DR, and Chemtob S. Increases in retinovascular prostaglandin receptor functions by cyclooxygenase-1 and -2 inhibition. Invest Ophthalmol Vis Sci 39: 1888-1898, 1998[Abstract/Free Full Text].

24.   Hartley, DM, and Choi DW. Delayed rescue of N-methyl-D-aspartate receptor-mediated neuronal injury in cortical culture. J Pharmacol Exp Ther 250: 752-758, 1989[Abstract/Free Full Text].

25.   Henkes, HE. Electroretinography in circulatory disturbances of the retina. Arch Ophthalmol 49: 190-201, 1953[Abstract/Free Full Text].

26.   Ichord, RN, Kirsch JR, Helfaer MA, Haun S, and Traystman RJ. Age-related differences in recovery of blood flow and metabolism after cerebral ischemia in swine. Stroke 22: 626-634, 1991[Abstract/Free Full Text].

27.   Iijima, T, Sawa H, Shiokawa Y, Saito I, Ishii H, Nakamura Z, and Sankawa H. Thromboxane synthetase inhibitor ameliorates delayed neuronal death in the CA1 subfield of the hippocampus after transient global ischemia in gerbils. J Neurosurg Anesthesiol 8: 237-242, 1996[Web of Science][Medline].

28.   Ito, U, Spatz M, Walker JT, Jr, and Klatzo I. Experimental cerebral ischemia in Mongolian gerbils. I. Light microscopic observations. Acta Neuropathol (Berl) 32: 209-223, 1975[Medline].

29.   Jones, SA, Adamson SL, Bishai I, Lees J, Engelberts D, and Coceani F. Eicosanoids in third ventricular cerebrospinal fluid of fetal and newborn sheep. Am J Physiol Regulatory Integrative Comp Physiol 264: R135-R142, 1993[Abstract/Free Full Text].

30.   Kaufmann, W, Worley PF, Pegg J, Bremer M, and Isakson P. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci USA 93: 2317-2321, 1996[Abstract/Free Full Text].

31.   Kochanek, PM, Dutka AJ, Kumaroo KK, and Hallenbeck JM. Effects of prostacyclin, indomethacin, and heparin on cerebral blood flow and platelet adhesion after multifocal ischemia of canine brain. Stroke 19: 693-699, 1988[Abstract/Free Full Text].

32.   Kuhn, JE, Steimle CN, Zelenock GB, and D'alecy LG. Ibuprofen improves survival and neurologic outcome after resuscitation from cardiac arrest. Resuscitation 14: 199-212, 1986[Web of Science][Medline].

33.   Kunievsky, B, and Yavin E. Regulation of eicosanoid synthesis by whole fetal rat brain ex vivo. Mol Chem Neuropathol 13: 155-163, 1990[Web of Science][Medline].

34.   Lagercrantz, H. Stress, arousal, and gene activation at birth. News Physiol Sci 11: 214-218, 1996[Abstract/Free Full Text].

35.   Lagercrantz, H, and Slotkin TA. The "stress" of being born. Sci Am 254: 100-107, 1986[Web of Science][Medline].

36.   Leffler, CW, and Busija DW. Prostanoids in cortical subarachnoid cerebrospinal fluid and pial arterial diameter in newborn pigs. Circ Res 57: 689-694, 1985[Abstract/Free Full Text].

37.   Li, DY, Abran D, Peri KG, Varma DR, and Chemtob S. Inhibition of prostaglandin synthesis in newborn pigs increases cerebral microvessel prostaglandin F2alpha and prostaglandin E2 receptors, their second messengers and vasoconstrictor response to adult levels. J Pharmacol Exp Ther 278: 370-377, 1996[Abstract/Free Full Text].

38.   Li, DY, Varma DR, Chatterjee TK, Fernandez H, Abran D, and Chemtob S. Fewer PGE2 and PGF2alpha receptors in brain synaptosomes of newborn than of adult pigs. J Pharmacol Exp Ther 267: 1292-1297, 1993[Abstract/Free Full Text].

39.   Li, DY, Varma DR, and Chemtob S. Upregulation of brain PGE2 and PGF2alpha receptors and receptor-coupled second messengers by cyclooxygenase inhibition in newborn pigs. J Pharmacol Exp Ther 272: 12-19, 1995.

40.   Masuda, Y, Ochi Y, Ochi Y, Karasawa T, Hatano N, Kadokawa T, and Okegawa T. Protective effect of a new prostacyclin analog OP-2507 against cerebral anoxia and edema in experimental animals. Eur J Pharmacol 123: 335-344, 1986[Web of Science][Medline].

41.   McGowan, JE, McGowan JC, III, Mishra OP, and Delivoria-Papadopoulos M. Effect of cyclooxygenase inhibition on brain cell membrane lipid peroxidation during hypoxia in newborn piglets. Biol Neonate 66: 367-375, 1994[Web of Science][Medline].

42.   Ment, LR, Stewart WB, Petroff OA, and Duncan CC. Thromboxane synthesis inhibitor in a beagle pup model of perinatal asphyxia. Stroke 20: 809-814, 1989[Abstract/Free Full Text].

43.   Miller, VT, Coull BM, Yatsu FM, Shah AB, and Beamer NB. Prostacyclin infusion in acute cerebral infarction. Neurology 34: 1431-1435, 1984[Abstract/Free Full Text].

44.   Mitchell, MD, Lucas A, Etches PC, Brant JD, and Turnbull AC. Plasma prostaglandin levels during early neonatal life following term and preterm delivery. Prostaglandins 16: 319-326, 1978[Web of Science][Medline].

45.   Nishijima, MK, Koehler RC, Hurn PD, Eleff SM, Norris S, Jacobus WE, and Traystman RJ. Postischemic recovery rate of cerebral ATP, phosphocreatine, pH, and evoked potentials. Am J Physiol Heart Circ Physiol 257: H1860-H1870, 1989[Abstract/Free Full Text].

46.   Norcia, AM, Tyler CW, Piecuch R, Clyman R, and Grobstein J. Visual acuity development in normal and abnormal preterm human infants. J Pediatr Ophthalmol Strabismus 24: 70-74, 1987[Medline].

47.   Norton, ME, Merrill J, Cooper BA, Kuller JA, and Clyman RI. Neonatal complications after the administration of indomethacin for preterm labor. N Engl J Med 329: 1602-1607, 1993[Abstract/Free Full Text].

48.   Osborne, NN, Cazevieille C, Carvalho AL, Larsen AK, and DeSantis L. In vivo and in vitro experiments show that betaxolol is a retinal neuroprotective agent. Brain Res 751: 113-123, 1997[Web of Science][Medline].

49.   Otsuki, H, Yamada K, Yuguchi T, Taneda M, and Hayakawa T. Prostaglandin E1 induces c-Fos and Myc proteins and protects rat hippocampal cells against hypoxic injury. J Cereb Blood Flow Metab 14: 150-155, 1994[Web of Science][Medline].

50.   Parys-Van Ginderdeuren, R, Malcolm D, Varma DR, Aranda JV, and Chemtob S. Dissociation between prostaglandin levels and blood flow to the retina and choroid in the newborn pig following nonsteroidal anti-inflammatory drugs. Invest Ophthalmol Vis Sci 33: 3378-3384, 1992[Abstract/Free Full Text].

51.   Petrova, TV, Akama KT, and Van Eldik LJ. Cyclopentenone prostaglandins suppress activation of microglia: down-regulation of inducible nitric-oxide synthase by 15-deoxy-Delta -12,14-prostaglandin J2. Proc Natl Acad Sci USA 96: 4668-4673, 1999[Abstract/Free Full Text].

52.   Pettigrew, LC, Grotta JC, Rhoades HM, and Wu KK. Effect of thromboxane synthase inhibition on eicosanoid levels and blood flow in ischemic rat brain. Stroke 20: 627-632, 1989[Abstract/Free Full Text].

53.   Pickard, J, Tamura A, Stewart M, McGeorge A, and Fitch W. Prostacyclin, indomethacin and the cerebral circulation. Brain Res 197: 425-431, 1980[Web of Science][Medline].

54.   Pourcyrous, M, Leffler CW, and Busija DW. Postasphyxial increases in prostaglandins in cerebrospinal fluid in piglets. Pediatr Res 24: 229-232, 1988[Web of Science][Medline].

55.   Rehncrona, S, Rosen I, and Smith ML. Effect of different degrees of brain ischemia and tissue lactic acidosis on the short-term recovery of neurophysiologic and metabolic variables. Exp Neurol 87: 458-473, 1985[Web of Science][Medline].

56.   Renkawek, K, Herbacyznska-Cedro K, and Mossakowsk MJ. The effect of prostacyclin on the morphological and enzymatic properties of CNS cultures exposed to anoxia. Acta Neurol Scand 73: 111-118, 1986[Web of Science][Medline].

57.   Shohami, E, Rosenthal J, and Lavy S. The effect of incomplete cerebral ischemia on prostaglandin levels in rat brain. Stroke 13: 494-499, 1982[Abstract/Free Full Text].

58.   Silver, S, Kapitulnik J, and Sohmer H. Postnatal development of flash visual evoked potentials in the jaundiced Gunn rat. Pediatr Res 30: 469-472, 1991[Web of Science][Medline].

59.   Stevens, MK, and Yaksh TL. Time course of release in vivo of PGE2, PGF2alpha , 6-keto-PGF1alpha , and TxB2 into the brain extracellular space after 15 min of complete global ischemia in the presence and absence of cyclooxygenase inhibition. J Cereb Blood Flow Metab 8: 790-798, 1988[Web of Science][Medline].

60.   Thery, C, Dobbertin A, and Mallat M. Downregulation of in vitro neurotoxicity of brain macrophages by prostaglandin E2 and an beta -adrenergic agonist. Glia 11: 383-386, 1994[Web of Science][Medline].

61.   Tuimala, R, Kauppila A, Ronnberg L, Jouppila R, and Haapalahti J. The effect of labour on ACTH and cortisol levels in amniotic fluid and maternal blood. Br J Obstet Gynaecol 83: 707-710, 1976[Web of Science][Medline].

62.   Ulatowski, JA, Kirsch JR, and Traystman RJ. Hypoxic reperfusion after ischemia in swine does not improve acute brain recovery. Am J Physiol Heart Circ Physiol 267: H1880-H1887, 1994[Abstract/Free Full Text].

63.   Van Lith, G. Subnormal and absent ERGs: what do we mean by these terms? Doc Ophthalmol 31: 13-17, 1982.

64.   Winkler, BS, Kapousta-Bruneau N, Arnold MJ, and Green DG. Effects of inhibiting glutamine synthetase and blocking glutamate uptake on b-wave generation in the isolated rat retina. Vis Neurosci 16: 345-353, 1999[Web of Science][Medline].

65.   Wood, JR, Jr, Coppes V, Brooks DE, Knowles PJ, Freeman M, Parisi V, Omara P, and McCarty GE. Birth asphyxia. I. Measurement of visual evoked potential (VEP) in the healthy fetus and newborn lambs. Pediatr Res 15: 1429-1432, 1981[Web of Science][Medline].

66.   Yamagata, K, Andreasson KI, Kaufmann WE, Barnes CA, and Worley PF. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 11: 371-386, 1993[Web of Science][Medline].

J APPL PHYSIOL 89(2):777-784
8750-7587/00 $5.00 Copyright © 2000 the American Physiological Society


This article has been cited by other articles:


Home page
 IOVSHome page
N. N. Osborne, G.-Y. Li, D. Ji, B. L. Andrade da Costa, R. J. Fawcett, K. D. Kang, and K. D. Rittenhouse
Expression of Prostaglandin PGE2 Receptors under Conditions of Aging and Stress and the Protective Effect of the EP2 Agonist Butaprost on Retinal Ischemia
Invest. Ophthalmol. Vis. Sci., July 1, 2009; 50(7): 3238 - 3248.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
A. Bouayad, J.-C. Fouron, X. Hou, M. Beauchamp, C. Quiniou, D. Abran, K. Peri, R. I. Clyman, D. R. Varma, and S. Chemtob
Developmental regulation of prostaglandin E2 synthase in porcine ductus arteriosus
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2004; 286(5): R903 - R909.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
D. H. Wright, D. Abran, M. Bhattacharya, X. Hou, S. G. Bernier, A. Bouayad, J.-C. Fouron, A. Vazquez-Tello, M. H. Beauchamp, R. I. Clyman, et al.
Prostanoid receptors: ontogeny and implications in vascular physiology
Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2001; 281(5): R1343 - R1360.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Najarian, T.
Right arrow Articles by Chemtob, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Najarian, T.
Right arrow Articles by Chemtob, S.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online