Regulation of heme oxygenase expression by cyclopentenone prostaglandins.
ABSTRACT Prostaglandins (PGs) originate from the degradation of membranar arachidonic acid by cyclooxygenases (COX-1 and COX-2). The prostaglandin actions in the nervous system are multiple and have been suggested to play a significant role in neurodegenerative disorders. Some PGs have been reported to be toxic and, interestingly, the cyclopentenone PGs have been reported to be cytoprotective at low concentration and could play a significant role in neuronal plasticity. They have been shown to be protective against oxidative stress injury; however, the cellular mechanisms of protection afforded by these PGs are still unclear. It is postulated that the cascade leading to neuronal cell death in acute and chronic neurodegenerative conditions, such as cerebral ischemia and Alzheimer's disease, would be mediated by free radical damage. We tested the hypothesis that the neuroprotective action of cyclopentanone could be caused partially by an induction of heme oxygenase 1 (HO-1). We and others have previously reported that modulation of HO total activity may well have direct physiological implications in stroke and in Alzheimer's disease. HO acts as an antioxidant enzyme by degrading heme into iron, carbon monoxide, and biliverdin that is rapidly converted into bilirubin. Using mouse primary neuronal cultures, we demonstrated that PGs of the J series induce HO-1 in a dose-dependent manner (0, 0.5, 5, 10, 20, and 50 micro g/ml) and that PGJ(2) and dPGJ(2) were more potent than PGA(2), dPGA(2), PGD(2), and PGE(2). No significant effects were observed for HO-2 and actin expression. In regard to HO-3 expression found in rat, with its protein deducted sequence highly homologous to HO-2, no detection was observed in HO-2(-/-) mice, suggesting that HO-3 protein would not be present in mouse brain. We are proposing that several of the protective effects of PGJ(2) could be mediated through beneficial actions of heme degradation and its metabolites. The design of new mimetics based on the cyclopentenone structure could be very useful as neuroprotective agents and be tested in animal models of stroke and Alzheimer's disease.
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ABSTRACT: Buyang Huanwu Decoction fraction extracted from Buyang Huanwu Decoction contains saponins of Astragalus, total paeony glycoside and safflower flavones. The aim of this study was to demonstrate the neuroprotective effect and mechanism of Buyang Huanwu Decoction fraction on ischemic injury both in vivo and in vitro. In vivo experiments showed that 50-200 mg/kg Buyang Huanwu Decoction fraction reduced infarct volume and pathological injury in ischemia/reperfusion rats, markedly inhibited expression of nuclear factor-κB and tumor necrosis factor-α and promoted nestin protein expression in brain tissue. Buyang Huanwu Decoction fraction (200 mg/kg) exhibited significant effects, which were similar to those of 100 mg/kg Ginkgo biloba extract. In vitro experimental results demonstrated that 10-100 mg/L Buyang Huanwu Decoction fraction significantly improved cell viability, decreased the release of lactate dehydrogenase and malondialdehyde levels, and inhibited the rate of apoptosis in HT22 cells following oxygen-glucose deprivation. Buyang Huanwu Decoction fraction (100 mg/L) exhibited significant effects, which were similar to those of 100 mg/L Ginkgo biloba extract. These findings suggest that Buyang Huanwu Decoction fraction may represent a novel, protective strategy against cerebral ischemia/reperfusion injury in rats and oxygen-glucose deprivation-induced damage in HT22 cells in vitro by attenuating the inflammatory response and cellular apoptosis.Neural Regeneration Research 01/2013; 8(3):197-207. · 0.14 Impact Factor
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ABSTRACT: Unconjugated hyperbilirubinemia is a common condition in the first week of postnatal life. Although generally harmless, some neonates may develop very high levels of unconjugated bilirubin (UCB), which may surpass the protective mechanisms of the brain in preventing UCB accumulation. In this case, both short-term and long-term neurodevelopmental disabilities, such as acute and chronic UCB encephalopathy, known as kernicterus, or more subtle alterations defined as bilirubin-induced neurological dysfunction (BIND) may be produced. There is a tremendous variability in babies' vulnerability toward UCB for reasons not yet explained, but preterm birth, sepsis, hypoxia, and hemolytic disease are comprised as risk factors. Therefore, UCB levels and neurological abnormalities are not strictly correlated. Even nowadays, the mechanisms of UCB neurotoxicity are still unclear, as are specific biomarkers, and little is known about lasting sequelae attributable to hyperbilirubinemia. On autopsy, UCB was shown to be within neurons, neuronal processes, and microglia, and to produce loss of neurons, demyelination, and gliosis. In isolated cell cultures, UCB was shown to impair neuronal arborization and to induce the release of pro-inflammatory cytokines from microglia and astrocytes. However, cell dependent sensitivity to UCB toxicity and the role of each nerve cell type remains not fully understood. This review provides a comprehensive insight into cell susceptibilities and molecular targets of UCB in neurons, astrocytes, and oligodendrocytes, and on phenotypic and functional responses of microglia to UCB. Interplay among glia elements and cross-talk with neurons, with a special emphasis in the UCB-induced immunostimulation, and the role of sepsis in BIND pathogenesis are highlighted. New and interesting data on the anti-inflammatory and antioxidant activities of different pharmacological agents are also presented, as novel and promising additional therapeutic approaches to BIND.Frontiers in Pharmacology 01/2012; 3:88.
- The Korean Journal of Parasitology 01/2014; 48(1):15-21. · 0.88 Impact Factor
Experimental Biology and Medicine
The online version of this article can be found at:
2003 228: 499Exp Biol Med (Maywood)
Hean Zhuang, Sokhon Pin, Xiaoling Li and Sylvain Doré
Regulation of Heme Oxygenase Expression by Cyclopentenone Prostaglandins
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Regulation of Heme Oxygenase Expression by
HEAN ZHUANG, SOKHON PIN, XIAOLING LI, AND SYLVAIN DORÉ1
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University,
Baltimore, Maryland 21217
Prostaglandins (PGs) originate from the degradation of mem-
branar arachidonic acid by cyclooxygenases (COX-1 and COX-
2). The prostaglandin actions in the nervous system are mul-
tiple and have been suggested to play a significant role in neu-
rodegenerative disorders. Some PGs have been reported to be
toxic and, interestingly, the cyclopentenone PGs have been re-
ported to be cytoprotective at low concentration and could play
a significant role in neuronal plasticity. They have been shown
to be protective against oxidative stress injury; however, the
cellular mechanisms of protection afforded by these PGs are
still unclear. It is postulated that the cascade leading to neuro-
nal cell death in acute and chronic neurodegenerative condi-
tions, such as cerebral ischemia and Alzheimer’s disease,
would be mediated by free radical damage. We tested the hy-
pothesis that the neuroprotective action of cyclopentanone
could be caused partially by an induction of heme oxygenase 1
(HO-1). We and others have previously reported that modulation
of HO total activity may well have direct physiological implica-
tions in stroke and in Alzheimer’s disease. HO acts as an anti-
oxidant enzyme by degrading heme into iron, carbon monoxide,
and biliverdin that is rapidly converted into bilirubin. Using
mouse primary neuronal cultures, we demonstrated that PGs of
the J series induce HO-1 in a dose-dependent manner (0, 0.5, 5,
10, 20, and 50 µg/ml) and that PGJ2and dPGJ2were more po-
tent than PGA2, dPGA2, PGD2, and PGE2. No significant effects
were observed for HO-2 and actin expression. In regard to HO-3
expression found in rat, with its protein deducted sequence
highly homologous to HO-2, no detection was observed in HO-
2−/−mice, suggesting that HO-3 protein would not be present in
mouse brain. We are proposing that several of the protective
effects of PGJ2could be mediated through beneficial actions of
heme degradation and its metabolites. The design of new mi-
metics based on the cyclopentenone structure could be very
useful as neuroprotective agents and be tested in animal mod-
els of stroke and Alzheimer’s disease. Exp Biol Med 228:499–505,
Key words: Alzheimer’s disease; antioxidant; cerebral ischemia;
free radical; iron; oxidative stress; prostaglandin; neurodegenera-
the enzymatic degradation of 20-carbon arachidonic acid by
cyclooxygenases. There are two isoforms of cyclooxygen-
ase: COX-1 is expressed constitutively in most tissues and
is present under normal conditions at very low levels in the
brain. COX-2, the inducible isoform, is found acutely ex-
pressed in several cell types after head injury, in cerebral
ischemia, and in Alzheimer’s disease. Ischemic infarct, es-
pecially the reperfusion phase, is associated with significant
formation and release of arachidonic acid and its metabo-
lites. Within the PG family, the PGs of A and J series
contain a cyclopentenone ring structure that is characterized
by ?,?-unsaturated carbonyl group (1). Evidence indicates
that this reactive unsaturated group is required for many of
the biological actions (1, 2). The cyclopentenone PGs PGA2
and PGJ2are made from dehydration within the cyclopen-
tane ring of PGE2and PGD2, respectively. Note that PGD2
is the major prostanoid in the murine central nervous system
(3, 4). Some of the effects of these eicosanoids have been
described as an increase in blood flow, inhibition of platelet
function, and inhibition of the activation/extravasation of
granulocytes (5). Many of these effects are receptor-
mediated through either stimulation of phospholipase C to
produce inositol 1, 4, 5-trisphosphate (IP3) and diacylglyc-
erol or through modulation of adenylyl cyclase via the gua-
nine nucleotide-binding regulator proteins (G-proteins) (6–
14). In contrast with other PGs, most of the cyclopentenones
interact with other specific cellular targets. These cyclopen-
tenone PG members have been shown to be “cytoprotec-
tive” and have antineoplastic, anti-inflammatory and anti-
viral properties (see review in ref. 1), although the mecha-
nisms of action are still unclear.
In this study we investigated whether some of the bio-
logical actions of these cyclopentenone PGs could be par-
tially mediated through modulation of HO. HO catalyzes
the cleavage of the heme to form iron, carbon monoxide,
and biliverdin/bilirubin. We and others have previously
shown that modulation of HO activity could afford neuro-
protection (see Refs. 15–18 for reviews). There are abun-
dant heme-containing enzymes in mitochondria and endo-
rostaglandins (PGs) were first discovered in the
1930s and it is now known that they have various
intrinsic biological actions. PGs are generated from
This work was supported by a Grant-in-Aid from the American Heart Association, the
Alzheimer’s Association and the American Heath Assistance Foundation.
1To whom requests for reprints should be addressed at Johns Hopkins University,
School of Medicine, Department of Anesthesiology and Critical Care Medicine, 600
N. Wolfe Street, (Blalock 1404A), Baltimore, MD 21217. E-mail: email@example.com
Copyright © 2003 by the Society for Experimental Biology and Medicine
PGJ2INDUCES HO-1 IN NEURONAL CULTURES499
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plasmic reticulum, which presumably undergo turnover dur-
ing oxidative stress; as such, HO would play an important
role in assuring that pro-oxidant heme does not increase to
toxic levels. Furthermore, in cultured neurons, HO could
make biliverdin/bilirubin at sufficient concentrations to act
as antioxidants (19). A specific significant increase of HO
levels is observed after treatment of primary neuronal cul-
tures with PGA2and PGJ2, or their derivatives, while no
induction is detectable with PGE2and PGD2.
This family of compounds offers unique mechanisms of
action and their roles and potential therapeutic applications
in acute and/or chronic neurological conditions are still un-
der investigation. We are proposing that several of the pro-
tective effects of PGA2and PGJ2could be mediated through
beneficial actions of heme degradation and its metabolites.
Materials and Methods
Primary Cultures of Neuronal Cells. Cultures of
cortical neuronal cells were obtained from 17-day-old em-
bryos of timed pregnant mice. Animal care was adminis-
tered according to protocols and guidelines of the Johns
Hopkins University Animal Care Committee. Cultures were
prepared in serum-free conditions. Neurons were plated
onto poly-D-lysine coated 24-well dishes at a density of 1 ×
106cells/well in the B27 supplement HEPES-buffered high
glucose Neurobasal medium, as previously described (19).
Half of the initial medium was removed at day 4 and re-
placed with the prewarmed medium. Cells were maintained
in growth medium at 37°C in a 95% air/5% CO2humidified
atmosphere until the day of experiment. Materials used for
cell cultures were obtained from InvitroGen (Carlsbad, CA).
Unless stated otherwise, all other chemicals were purchased
from Sigma Co. (St. Louis, MO).
Experimental Treatments. After 8 days in culture,
cells were incubated in fresh medium containing PGs ob-
tained from Cayman Chemical (Ann Arbor, MI). Ex-
perimental treatments with PGs, or with vehicle-control,
were conducted in the B27 minus antioxidant supplement
(InvitroGen) HEPES-buffered high-glucose Neurobasal me-
dium. All experiments were conducted under a dim light to
avoid heme pigment photodegradation.
Assessment of Cell Survival. After treatments,
neurons were maintained for an additional period of 23 hr
and their survival was assessed by phase-contrast micros-
copy with Trypan Blue exclusion assay and quantified using
MTT [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoli-
um bromide)] (Sigma) colorimetric assay. MTT is an indi-
cator of the mitochondrial activity of living cells and is
widely used as an index of cell survival (19). After a 2-hr
incubation at 37°C, living cells containing MTT formazan
crystals were solubilized in a solution of anhydrous isopro-
panol, HCl 0.1 N, and 0.1% Triton X100. The optical den-
sity was determined at 570 nm. Experiments were per-
formed in triplicates and repeated with at least three sepa-
rate batches of cultures.
Preparation of Mouse Brain Homogenates. Cor-
tical brain region from mouse brains was dissected on ice,
rinsed with cold PBS (phosphate buffered saline), add 600
?l of lysis buffer [phosphate-buffered saline, containing
protease inhibitor cocktail (Roche Molecular Biochemicals,
Indianapolis, IN) and 0.1 mM phenylmethylsulfonyl fluo-
ride (PMSF; Sigma)]. The mixtures were sonicated for 7 sec
twice, and then centrifuged at 7000g at 4°C for 30 min. The
supernatants collected and centrifuged at 100,000g at 4°C
for 40 min. The supernatant (cytosol-enriched fraction) and
pellet (microsome-enriched fraction) were collected. Micro-
somal fractions were resuspended into 600 ?l of lysis
buffer, and protein concentration was determined and 25 ?g
was loaded onto the gel.
Western Blot Analysis. Neuronal cultures were
solubilized with 250 ?l of lysis buffer (50 mM Tris-HCl, pH
7.4; 150 mM NaCl, 0.5% Triton X-100) including protease
inhibitor cocktail (Roche) on ice for 30 min and then cen-
trifuged for 10 min at 12,000g then collected the superna-
tant. Protein quantification was accomplished using BCA
assay (Pierce, Rockford, IL). Western blots (sodium dodec-
yl sulfate polyacrylamide gel electrophoresis) were per-
formed using 12% gels (Novex, San Diego, CA) and pro-
teins were transferred to nitrocellulose membranes (Novex)
(19). Membranes were blocked for 1h at RT with 5% milk
in PBS with 0.1% Tween 20 before incubation at 4°C over-
night with primary antibodies. Blots were washed and in-
cubated with second antibodies for 1 hr at room temperature
and then developed by ECL (Amersham Biosciences, Pis-
cataway, NJ). Gels were stained with Ponceau S Solution to
verify that equal amounts of proteins were loaded in each
lane. Primary polyclonal antibodies to HO-1 and HO-2 were
obtained from StressGen Inc. (Victoria, BC) and anti-actin
was obtained from Sigma, and used at a dilution of 1:3,500,
1:2,500, and 1:5,000 respectively.
Results and Discussion
Our data demonstrate that the cyclopentenones (Fig. 1),
and especially the ones of the J series can induce HO-1
protein expression in mouse primary cortical cells (Figs. 2
and 3). Our results indicate that the HO-1 induction effect of
dPGJ2was dose dependent. It was observed as low as 0.5
?M with a maximal effect at 20 ?M after a 6-hr incubation
(Fig. 2). Previous studies have shown that induction of
HO-1 could act as an antioxidant system. Moreover, no
significant effect was observed on the HO-2 expression lev-
els, which was also confirmed by similar expression levels
of actin (Fig. 1). We also observed that at these concentra-
tions no toxicity effect would be measured, and this up to 24
hr of treatment (data not shown). It has been previously
reported that a cDNA coding for a transcript, with a pre-
dicted amino acid sequence close to 90% similar to HO-2
and a similar pattern of distribution, could be present in rat
tissues (20). This transcript was referred as HO-3, although
its mRNA expression is present in several tissues, its protein
expression has not been detected. Using different polyclonal
500PGJ2INDUCES HO-1 IN NEURONAL CULTURES
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Figure 1. Diagram of the cyclopenta-
none PG synthesis pathway.
Figure 2. Effect of different concentrations of the cyclopentenone
prostaglandin of the J series, dPGJ2on the expression of HO-1,
HO-2, and actin in mouse primary cortical neuronal cultures. Cells
were treated with different concentrations (0, 0.5, 5, 10, 20, and 50
µM) of dPGJ2for 6 hr before being harvested and analyzed. (A)
Dose-dependent HO-1 protein induction by dPGJ2. (B) No significant
differences in the HO-2 protein levels were found after treatment with
dPGJ2. Using antibodies against actin probed on the same blot. (C)
Similar loading in different lanes.
Figure 3. Effect of different PGs on HO expression in mouse pri-
mary cortical neuronal cultures. Cells were treated with 5 µM of
PGJ2, dPGJ2, PGA2, dPGA2, PGD2, and PGE2for 6 hr before being
harvested and analyzed. (A) HO-1 protein induction by different PGs
and predominantly by PGJ2and dPGJ2. (B) No significant effect of
these PGs on HO-2 protein was revealed. (C) Using antibodies
against actin probed on the same blot, similar loading in different
lanes is indicated.
PGJ2INDUCES HO-1 IN NEURONAL CULTURES501
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antibodies against HO-2 (raised against peptides which
shares approximately 75% homology and against a rat pu-
rified native HO-2), we could not detect the presence of
other cross-reacting proteins in mouse brain tissues obtained
from HO-2−/−mice (Fig. 4). This would suggest that, at least
in mouse, HO3 protein would not be detectable.
PGJ2have been shown to have intrinsic cytoprotective
properties in addition to anti-inflammatory indications. It
has been suggested that they could also reduce ischemic
brain damage (2). It is possible that these protective effects
could be extended to the treatment of impairments and
symptoms in traumatic brain injury, stroke, multi-infarct
dementia, cerebral atherosclerosis, cerebral insufficiency,
cerebral edema, inflammation, as well as Alzheimer’s and
age-associated dementia. It is postulated that the determi-
nants of neuronal cell death in acute and chronic neurode-
generative conditions, such as cerebral ischemia and Alz-
heimer’s disease, may be mediated by free radical damage.
PGJ2does not appear to have significant direct antioxidant
properties, but its protective cellular mechanism is still un-
clear. HO cleaves the heme ring to form biliverdin, which is
rapidly reduced to bilirubin, carbon monoxide, and iron
(Fig. 5). We questioned whether HO activity could play a
role in dPGJ2’s neuroprotective function.
As represented in Figure 5, HO degrades the pro-
oxidant heme. Free heme in the cell can be rapidly gener-
ated from heme-containing proteins/enzymes (such as myo-
globin, catalase, glutathione peroxidase, cytochrome,
soluble guanylate cyclase, superoxide dismutase, nitric ox-
ide synthase, etc.). For example, hypoxia during ischemic
injury may trigger micromolar concentrations of heme to be
released in the intracellular pool. HO, through rapid degra-
dation of pro-oxidant heme, can limit its capacity to enter
into a generation of free radical cycle. HO, by directly me-
tabolizing heme, acts by itself as a potent antioxidant en-
zyme. The observation reported here that PGJ2can increase
HO-1 levels in neuronal cultures is likely to be an important
factor in degradation of the pro-oxidant heme. In addition,
this HO enzymatic reaction generates several catalytic me-
tabolites with intrinsic actions (i.e., iron, carbon monoxide
The degradation of hemin/heme by HO generates iron.
Then, modulation of HO activity could be a limiting factor
in controlling the rate by which iron is being eliminated
from the cells (21). Controlling the iron homeostasis within
the cell is essential. For example, free iron is a key element
in the traditional Fenton reaction, which, by reaction with
H2O2, generates free radicals. The iron cellular homeostasis
is a complex system and is regulated by abundant proteins,
some of which are being identified and characterized. The
strict control of the iron level within a cell is critical, and we
believe that our previous work suggests that HO is an im-
portant enzyme in this regard. The direct increase of HO-1
by dPGJ2is likely to directly affect the intracellular iron
levels. In the opposite scenario, one would expect that a
decrease in HO activity would be sufficient to change the
iron levels within cells. In fact, this is what was revealed by
the use of the HO-1 knockout mice generated by Poss and
Tonegawa, in which they observed accumulation of iron in
several organs (22). PGJ2, and its analogues, could then be
protective by acting indirectly through the modulation of
iron free levels via other iron binding proteins. Numerous
iron-binding proteins have been found and their expression
can modulate the iron intracellular free pool (23). To cite
only one example, ferritin in the cell can sequester free iron,
and its intracellular levels can be very rapidly induced by
free iron (24), which could represent by itself another path-
way by which dPGJ2can be protective. The therapeutic
implications of controlling iron levels are numerous. For
instance, one study revealed that the administration of des-
ferroxiamine, a trivalent ion chelator, over a two-year pe-
riod slowed the clinical progression of symptoms in AD
(25). By demonstrating here that dPGJ2significantly alters
HO-1 levels, it could subsequently protect several cells and
organs against iron-mediated toxicity.
The opening of the heme porphyrin ring by HO gener-
ates biliverdin. We and others have demonstrated that bili-
verdin by itself could be a potent antioxidant (26–28). It is
generally believed that biliverdin is almost immediately
converted into bilirubin by biliverdin reductase (29). More-
over, it has been recently proposed that the production of
bilirubin (BR) is dependent on the autophosphorylation of
biliverdin reductase (30). BR is well known as a toxic agent
in infants because an accumulation of micromolar concen-
trations in the brain tends to aggregate. Yellowing of several
brain regions is a landmark of kinecterus. Similarly, we
have observed in neuronal cultures at high micromolar con-
centrations that BR can aggregate and stick to cellular mem-
branes (28), lending a yellow appearance to the cells. Ag-
gregates of BR incorporated to the cell membrane are likely
to affect the normal cellular functions. However, when BR
is used at physiological levels, it is protective against oxi-
dative stress injury (19, 31–33). Interestingly, BR, by re-
ducing free radicals, would partially be converted into bil-
iverdin (Fig. 5). A reducing loop can then be an effective
way to act as a radical scavenger; in addition, its has been
Figure 4. Detection of immunoreactive HO-2-related protein in wild-
type (WT) and HO-2 gene knockout (HO-2−/−) mouse brain homog-
enates. On this representative Western blot, mouse brain tissues
were processed for microsomal and cytosolic fractions as described
in the Materials and Methods section.
502 PGJ2INDUCES HO-1 IN NEURONAL CULTURES
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suggested that BR metabolites can have intrinsic vasodilat-
ing properties (34).
Carbon monoxide (CO) is a gas that in cells is mostly
generated by the degradation of heme from HO (35, 36). CO
can travel freely throughout intracellular and extracellular
compartments. The literature regarding the role of carbon
monoxide is complex, with many controversies that have
yet to be resolved (18, 37–41). CO is known to be toxic and
the inhalation of high concentrations can cause death. Some
of this toxicity has been attributed to the fact that it saturates
hemoglobin and decreases the ability to transport oxygen.
The affinity of CO to several proteins is generally lower
than nitric oxide, though its longer half-life could be a key
factor in modifying several key enzymes containing a heme
moiety (42). At a cellular level, physiological levels of CO
generated from degradation of intracellular heme are then
likely to have biological actions on several heme-containing
proteins. For example, CO may act as a vasodilator by bind-
ing to soluble guanylate cyclase and modulate its activity
(18, 38). CO can also act by opening calcium-activated
potassium channels (KCachannels; ref. 43). CO has also
been reported to have specific anti-inflammatory and anti-
apoptotic effects (44, 45). Further investigations are neces-
sary to clarify the cellular effect of physiologic concentra-
tions of CO. dPGJ2, by increasing HO activity, would gen-
erate more CO, within physiological levels, allowing cells
and tissues to benefit from many of its biological actions
especially in a scenario where blood flow is reduced and
cell survival is triggered.
Puzzling effects of the PGs have been reported (46),
sometimes good and sometimes bad. We are proposing here
that significant induction of HO-1 in neuronal cultures
would participate in the protective actions of dPGJ2. At this
point, we have not yet identified the specific cascade that
triggers HO-1 upregulation: influence of HO-1 mRNA lev-
els, longer mRNA half-life or longer HO-1 half-life (47).
An increase of HO activity in cells provides a way to de-
grade free heme generated from heme-containing proteins,
and generation of the different metabolites (i.e., iron, bili-
verdin/bilirubin, carbon monoxide). These are likely to ef-
fect cell survival and may contribute to the beneficial effects
of dPGJ2in therapeutic situations. Design of new mimetics
based on the cyclopentenone structure could be very useful
as neuroprotective agents (48). Further studies will be nec-
essary to determine whether the cyclopentenone PGs or ana-
logues can be of use as preventive agents against acute
neurodegenerative conditions, especially in limiting damage
following a stroke, or reducing the progression of diseases
with chronic neurodegeneration like Alzheimer’s disease
and possibly even retarding signs of “normal” aging.
The authors wish to thank James M. Carlisle for his assistance.
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