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Synthesis of prostaglandins

The prostaglandins are made up of unsaturatedfatty acidsthat contain a cyclopentane (5-carbon) ring and are

derived from the 20-carbon, straight-chain, polyunsaturatedfatty acidprecursorarachidonic acid.

Arachidonic acid is a key component ofphospholipids, which are themselves integral components ofcell

membranes. In response to many different stimuli, including various hormonal, chemical, or physical agents, a chain

of events is set in motion that results in prostaglandin formation and release. These stimuli, either directly or

indirectly, result in the activation of an enzyme called phospholipase A2.

Arachidonic Acid

Daniele Piomelli

Professor of Pharmacology; 360 Med Surge II; University of California, Irvine; Irvine, CA 92697-4625.

A TALE OF TWO ROLES

When a neurotransmitter binds to its receptor on the membrane of a target neuron, it triggers the formation of

second messengers, responsible for translating receptor occupation into cellular responses. For example, thebinding of dopamine to D1-type receptors stimulates the activity of adenylyl cyclase, which catalyzes the

conversion of ATP into cyclic AMP. This second messenger, in turn, binds to and activates a specific protein

kinase, protein kinase A, which puts inorganic phosphate on select intracellular proteins. Phosphorylationmodifies the biological activity of these proteins and constitutes the basis for many physiological effects of

dopamine in the central nervous system (CNS) (seeCholinergic TransductionandSignal Transduction

Pathways for Catecholamine Receptors).

This model of transmembrane signaling assumes that the range of action of a second messenger is confined to

the intracellular environment. In agreement with this view, most "classical" signaling systemscyclic AMP,cyclic GMP, Ca2+, inositol trisphosphate, and diacylglycerolproduce their effects by binding to protein

receptors located within the cell, whether they be protein kinases, protein phosphatases, Ca2+-binding proteins,

or ion channels. Such a model is not likely to account, however, for all known transduction pathways. Examplesof more complex scenarios include the arachidonic acid cascade, examined in the present chapter, and nitric

oxide, outlined inNitric Oxide and Related Substance as Neural Messengers).

A schematic picture of the ways in which arachidonic acid and its metabolites may act in regulating neuronal

activity is shown inFig. 1. Arachidonic acid is released from phospholipids in cells stimulated by many firstmessengers, including neurotransmitters, neuromodulators, and neurohormones. The free fatty acid has, as such,a short lifespan, during which it may interact with and affect the activity of ion channels and protein kinases

within the cell. Alternatively, it may be transformed to a family of metabolitesthe eicosanoidswhich may

also produce important effects on intracellular targets. In both cases, the arachidonic acid cascade affectsneuronal excitability by fulfilling the primary criteria defining a second messenger systemthat is, receptor-

dependent formation and intracellular site of action.

Where the eicosanoids differ from "classical" second messengers is in their ability to cross the cell membrane,

diffuse through the extracellular space, and interact with high-affinity receptors located on neighboring neurons

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(Fig. 1

). Eicosanoid receptors have been characterized in the brain and have been shown to be linked to second

messengers, such as cyclic AMP, very much like the receptors recognized by dopamine, noradrenaline, and soon. Therefore, thanks to the ability to branch at the same time within and without a cell, the arachidonic acid

cascade may give rise both to intracellular second messengers and to local mediators, bridging the gap between

transmembrane and transcellular communication. This two-pronged role may be important in integrating the

responses of postsynaptic neurons with the activity of presynaptic terminals and of other contacting cells.

AN OVERVIEW OF THE ARACHIDONIC ACID CASCADE

In resting cells, arachidonic acid is stored within the cell membrane, esterified to glycerol in phospholipids (Fig.

2). A receptor-dependent event, requiring a transducing G protein, initiates phospholipid hydrolysis and releases

the fatty acid into the intracellular medium. Three enzymes may mediate this deacylation reaction:

phospholipase A2 (PLA2), phospholipase C (PLC), and phospholipase D (PLD), whose different sites of attackon the phospholipid backbone are shown inFig. 2(inset). PLA2 catalyzes the hydrolysis of phospholipids at the

sn (stereospecific numbering)-2 position. Therefore, this enzyme can release arachidonate in a single-step

reaction. By contrast, PLC and PLD do not release free arachidonic acid directly. Rather, they generate lipidproducts containing arachidonate (diacylglycerol and phosphatidic acid, respectively), which can be released

subsequently by diacylglycerol- and monoacylglycerol-lipases (Fig. 2).

Once released, free arachidonate has three possible fates: reincorporation into phospholipids, diffusion outsidethe cell, and metabolism. Metabolism is carried out by three distinct enzyme pathways expressed in neural cells:

cyclooxygenase, lipoxygenases, and cytochrome P450. Several products of these pathways act within neuronsto modulate the activities of ion channels, protein kinases, ion pumps, and neurotransmitter uptake systems. The

newly formed eicosanoids may also exit the cell of origin and act at a distance, by binding to G-protein-coupled

receptors present on nearby neurons or glial cells. Finally, the actions of the eicosanoids may be terminated bydiffusion, uptake into phospholipids, or enzymatic degradation.

HOW IS ARACHIDONIC ACID PROVIDED TO NEURONS?

Neurons can take up preformed arachidonic acid, but they cannot synthesize it ex novo, as other cells do, by

elongation and desaturation of dietary linoleic acid. Yet, neuronal lipids are highly enriched in arachidonate,raising the question as to how does the fatty acid get there. The liver is a major source, via the circulation, buttwo types of cells in the CNS appear also to play an important role: cerebral endothelium and astrocytes. These

cells accumulate circulating linoleate, use it to synthesize arachidonic acid, and secrete the latter into the

interstitial medium, making it available to neurons (45, 46).

FREE ARACHIDONIC ACID IS RAPIDLY STORED IN NEURONAL PHOSPHOLIPIDS

Neurons take up free arachidonic acid and store it rapidly by esterifying it to membrane phospholipids (10, 26).As a result, only trace levels of free arachidonate may be found in resting cells. Such tight control, justified both

by the signaling role of this lipid and by its potential toxicity, is exerted by two concerted enzymatic activities,

arachidonoyl-coenzyme A (CoA) synthetase and arachidonoyl-CoA:lysophospholipid transferase (note that alysophospholipid lacks one of the two phospholipid acyl chains).

Arachidonoyl-CoA synthetase catalyzes the ATP- and Mg2+-dependent formation of arachidonoyl-CoA, using

fatty acid and reduced CoA as substrates (35, 48, 83, 88). Next, the activated fatty acid is incorporated into

lysophospholipid by arachidonoyl-CoA:lysophospholipid transferase (11!popup(ch59ref11)). After

ultracentrifugation of brain extracts, both enzymes are found in the particulate fraction, and indirect evidencesuggests that they may be organized in a multienzyme complex on the intracellular aspect of the neuronal

membrane (77).

ARACHIDONIC ACID IS RELEASED FROM PHOSPHOLIPIDS BY RECEPTOR

STIMULATION

Several neuromodulators stimulate the deacylation of phospholipids, causing release of free arachidonate. Theseinclude excitatory amino acids (such as glutamate), biogenic amines (such as serotonin and histamine), and

peptides (such as bradykinin) (1, 14, 17, 30, 36, 57, 58, 59, 60). Even though the final effect of these various

substances on arachidonate turnover is similar, they may use different mechanisms to achieve it. As we haveseen above, at least three distinct phospholipases are thought to generate free arachidonic acid, either directly or

indirectly: PLA2, PLC, and PLD. Recent studies have shown that all of them may be activated by

neurotransmitters.

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Julius Axelrod and his colleagues at the National Institutes of Health have used primary cultures of

hippocampal neurons to study the effect of serotonin on arachidonic acid release (17). They labeled neuronalphospholipids by prolonged incubation with [3H]arachidonic acid, and then exposed the neurons to serotonin or

to drugs acting at select serotonin (5-HT) receptors. They discovered that stimulating the 5-HT2 receptor, a

subtype known to be linked to transducing G proteins, resulted in the accumulation of unesterified radioactive

fatty acid. Which phospholipase activity mediated this effect? To answer this question, Axelrod and hiscolleagues examined the ability of serotonin to stimulate the formation of lysophosphatidylcholine, which (as

shown inFig. 2) is produced selectively by PLA2 activity, but not by PLC or PLD. Using a radiolabeled

precursor, they found that the quantity of radioactive lysophospholipid in the membrane was increased byserotonin, strongly arguing for a participation of PLA2 in the response (17). These results, and those obtained in

several other laboratories using different experimental preparations (30, 64), support the idea that PLA2 may

play a widespread role in receptor-dependent release of arachidonic acid. Despite these progresses, important

information on the mechanism of activation of PLA2 in neurons is still lacking. For example, most researchersbelieve that a G protein ensures the coupling of receptors with PLA2. This convinction is based on the ability of

pertussis toxin (aBordetella toxin which inactivates two families of G proteins, Gi and Go) to prevent receptor-

stimulated arachidonate release, as well as on the ability of nonhydrolyzable GTP analogues to evoke it (7). Theprecise identity of the G protein(s) involved remains, however, unknown, because the existing pharmacological

tools do not allow us to discriminate among the various members of the Gi and Go families. Likewise, recent

findings indicate that multiple PLA2s may be expressed in neurons and in other cells (8, 12, 82, 92). Do these

different isoforms couple selectively to different receptors? Or rather, do they serve distinct functions? And ifso, which functions? Answering these questions will require the development of new classes of

PLA2 inhibitors, more specific and more potent than those available at present. We have seen above thatin

addition to PLA2arachidonic acid release may also proceed from the sequential activation of PLC,

diacylglycerol-lipase and monoacylglycerol-lipase. The reactions carried out by these enzymes, which werediscovered in the laboratory of Philip Majerus (5), are shown inFig. 2: PLC cleaves the polar heads of

phospholipids, thereby forming diacylglycerol, which is then hydrolyzed to glycerol and free fatty acids by

diacylglycerol-and monoacylglycerol-lipases (16). Recently, Pierre Morell and colleagues, at the University ofNorth Carolina, were able to show that, in primary cultures of sensory neurons, bradykinin may evoke

arachidonic acid release by activating selectively this enzyme pathway. Neurons obtained from the spinal cord

of embryonic rats were labeled by incubation with various radioactive lipid precursors and were exposed to

bradykinin. Application of the neuroactive peptide raised the levels of unesterified arachidonate, but had noeffect on lysophospholipids, arguing against an involvement of PLA2. By contrast, appearance of the free fatty

acid was preceded by a transient increase in diacylglycerol content, likely caused by PLC activation, which took

place within a few seconds of exposure to bradykinin. In addition, arachidonate release could be prevented byan inhibitor of diacylglycerol lipase, the compound RG 80267 (1).

In contrast with PLA2 and PLC, participation of PLD in receptor-dependent arachidonic acid release has not

been demonstrated yet. However, one of the products of its activity, phosphatidic acid (the other is a

phospholipid head-group, such as choline or inositol), is dephosphorylated to diacylglycerol, which, as we have

seen, enters the diacylglycerol-lipase pathway yielding free arachidonate (Fig. 2) (15). In addition, the ability ofsome neurotransmitters to stimulate PLD activity adds further support to the possibility that this lipase may

participate in receptor-mediated arachidonate release (15).

SOME NEUROTRANSMITTER RECEPTORS INHIBIT ARACHIDONIC ACID RELEASE

Nonhydrolyzable GTP analogues, such as GTP--S, have been very useful to determine the role of G proteins intransmembrane transduction. As a rule, their ability to produce a certain response is taken as good evidence for

the presence of a G-protein-mediated coupling mechanism. By using GTP analogues, Carol Jelsema and Julius

Axelrod have provided the first evidence of an inhibitory control by G proteins over the activity of PLA2.While studying signaling events in retinal photoreceptors, they observed that flashing light on dark-adapted rod

outer segments (ROS) enhanced PLA2 activity. However, when the ROS were exposed to light after incubation

with GTP--S, this increase was significantly smaller. They concluded that an unidentified G protein, which

could be activated by the GTP analogue, exerted an inhibitory action on the activity of retinal PLA2when thisenzyme was stimulated by light (27, 28).

Do neurotransmitter receptors link to inhibition of arachidonate release? Experiments carried out on aheterologous expression system, in the laboratory of Jean-Charles Schwartz in Paris, suggest this possibility

(78). Chinese hamster ovary (CHO) cells were transfected with a plasmid vector directing expression of

histamine H2-type receptor, which is known to be positively coupled to adenylyl cyclase via a Gs protein. CHO

cells were no exception to this rule, and the transfected receptor was found to be very effective in evokingcyclic AMP formation when stimulated with an H2 agonist. Unexpectedly, in addition to this response, H2-

receptor occupation was also found to reduce the release of arachidonic acid evoked by raising intracellular

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Ca2+ levels (a stimulus for PLA2). The mechanism underlying this effect has been only partially uncovered, but

the evidence collected allows us to draw a few conclusions. First, inhibition of arachidonate release wasindependent of the rises in cAMP produced by stimulating the H2 receptor, because membrane-permeant cAMP

analogues did not mimic the response. Second, inhibition was not secondary to a reduction in Ca2+ entry,

because H2-receptor stimulation had no effect on either basal or stimulated Ca2+ levels. The results, therefore,

support the possibility that transfected H2 receptors in CHO cells are directly coupled to inhibition ofPLA2 activity (78). It remains to be determined whether a similar response occurs in neurons or in other cells

expressing this receptor constitutively.

A THIRD GROUP OF RECEPTORS FACILITATES ARACHIDONIC ACID RELEASE, BUT

DOES NOT STIMULATE IT DIRECTLY

Several structurally different neurotransmitter receptorsincluding D2-dopaminergic and 2-adrenergicshare the ability to reduce adenylyl cyclase activity and to lower cAMP levels in cells, through the intermediate

of an "inhibitory" G protein (Gi). When transfected in CHO cells, receptors of this group produce, in addition,

what appears to be a "silent" facilitation of arachidonic acid release. Namely, receptor activation has no effect,per se, on arachidonate release, but, if release is triggered by a second agentfor example, by stimulation of a

different receptor or by a Ca2+ ionophoreit will greatly potentiate it (18, 63). This novel form of regulation

involves, like adenylyl cyclase inhibition, a Gi protein, as shown by the ability of pertussis toxin to inhibit the

response, and of GTP--S to mimic it (63).

ARACHIDONIC ACID METABOLISM IN THE BRAIN

The three pathways of arachidonic acid metabolism discovered in most animal tissueslipoxygenases,cyclooxygenase, and cytochrome P450have been also described in brain (Fig. 3).

LIPOXYGENASES

Lipoxygenases are a family of enzymes which catalyze the oxygenation of arachidonic acid, each lipoxygenase

forming a distinct hydroperoxy-eicosatetraenoic acid (HPETE) (90). HPETEs may undergo a series of

metabolic transformationswhat is referred to as a lipoxygenase pathway. Here, we will focus our attention onthe two lipoxygenases whose presence in the CNS has been best characterized: 12- and 5-lipoxygenase (Fig. 3).

12-Lipoxygenase converts arachidonic acid into 12(S)-HPETE (containing a -OOH group on the chiral carbon

12), which may be further metabolized into four distinct products: an alcohol [12( S)-hydroxy-eicosatetraenoic

acid, 12(S)-HETE], a ketone (12-keto-eicosatetraenoic acid, 12-KETE), or two epoxy alcohols (hepoxilinA3 and B3) (54, 55, 60, 61).

The sequence of reactions initiated by 5-lipoxygenase is more complex. To become active, 5-lipoxygenase

requires three cofactors: Ca2+, ATP, and an integral membrane protein calledfive lipoxygenase-activating

protein (FLAP). Inactive 5-lipoxygenase binds Ca2+ and ATP and translocates onto the membrane, where itanchors to FLAP. Membrane translocation activates 5-lipoxygenase, which carries out two sequential reactions:

First, it converts arachidonic acid into 5(S)-HPETE; second, it dehydrates 5(S)-HPETE to yield the epoxide,leukotriene A4 (LTA4). The newly formed leukotriene leaves the active site of 5-lipoxygenase but, being itself

quite short-lived, is rapidly metabolized to form, by hydrolysis, LTB4 (via an LTA4-hydrolase) or, by additionof glutathione, LTC4 (via a glutathione-S-transferase) (68).

Brain 12-lipoxygenase was purified, and a complementary DNA encoding it was cloned (51, 86).

Immunohistochemical studies revealed the occurrence of this enzyme in neurons (particularly in hippocampus,

striatum, and olivary nucleus), as well as in glial and in cerebral endothelial cells (50). In agreement with thesefindings, 12-lipoxygenase metabolites are among the most abundant eicosanoids produced by nervous tissue, as

first shown by Lidia Sautebin and co-workers, at the University of Milan (69).

5-Lipoxygenase activity in the CNS was demonstrated by Samuelsson and his colleagues at the KarolinskaInstitut in Stockholm and was confirmed by further studies (32, 39, 68, 75)). Even though several of theproducts formed have been identified (notably, LTC4 and LTB4), little is known on the distribution in the CNS

of 5-lipoxygenase, FLAP, and glutathione-S-transferase. The laboratory of Takao Shimizu in Tokyo has shown

that LTA4-hydrolase is expressed in virtually all regions of the brain, suggesting thatin addition to convertingLTA4 into LTB4this enzyme may serve more general functions, possibly unrelated to arachidonic acid

metabolism (75).

CYCLOOXYGENASE

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Cyclooxygenase (prostaglandin G/H synthase) catalyzes the stepwise conversion of arachidonic acid into two

short-lived intermediates, prostaglandin G (PGG) and prostaglandin (PGH). The latter is metabolized to PGs,prostacyclin (PGI2), and thromboxane A2 (TXA2) by the activity of specific enzymes: prostaglandin

isomerases for the various PGs, prostacyclin synthase for PGI2, and thromboxane synthase for TXA2 (Fig. 3).

Since the pioneering work of Bengt Samuelsson (at the Karolinska Institut) and Leonard Wolfe (at the Hospital

for Sick Children in Toronto), three most prominent cyclooxygenase products have been identified in nervous

tissue (PGF2, PGD2, and PGE2), and the enzymes involved in their biosynthesis have been purified and

characterized (22, 31, 52, 79, 89). Immunohistochemical studies, carried out primarily by Osamu Hayaishi andhis colleagues (80) have established the presence of these enzymes in both neurons and glia. These studies have

been supported by experiments demonstrating that primary cultures enriched in either neurons or glial cellshave the ability to synthesize prostaglandins (72, 81)).

CYTOCHROME P450

Cytochrome P450, the microsomal enzyme complex participating in drug metabolism, may also act on

endogenous arachidonic acid, catalyzing its conversion into epoxy-eicosatrienoic acids (EETs). The epoxidering of these EETs may be cleaved by the action of epoxide hydrolases, to yield the corresponding vicinal diols.

In addition, cytochrome P450 has been shown to produce a family of HETEs by hydroxylation

(monooxygenation) of arachidonic acid (Fig. 3

) (41).

Even though mammalian brain tissue contains very low levels of cytochrome P450, several isoforms of this

enzyme were detected in both neural and glial cells by immunohistochemistry, and biosynthesis of arachidonatemetabolites via the cytochrome P450 pathway has been reported (2, 29, 84).

ANANDAMIDE, AN ENDOGENOUS CANNABINOID SUBSTANCE

A novel arachidonic acid derivative was recently isolated from brain and was identified as the ethanolamide of

arachidonic acid (Fig. 4

). This compound was shown to (a) inhibit the specific binding of a radiolabeled agonist

to the cannabinoid receptor and (b) produce inhibition of the twitch response in mouse vas deferens, a typical

response to cannabinoids. These properties have led to the suggestion that arachidonoylethanolamide (dubbed"anandamide" after the sanskrit word for bliss, "ananda") may act as the endogenous ligand for brain

cannabinoid receptors (13). The pathways leading to the biosynthesis and the degradation of anandamide in theCNS are not known.

IN SEARCH OF A FUNCTION

The arachidonic acid cascade is arguably the most elaborate signaling system neurobiologists have to deal with.

Not only can it generate multiple messenger molecules (at least 16, according to a conservative estimate limited

to the brain), but these molecules may act both within and without the neuron, bringing into play intracellular aswell as extracellular targets. To help find our way in this complex network, it may be helpful, rather than listing

all known neuronal actions of the eicosanoids, to discuss in greater depth a few examples representative of theroles of these lipids as either intracellular second messengers or transcellular mediators.

INTRACELLULAR SECOND MESSENGERS OF PRESYNAPTIC INHIBITION?

The potential role of arachidonic acid in mediating K+ channel modulation and presynaptic inhibition ofneurotransmitter releaseour first example of a second messenger role for the eicosanoidswas first suggested

by experiments carried out in the laboratory of James Schwartz at Columbia University, using the simple

nervous system of the marine mollusk,Aplysia californica. Aplysia has large, easily identifiable and well-characterized neurons, which can be dissected out individually and maintained in culture for several days. When

these neurons were stimulated with the neurotransmitter, histamine, they released both 12- and 5-lipoxygenase

products (58). Histamine is known to exert inhibitory actions on identifiedAplysia neurons, causing membranehyperpolarization and reducing neurotransmitter release at specific synapses. This clue led to the idea thatarachidonic acid metabolites may be involved in inhibitory responses, and it prompted the study of a

neurotransmitter with better-defined electrophysiological effects. FMRF-amide, a neuroactive tetrapeptide,

hyperpolarizesAplysiasensory neurons and inhibits neurotransmitter release at sensorymotor synapses, by

increasing the activity of a subclass of K+ channels termed S-K+ channels. To determine whether arachidonicacid metabolites participate in the effects of FMRF-amide, a series of biochemical, pharmacological, and

electrophysiological experiments were carried out. First, application of FMRF-amide to sensory cells resulted in

the formation of 12- and 5-lipoxygenase metabolites. Next, drugs that inhibit PLA2 and lipoxygenase activities

prevented the electrophysiological actions of FMRF-amide on sensory neurons, whereas cyclooxygenase

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inhibitors had no effect. Finally, applications of arachidonic acid or 12-HPETE mimicked the effects of FMRF-

amide on both S-K+ channels and transmitter release. By contrast, 12-HETE, 5-HPETE and 5-HETE had noeffect (59).

In subsequent studies, it was shown that the actions of 12-HPETE on S-K+ channel activity required

metabolism of the hydroperoxyacid via an enzymatic activity sensitive to cytochrome P450 inhibitors (4). The

results support the possibility that a 12-lipoxygenase metabolite, possibly a hepoxilin, acts as a secondmessenger in mediating the effects of FMRF-amide on K+ channels and neurotransmitter release (Fig. 5

).

FMRF-amide is a modulatory neurotransmitter, and its effects on K+ channels occur within seconds of its

application and last as long as the application lasts. Repeated administrations of FMRF-amide may result,

however, in long-term changes in neuronal excitability. Samuel Schacher and his colleagues at Columbia

University found that prolonged exposure ofAplysia sensory neurons to FMRF-amide (2 hr), produced adepression in synaptic transmission that lasted for several days and was accompanied by a significant reduction

in the number of varicosities on sensory neuron dendrites. As with the short-term modulation discussed above,

this form of long-term depression may be mediated by arachidonic acid. In agreement, the number ofvaricosities was significantly reduced 24 hr after a 2-hr application of arachidonic acid to sensory neurons. This

effect is likely to involve gene expression and protein synthesis, because it could be prevented by protein

synthesis inhibitors (43, 44).

Actions of the eicosanoids similar to those described inAplysia have also been found in mammalian brain. For

example, 12-lipoxygenase products were shown to inhibit glutamate release from hippocampal mossy fibernerve endings (19), whereas 5-lipoxygenase metabolites were found to increase the activity of muscarine-

inactivated M-K+ channels in rat hippocampal CA1 neurons (71). K+ channel modulation by lipoxygenase

products has also been reported in a number of non-neural cells, including heart myocytes (33, 34).

Phosphorylation of specific proteins in the presynaptic nerve terminal may participate, together with ionchannel modulation, in regulating neurotransmitter release. The state of phosphorylation of the synaptic-vesicle-

associated protein, synapsin I, is thought to regulate the availability of synaptic vesicles for exocytosis. In its

dephosphorylated state, synapsin I may cross-link synaptic vesicles to the surrounding cytoskeletal lattice.

According to this model, when synapsin I is phosphorylated on its "tail"-region by Ca2+/calmodulin-dependentprotein kinase II, its interaction both with synaptic vesicles and with cytoskeletal elements is reduced, resulting

in dissociation of the vesicles from the cytoskeleton. This would, in turn, increase the number of vesicles

available for exocytosis. Therefore, reducing the state of phosphorylation of synapsin I may be a way to reducesynaptic strength independent of, and possibly parallel to, ion channel modulation (see Electrophysiology

).

Arachidonic acid and its metabolites may regulate neurotransmitter release partly through such a

phosphorylation-dependent mechanism. In agreement, experiments carried out in Paul Greengard's laboratory at

the Rockefeller University showed that lipoxygenase-derived eicosanoids are potent and selective inhibitors ofpurified Ca2+/calmodulin-dependent protein kinase II. 12-HPETE inhibited activity of this protein kinase with a

half-maximal effect at a concentration of 0.7 M. By contrast, the eicosanoid has no effect on the activities of

protein kinase C, cAMP-dependent protein kinase, Ca2+/calmodulin-dependent protein kinase I and III, or theCa2+/ calmodulin-activated phosphatase, calcineurin (62).

The effects of the eicosanoids on K+ channels and on Ca2+/calmodulin-dependent protein kinase II may be

integrated in a model, shown inFig. 5, for the role played by these lipids in presynaptic inhibition. Free

arachidonic acid, produced as a result of receptor activation, is metabolized by 12-lipoxygenase to form 12-HPETE. The hydroperoxyacid may, on the one hand, modulate the activity of K+ channels and, on the other,

inhibit Ca2+/calmodulin-dependent protein kinase II, reducing Ca2+-evoked protein phosphorylation. These

two parallel effects might be synergistic in decreasing synaptic strength.

ARACHIDONIC ACID, A SECOND MESSENGER ACTIVATOR OF PROTEIN KINASE C?

In addition to these actions mediated by the eicosanoids, arachidonic acid and other fatty acids may regulate

neuronal excitability directly, by mechanisms that do not involve metabolism or intervention of other secondmessenger pathways. For example, fatty acids may modify the activity of a variety of ion channels, possibly by

interacting with hydrophobic binding sites within the channel protein (like local anesthetic or antiarrhythmic

drugs). The interested reader is referred to a recent review on this topic (53). In this section, I will examineinstead an additional potential role of unsaturated fatty acidsthat of second messengers in the receptor-

dependent stimulation of protein kinase C (PKC) activity.

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PKC, which was originally described as a Ca2+- and phospholipid-dependent protein kinase activated by

diacylglycerol, is now recognized to consist of a family of at several related isoenzymes with differentproperties and distribution in the brain. Nishizuka and his colleagues (47, 73) have recently shown that low

concentrations of unsaturated fatty acids (110 M), which are likely to be attained in stimulated cells, activatewith high selectivity a single PKC isoform, type I, in the absence of Ca2+ and phospholipid.

What is the physiological significance of this stimulation, and how does it relate to the well-characterizedability of diacylglycerol to activate PKC? To address these questions, David Linden and collaborators (in John

Connor's laboratory at the Roche Institute) have carried out a series of electrophysiological experiments onprimary cultures of rat cerebellar neurons (38). In rat cerebellum, type I and type II PKC are segregated: Type I

is expressed in Purkinje cells, whereas type II is expressed in granule cells. The application of phorbol esters,which causes a nonselective stimulation of all PKC isoforms, reduced voltage-gated K+ currents equally in both

neurons. By contrast, the administration of unsaturated fatty acids affected K+ currents selectively in Purkinje

cells, not in granule cells. The findings suggest that, in neurons expressing type I PKC, activation of this proteinkinase isoform may result from the receptor-dependent stimulation of PLA2 activity and from the generation of

free arachidonic acid (as well as other fatty acids) (38).

TRANS-SYNAPTIC ACTIONS OF THE EICOSANOIDS

The examples discussed thus far illustrate one possible role played by the eicosanoidsthat of intracellularsecond messengers. We will examine now the alter ego of the arachidonic acid cascade: its ability to act as atranscellular (or trans-synaptic) signaling system.

Diffusible signals may exert important neurophysiological functions. Neurons in the CNS are organized as

interconnected groups of functionally related cells (e.g., in sensory systems). A diffusible factor released from a

neuron into the interstitial fluid, and able to interact with membrane receptors on adjacent cells, would be

ideally used to "synchronize" the activity of an ensemble of interconnected neural cells. Furthermore, duringdevelopment and in certain forms of learning, postsynaptic cells may secrete regulatory factors which diffuse

back to the presynaptic component, determining its survival as an active terminal, the amplitude of its sprouting,

and its efficacy in secreting neurotransmittersa phenomenon known as retrograde regulation. The

participation of arachidonic acid metabolites in retrograde signaling and in other forms of local modulation ofneuronal activity has been proposed.

RETROGRADE MESSENGERS OF LONG-TERM POTENTIATION?

Long-term potentiation of synaptic transmission (LTP) is a mammalian model of synaptic plasticity and

information storage. LTP is believed to consist of two phases: induction and maintenance. Induction is initiatedby the postsynaptic entry of Ca2+, which occurs through glutamateN-methyl-D-aspartate (NMDA)-type

receptor channels. Maintenance appears to be produced at least partly by presynaptic mechanisms. To bridge

postsynaptic induction with presynaptic maintenance, the existence of a diffusible retrograde messenger wasproposed (6).

Arachidonic acid was suggested as a potential candidate for this role (59). In agreement, stimulation of

glutamate receptors evokes arachidonic acid release from a variety of neural cell preparations (14, 36). In

addition, nonselective PLA2 inhibitors (such asp-bromophenacylbromide) prevent induction of LTP, while

application of arachidonic acid (or other unsaturated fatty acids) to hippocampal slices causes a slow-onsetenhancement of synaptic transmission that resembles LTP (37, 87). The mechanism of action of arachidonic

acid in enhancing neurotransmission remains to be established, and several potential targets have been

proposed. The fatty acid may increase glutamate release from hippocampal nerve terminals, block glutamateuptake, or potentiate NMDA receptor current (41, 93). Alternatively, it may act by enabling presynaptic

glutamate receptors to produce enhanced glutamate release (25).

RETROGRADE MESSENGERS AT THE DEVELOPING SYNAPSE?

Orna Harish and Mu-Ming Poo at Columbia University have provided evidence suggesting that a 5-

lipoxygenase metabolite of arachidonic acid may act as a retrograde messenger at the developing neuromuscularsynapse (21) (Fig. 6). Using primary cultures of innervated muscle cells fromXenopus, they found that

injections of GTP--S into the myocyte caused an increase in the frequency of spontaneous synaptic currents

(SSCs), an indication that acetylcholine release from presynaptic terminals was enhanced. They concluded that

a G-protein-driven signal was released from the muscle cell, crossed the synaptic cleft, and acted on the

presynaptic neuron to modulate transmitter secretion. To determine the nature of this diffusible signal, theyinjected drugs that activate cAMP-dependent protein kinase or PKC, but found no effect. However, when they

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loaded arachidonic acid into the myocyte, a significant increase in SSC frequency occurred, an effect which

could be prevented by the selective 5-lipoxygenase inhibitor, AA861. In agreement with an involvement of 5-lipoxygenase-mediated metabolism, the postsynaptic application of 5-HPETE, but not of 12-HPETE, resulted in

an increase in the spontaneous synaptic events (21).

PROSTAGLANDINS AND LEUKOTRIENES AS NEUROMODULATORS

After the discovery of the PGs in the CNS, much attention has been given to the roles these eicosanoids may

play in modulating neurotransmission, by interacting with presynaptic or with postsynaptic PG receptors. Theexistence of such receptors is well-demonstrated, and, in the brain, high-affinity binding sites have been

described for both PGE2 and PGD2 (65, 66, 74, 85, 91). Peripheral PGE2 receptors are subdivided into three

subtypesEP1, EP2 and EP3characterized by distinct pharmacological properties and intracellular signaling

systems (9). EP1 receptors are coupled to phosphoinositide-specific PLC activity, while EP2 and EP3 receptorsstimulate and inhibit, respectively, adenylyl cyclase activity. Recently, a cDNA encoding an EP3-type

PGE2 receptor was isolated and characterized, and expression of its mRNA in brain tissue was demonstrated by

Northern blot. Sequence analysis of EP3-type receptor cDNA revealed the presence in this molecule of sevenputative transmembrane domains, characteristic of G-protein-coupled receptors (76).

Presynaptic PG receptors have been often, but not always, linked to inhibition of neurotransmitter release. For

example, PGE2 (as well as its analogue, PGE1) inhibits noradrenaline release in a variety of nervous tissuepreparations (20, 23, 24, 67). This inhibitory role is by no means universal, however. For example, in dorsal

root ganglion neurons in culture, PGE2 was shown to increase Ca2+ conductance and to stimulate release ofsubstance P (49). Such an effect may be related to the sensitizing and hyperalgesic properties of this PG, and it

might mediate the hyperalgesia produced, in the spinal cord, by the stimulation of glutamate and substance P

receptors (40).

The receptor-dependent effects produced by lipoxygenase products in brain have been poorly characterized thusfar, even though the existence of a high-affinity binding site for the leukotriene, LTC4, was reported (70). Both

LTC4 and LTB4 were shown to evoke the rapid release of luteinizing hormone (LH), when applied at

picomolar concentrations in primary cultures of anterior pituitary cells (32). Because gonadotropin-releasing

hormone was shown to stimulate leukotriene biosynthesis, it is possible that the leukotrienes play a role in LHsecretion.

Cerebellar Purkinje neurons display a remarkable response to the iontophoretic administration of LTC4. The

leukotriene was found to cause a slowly developing increase in the firing rate of these cells, which could last for

up to 1.5 hr after application. The lack of effect of LTB4, along with the ability of a leukotriene-receptorantagonist, the compound FPL 55712, to prevent this response, indicates the selective participation of

LTC4receptors (56). The physiological significance of this intriguing response remains unknown.

published 2000

Introduction

The basic function of thecervixduring pregnancy is to retain the foetus within the uterus and to

maintain the internal environment of the uterus by preventing the external environment accessing the

uterus. Therefore the cervix regulates the passage to and from the uterine cavity. This ensures that

any micro-organisms within the external environment are unable to enter the uterus. During

pregnancy theuterine bodybecomes distended whilst stretch resistant tissues allow the cervix to be

maintained in a closed state. For the foetus to move out of the uterus, the cervix must soften or

'ripen'.

Cervix Structure

The cervix has only a small amount of musculature and is mainly composed of collagen fibrebundles and proteoglycan matrices. The collagen fibres are helical strands of amino acids bound

together to form fibrils whilst the proteoglycan matrix are made up of a protein core

with glycosaminoglycan branches orGAGs. GAGs determine the degree of collagen fibre

aggregation. An increased GAG content reduces collagen aggregation and vice versa.

The texture of the cervical tissues is influenced by the relative levels

ofoestrogenandprogesteroneand therefore are changable dependant on the stage of theoestrous

cycle. The mucous membrane of the cervix is highly folded and contains mucin producing cells.

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Mucin production increases under the influence of oestradiol and helps to lubricate the vagina in

preparation for copulation. Mucin is also responsible for the transport of bacteria and foreign bodies

away from the uterus. During theluteal phaseand during pregnancy small levels of mucin are

produced under the influence of progesterone to help form a 'cervical plug'. This plug ensures that the

external environment is unable to penetrate the uterus.

Cervical Species Differences

Inruminantsthe cervical mucus is expelled from the vagina during oestrous and is known as 'bulling

string'. Bulling string therefore indicates that animal is in oestrous and should be mated. For furtherdifferences between species please see;mares,ewe,goat,sow,bitchand thequeen.

Cervical Softening

A number of variables during pregnancy lead to the initiation of contractions of

themyometriumincluding oxytocin,prostaglandinsand neural inputs from theautonomic nervous

system. These contractions of the myometrium lead to an increased pressure within the amniotic fluid

and trigger a series of events that lead to the cervix becoming flexible and gradually beginning to

dilate. As the force of the contractions increases, the cervix will open completely. Much of the activity

related to the initiation of contractions is begun by fetal stress resulting in an increased production of

fetal cortisol. The effects listed below are all linked to the initial increase in fetal cortisol in some way.Endocrinology

Immediately prior to birth, the pre-parturition cervix loses firmness. Cervical softening involves two

changes in the intracellular matrix; firstly a reduction in the number of collagen fibres and secondly an

increase in GAGs to decrease aggregation of the remaining collagen fibres.

Several hormones are known to exhibit an effect on the cervix resulting in pre-parturition softening;

'prostaglandins' and'relaxin'. Prostaglandin levels increase markedly in the days prior to parturition,

peaking at parturition. There are three main types and sources of prostaglandin that are important in

cervical softening; prostaglandin E2 (PGE2), prostacyclin (PGI2) and Prostaglandin F2 (PGF2).

PGF2is produced by the placenta in response to the production of fetal corticoids. (PGF2 alsohelps to remove the progesterone block pre-parturition.) PGF2 is not thought to act directly on the

cervix and instead causes the myometrium of the uterus to become more active resulting in increased

cervical stimulation and therefore softening and dilation.

PGE2 is maternally derived and is the main driver of cervical softening. The production of PGE2

coincides with reductions inprogesteronelevels. PGE2 also acts on the uterus resulting in increased

myometrial contractions, increased uterine pressure and therefore also cervical stimulation.

PGI2 is also maternally derived and acts as a vasodilator and as an anticoagulant, playing another

important role in cervical relaxation.

With all types of prostaglandin, isoforms are produced locally and act locally and are therefore not

strictly classed as hormones.

Relaxinis produced by the ovaries and the placenta and together with progesterone prevent uterine

contractions throughout the pregnancy. However, relaxin also aids in the loosening of tissues in the

cervix and pelvic ligaments to loosen pre-parturition. Relaxin and PGE2 work in combination on the

cervix.

Progesterone Production

The initiation of myometrial contractions via fetal cortisol results in cells within the uterus and the

placenta undergoing a degree of stretch. This stretching is thought to activate several systems within

the cells resulting in the production of progesterone. Stretching can increase the availability of cyclo-

oxygenase 2 or COX-2, which is part of a chain of reactions converting arachadonic acid to PGE2

and PGF2 resulting in an increased cellular output. Both of these types of prostag landin potentiate

oxytocin once outside the cell and this in turn potentiates an increase in the level of arachidonic acid,

thus scaling up production in the entire system. Secondly the stretching within the cell also results in

increased expression of oxytocin receptors in the cell surface resulting in a greater impact on the cell

for a given level of oxytocin, further upregulating the system.

Outside the cell, levels of oestradiol are also increasing and this also has an impact on the systems

behind the production of prostaglandins. Oestradiol increases the availability of COX-2 within the cell

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and also the expression of oxytocin receptors providing a further mechanism to increase the total

prostaglandin output of the cell.

Softening Mechanisms

It is thought that prostagladins together with relaxin may induce cervical softening by inducing

collagen breakdown within the tissues and/or by altering the GAG/proteogylcan composition.

Collagen breakdown within the tissue would facilitate a higher degree of movement and stretch in the

tissue which is required for softening. Similarly, an increase in the GAG content of the tissues

stimulated by prostaglandin would result in a decrease in collagen fibril agglutination thereforereducing the stretch-resistance of the remaining collagen.

Development of the Fetal Membranes and Placenta

The Allantois(Figs. 25to28).The allantois arises as a tubular diverticulum of the posterior

part of the yolk-sac; when the hind-gut is developed the allantois is carried backward with it andthen opens into the cloaca or terminal part of the hind-gut: it grows out into the body-stalk, amass of mesoderm which lies below and around the tail end of the embryo. The diverticulum islined by entoderm and covered by mesoderm, and in the latter are carried the allantoic or

umbilical vessels.

1

In reptiles, birds, and many mammals the allantois becomes expanded into a vesicle whichprojects into the extra-embryonic celom. If its further development be traced in the bird, it is seento project to the right side of the embryo, and, gradually expanding, it spreads over its dorsalsurface as a flattened sac between the amnion and the serosa, and extending in all directions,ultimately surrounds the yolk. Its outer wall becomes applied to and fuses with the serosa, whichlies immediately inside the shell membrane. Blood is carried to the allantoic sac by the twoallantoic or umbilical arteries, which are continuous with the primitive aort, and after circulatingthrough the allantoic capillaries, is returned to the primitive heart by the two umbilical veins. Inthis way the allantoic circulation, which is of the utmost importance in connection with therespiration and nutrition of the chick, is established. Oxygen is taken from, and carbonic acid is

given up to the atmosphere through the egg-shell, while nutritive materials are at the same timeabsorbed by the blood from the yolk.

2

FIG. 24Diagram showing earliest observed stage of human ovum. (See enlarged image

)

FIG. 25Diagram illustrating early formation of allantois and differentiation of body-stalk. (See enlarged

image)

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FIG. 26Diagram showing later stage of allantoic development with commencing constriction of theyolk-sac. (See enlarged image)

FIG. 27Diagram showing the expansion of amnion and delimitation of the umbilicus. (See enlarged

image)

In man and other primates the nature of the allantois is entirely different from that just

described. Here it exists merely as a narrow, tubular diverticulum of the hind-gut, and neverassumes the form of a vesicle outside the embryo. With the formation of the amnion the embryois, in most animals, entirely separated from the chorion, and is only again united to it when theallantoic mesoderm spreads over and becomes applied to its inner surface. The human embryo,on the other hand, as was pointed out by His, is never wholly separated from the chorion, its tailend being from the first connected with the chorion by means of a thick band of mesoderm,named the body-stalk (Bauchstiel); into this stalk the tube of the allantois extends(Fig. 21).

3

The Amnion.The amnion is a membranous sac which surrounds and protects the embryo. It isdeveloped in reptiles, birds, and mammals, which are hence called Amniota; but not in

amphibia and fishes, which are consequently termed Anamnia.

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In the human embryo the earliest stages of the formation of the amnion have not beenobserved; in the youngest embryo which has been studied the amnion was already present as aclosed sac (Figs. 24and32), and, as indicated on page 46, appears in the inner cell-mass as a

cavity. This cavity is roofed in by a single stratum of flattened, ectodermal cells, the amnioticectoderm, and its floor consists of the prismatic ectoderm of the embryonic diskthe continuitybetween the roof and floor being established at the margin of the embryonic disk. Outside theamniotic ectoderm is a thin layer of mesoderm, which is continuous with that of the somatopleureand is connected by the body-stalk with the mesodermal lining of the chorion.

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FIG. 28

Diagram illustrating a later stage in the development of the umbilical cord. (See enlarged image)

When first formed the amnion is in contact with the body of the embryo, but about the fourth orfifth week fluid (liquor amnii) begins to accumulate within it. This fluid increases in quantity andcauses the amnion to expand and ultimately to adhere to the inner surface of the chorion, so thatthe extra-embryonic part of the celom is obliterated. The liquor amnii increases in quantity up tothe sixth or seventh month of pregnancy, after which it diminishes somewhat; at the end ofpregnancy it amounts to about 1 liter. It allows of the free movements of the fetus during the laterstages of pregnancy, and also protects it by diminishing the risk of injury from without. It containsless than 2 per cent. of solids, consisting of urea and other extractives, inorganic salts, a small

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amount of protein, and frequently a trace of sugar. That some of the liquor amnii is swallowed bythe fetus is proved by the fact that epidermal debris and hairs have been found among thecontents of the fetal alimentary canal.

In reptiles, birds, and many mammals the amnion is developed in the following manner: At thepoint of constriction where the primitive digestive tube of the embryo joins the yolk-sac areflection or folding upward of the somatopleure takes place. This, theamniotic fold(Fig.

29),first makes its appearance at the cephalic extremity, and subsequently at the caudal end

and sides of the embryo, and gradually rising more and more, its different parts meet and fuseover the dorsal aspect of the embryo, and enclose a cavity, the amniotic cavity. After the fusionof the edges of the amniotic fold, the two layers of the fold become completely separated, theinner forming the amnion, the outer the false amnion orserosa. The space between theamnion and the serosa constitutes the extra-embryonic celom, and for a time communicates withthe embryonic celom.

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FIG. 29Diagram of a transverse section, showing the mode of formation of the amnion in the chick. Theamniotic folds have nearly united in the middle line. (From Quains Anatomy.) Ectoderm, blue; mesoderm,

red; entoderm and notochord, black. (See enlarged image)

FIG. 30Fetus of about eight weeks, enclosed in the amnion. Magnified a little over two diameters.(Drawn from stereoscopic photographs lent by Prof. A. Thomson, Oxford.) (See enlarged image

)

The Umbilical Cord and Body-stalk.The umbilical cord(Fig. 28)attaches the fetus to the

placenta; its length at full time, as a rule, is about equal to the length of the fetus, i.e., about 50

cm., but it may be greatly diminished or increased. The rudiment of the umbilical cord isrepresented by the tissue which connects the rapidly growing embryo with the extra-embryonicarea of the ovum. Included in this tissue are the body-stalk and the vitelline ductthe formercontaining the allantoic diverticulum and the umbilical vessels, the latter forming thecommunication between the digestive tube and the yolk-sac. The body-stalk is the posteriorsegment of the embryonic area, and is attached to the chorion. It consists of a plate of mesodermcovered by thickened ectoderm on which a trace of the neural groove can be seen, indicating itscontinuity with the embryo. Running through its mesoderm are the two umbilical arteries and thetwo umbilical veins, together with the canal of the allantoisthe last being lined byentoderm(Fig. 31).Its dorsal surface is covered by the amnion, while its ventral surface is

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bounded by the extra-embryonic celom, and is in contact with the vitelline duct and yolk-sac.With the rapid elongation of the embryo and the formation of the tail fold, the body stalk comes tolie on the ventral surface of the embryo (Figs. 27and28), where its mesoderm blends with that

of the yolk-sac and the vitelline duct. The lateral leaves of somatopleure then grow round oneach side, and, meeting on the ventral aspect of the allantois, enclose the vitelline duct andvessels, together with a part of the extra-embryonic celom; the latter is ultimately obliterated. Thecord is covered by a layer of ectoderm which is continuous with that of the amnion, and itsvarious constitutents are enveloped by embryonic gelatinous tissue,jelly of Wharton. The

vitelline vessels and duct, together with the right umbilical vein, undergo atrophy and disappear;and thus the cord, at birth, contains a pair of umbilical arteries and one (the left) umbilical vein.

FIG. 31Model of human embryo 1.3 mm. long. (After Eternod.) (See enlarged image

)

Implantation or Imbedding of the Ovum.As described (page 44), fertilization of the ovumoccurs in the lateral or ampullary end of the uterine tube and is immediately followed bysegmentation. On reaching the cavity of the uterus the segmented ovum adheres like a parasite

to the uterine mucous membrane, destroys the epithelium over the area of contact, andexcavates for itself a cavity in the mucous membrane in which it becomes imbedded. In the ovumdescribed by Bryce and Teacher

7the point of entrance was visible as a small gap closed by a

mass of fibrin and leucocytes; in the ovum described by Peters, 8the opening was covered by a

mushroom-shaped mass of fibrin and blood-clot(Fig. 32),the narrow stalk of which plugged the

aperture in the mucous membrane. Soon, however, all trace of the opening is lost and the ovumis then completely surrounded by the uterine mucous membrane.

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The structure actively concerned in the process of excavation is the trophoblast of the ovum,which possesses the power of dissolving and absorbing the uterine tissues. The trophoblastproliferates rapidly and forms a network of branching processes which cover the entire ovum andinvade and destroy the maternal tissues and open into the maternal bloodvessels, with the resultthat the spaces in the trophoblastic network are filled with maternal blood; these spacescommunicate freely with one another and become greatly distended and form the intervillousspace.

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FIG. 32Section through ovum imbedded in the uterine decidua. Semidiagrammatic. (AfterPeters.) am. Amniotic cavity. b.c.Blood-clot. b.s. Body-stalk. ect. Embryonic

ectoderm. ent. Entoderm. mes. Mesoderm. m.v. Maternal vessels. tr.Trophoblast. u.e. Uterine

epithelium. u.g. Uterine glands.y.s. Yolk-sac. (See enlarged image)

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The Decidua.Before the fertilized ovum reaches the uterus, the mucous membrane of thebody of the uterus undergoes important changes and is then known as the decidua. Thethickness and vascularity of the mucous membrane are greatly increased; its glands areelongated and open on its free surface by funnel-shaped orifices, while their deeper portions aretortuous and dilated into irregular spaces. The interglandular tissue is also increased in quantity,

and is crowded with large round, oval, or polygonal cells, termed decidual cells. These changesare well advanced by the second month of pregnancy, when the mucous membrane consists ofthe following strata(Fig. 33):(1) stratum compactum, next the free surface; in this the uterine

glands are only slightly expanded, and are lined by columnar cells; (2) stratum spongiosum, inwhich the gland tubes are greatly dilated and very tortuous, and are ultimately separated fromone another by only a small amount of interglandular tissue, while their lining cells are flattenedor cubical; (3) a thin unaltered orboundary layer, next the uterine muscular fibers, containingthe deepest parts of the uterine glands, which are not dilated, and are lined with columnarepithelium; it is from this epithelium that the epithelial lining of the uterus is regenerated afterpregnancy. Distinctive names are applied to different portions of the decidua. The part whichcovers in the ovum is named the decidua capsularis; the portion which intervenes between theovum and the uterine wall is named the decidua basalis ordecidua placentalis; it is here thatthe placenta is subsequently developed. The part of the decidua which lines the remainder of thebody of the uterus is known as the decidua vera ordecidua parietalis.

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Coincidently with the growth of the embryo, the decidua capsularis is thinned andextended(Fig. 34)and the space between it and the decidua vera is gradually obliterated, so that

by the third month of pregnancy the two are in contact. By the fifth month of pregnancy thedecidua capsularis has practically disappeared, while during the succeeding months the deciduavera also undergoes atrophy, owing to the increased pressure. The glands of the stratumcompactum are obliterated, and their epithelium is lost. In the stratum spongiosum the glands arecompressed and appear as slit-like fissures, while their epithelium undergoes degeneration. Inthe unaltered or boundary layer, however, the glandular epithelium retains a columnar or cubical

form.

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FIG. 33Diagrammatic sections of the uterine mucous membrane:A. The non-pregnant uterus.B. Thepregnant uterus, showing the thickened mucous membrane and the altered condition of the uterine glands.

(Kundrat and Engelmann.) (See enlarged image)

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FIG. 34Sectional plan of the gravid uterus in the third and fourth month. (Modified from Wagner.) (Seeenlarged image)

The Chorion(Figs. 23 to28).The chorion consists of two layers: an outer formed by the

primitive ectoderm or trophoblast, and an inner by the somatic mesoderm; with this latter theamnion is in contact. The trophoblast is made up of an internal layer of cubical or prismatic cells,the cytotrophoblast orlayer of Langhans, and an external layer of richly nucleated protoplasmdevoid of cell boundaries, the syncytiotrophoblast. It undergoes rapid proliferation and formsnumerous processes, thechorionic villi, which invade and destroy the uterine decidua and atthe same time absorb from it nutritive materials for the growth of the embryo. The chorionic villiare at first small and non-vascular, and consist of trophoblast only, but they increase in size andramify, while the mesoderm, carrying branches of the umbilical vessels, grows into them, and inthis way they are vascularized. Blood is carried to the villi by the branches of the umbilicalarteries, and after circulating through the capillaries of the villi, is returned to the embryo by theumbilical veins. Until about the end of the second month of pregnancy the villi cover the entirechorion, and are almost uniform in size(Fig. 25),but after this they develop unequally. The

greater part of the chorion is in contact with the decidua capsularis(Fig. 34),and over this portion

the villi, with their contained vessels, undergo atrophy, so that by the fourth month scarcely atrace of them is left, and hence this part of the chorion becomes smooth, and is namedthechorion lve; as it takes no share in the formation of the placenta, it is also named the non-placental part of the chorion. On the other hand, the villi on that part of the chorion which is incontact with the decidua placentalis increase greatly in size and complexity, and hence this partis named the chorion frondosum(Fig. 28).

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FIG. 35Transverse section of a chorionic villus. (See enlarged image)

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FIG. 36Primary chorionic villi. Diagrammatic. (Modified from Bryce.) (See enlarged image)

The Placenta.The placenta connects the fetus to the uterine wall, and is the organ by meansof which the nutritive, respiratory, and excretory functions of the fetus are carried on. It iscomposed offetal and maternal portions.

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FIG. 37Secondary chorionic villi. Diagrammatic. (Modified from Bryce.) (See enlarged image)

Fetal Portion.The fetal portion of the placenta consists of the villi of the chorion frondosum;these branch repeatedly, and increase enormously in size. These greatly ramified villi aresuspended in the intervillous space, and are bathed in maternal blood, which is conveyed to thespace by the uterine arteries and carried away by the uterine veins. A branch of an umbilicalartery enters each villus and ends in a capillary plexus from which the blood is drained by atributary of the umbilical vein. The vessels of the villus are surrounded by a thin layer ofmesoderm consisting of gelatinous connective tissue, which is covered by two strata of

ectodermal cells derived from the trophoblast: the deeper stratum, next the mesodermic tissue,represents the cytotrophoblast or layer of Langhans; the superficial, in contact with the maternalblood, the syncytiotrophoblast (Figs. 36and37). After the fifth month the two strata of cells are

replaced by a single layer of somewhat flattened cells.

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Maternal Portion.The maternal portion of the placenta is formed by the decidua placentaliscontaining the intervillous space. As already explained, this space is produced by theenlargement and intercommunication of the spaces in the trophoblastic network. The changesinvolve the disappearance of the greater portion of the stratum compactum, but the deeper partof this layer persists and is condensed to form what is known as the basal plate. Between thisplate and the uterine muscular fibres are the stratum spongiosum and the boundary layer;

through these and the basal plate the uterine arteries and veins pass to and from the intervillousspace. The endothelial lining of the uterine vessels ceases at the point where they terminate inthe intervillous space which is lined by the syncytiotrophoblast. Portions of the stratumcompactum persist and are condensed to form a series of septa, which extend from the basalplate through the thickness of the placenta and subdivide it into the lobules or cotyledonsseenon the uterine surface of the detached placenta.

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FIG. 38Fetus in utero, between fifth and sixth months. (See enlarged image

)

The fetal and maternal blood currents traverse the placenta, the former passing through the

bloodvessels of the placental villi and the latter through the intervillous space(Fig. 39).The two

currents do not intermingle, being separated from each other by the delicate walls of the villi.Nevertheless, the fetal blood is able to absorb, through the walls of the villi, oxygen and nutritivematerials from the maternal blood, and give up to the latter its waste products. The blood, sopurified, is carried back to the fetus by the umbilical vein. It will thus be seen that the placenta notonly establishes a mechanical connection between the mother and the fetus, but subserves forthe latter the purposes of nutrition, respiration, and excretion. In favor of the view that theplacenta possesses certain selective powers may be mentioned the fact that glucose is moreplentiful in the maternal than in the fetal blood. It is interesting to note also that the proportion ofiron, and of lime and potash, in the fetus is increased during the last months of pregnancy.Further, there is evidence that the maternal leucocytes may migrate into the fetal blood, since

leucocytes are much more numerous in the blood of the umbilical vein than in that of theumbilical arteries.

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The placenta is usually attached near the fundus uteri, and more frequently on the posteriorthan on the anterior wall of the uterus. It may, however, occupy a lower position and, in rarecases, its site is close to the orificium internum uteri, which it may occlude, thus giving rise to thecondition known asplacenta previa.

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FIG. 39Scheme of placental circulation. (See enlarged image

)

Separation of the Placenta.After the child is born, the placenta and membranes are expelledfrom the uterus as the after-birth. The separation of the placenta from the uterine wall takesplace through the stratum spongiosum, and necessarily causes rupture of the uterine vessels.The orifices of the torn vessels are, however, closed by the firm contraction of the uterinemuscular fibers, and thuspostpartum hemorrhage is controlled. The epithelial lining of the uterusis regenerated by the proliferation and extension of the epithelium which lines the persistentportions of the uterine glands in the unaltered layer of the decidua.

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The expelled placenta appears as a discoid mass which weighs about 450 gm. and has adiameter of from 15 to 20 cm. Its average thickness is about 3 cm., but this diminishes rapidly

20

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