prostaglandin-d2 and Seizures

Accumulating clinical and experimental evidence suggests a role for prostaglandins (PGs) in epilepsy and isolated seizures. Prostaglandin levels are increased in the hippocampus of epileptic patients and in the cerebrospinal fluid of children with febrile seizures. Moreover, increased PGD2, PGE2 and PGF2α levels are found in the brain after chemically-induced seizures and in spontaneously epileptic mice. However, whether prostaglandins facilitate or decrease seizures has been a matter of debate in the literature. Both pro- and anticonvulsant activities have been described for most of prostaglandins, except for PGD2 and DP receptor agonists, for which a consistent anticonvulsant action has been reported. The study by Kaushik and colleagues elegantly extends this view by showing that hematopoietic PGD synthase (H-PGDS) and DP1 receptors are essential for seizure suppression and that lipocalin-type prostaglandin D synthase (L-PGDS)/PGD2/DP1 system regulates sleep that follows PTZ-induced seizures using knockout animals. This commentary discusses the experimental approach of the studies that have implicated prostaglandins and their receptors in seizures, the interesting approach and results of Kaushik and colleagues, and the challenges of considering PGD2 signaling as a therapeutic target in epilepsy.

Topics: Animals; Anticonvulsants; Humans; Mice; Prostaglandin D2; Receptors, Prostaglandin; Seizures; Sleep

We investigated whether prostaglandins (PGs), proinflammatory mediators implicated in excitatory activity, are involved in Shigella-related seizures. Pretreatment with S. dysenteriae sonicate (2LD(50)) enhanced mice response to pentylenetetrazole-induced seizures, without increase of brain concentrations of PGE(2), PGD(2) or PGF(2alpha). Preinjection of NS-398, an inhibitor of cyclooxygenase-2, before treatment with Shigella sonicate, had no effect on seizures. The anticonvulsive PGD(2) increased after injection of 8 LD(50) of Shigella sonicate, which did not enhance seizures (32 pg/mg vs 26 pg/ml, p=0.0063). The findings indicate that PGs are not involved in the enhanced seizure response after exposure to Shigella. However, induction of PGD(2) may play an inhibitory role.

Topics: Animals; Chi-Square Distribution; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Enzyme-Linked Immunosorbent Assay; Lethal Dose 50; Male; Mice; Mice, Inbred ICR; Nitrobenzenes; Pentylenetetrazole; Prostaglandin D2; Prostaglandins; Seizures; Shigella dysenteriae; Sulfonamides

This study was undertaken to evaluate the role of brain PGD2 activity during PTZ induced seizures in rats. Potentiation of endogenous PGD2 activity caused an anti-convulsant effect. Thus, after PGD2 injection (5 microg/icv) the latency of generalized tonic clonic convulsions was prolonged. ZK 118.182, a stable analogue of PGD2, dose-dependently inhibited the incidence and the intensity of seizures when injected at doses of 1-100 ng/icv. But on the other hand, inhibition of PGD2 activity either by a D-type PG receptor antagonist (AH 6809; 50 ng/icv) or by a PGD synthase inhibitor (sodium selenite; 0.2 microg/icv) produced a proconvulsant effect by increasing the incidence and the intensity of the seizures. These findings indicate that endogenous PGD2 activity in the brain may have a specific inhibitory role for the initiation and propagation of PTZ induced seizures in rats.

Topics: Animals; Anticonvulsants; Cerebral Ventricles; Dinoprost; Epilepsy, Tonic-Clonic; Injections, Intraventricular; Male; Pentylenetetrazole; Prostaglandin Antagonists; Prostaglandin D2; Rats; Rats, Wistar; Seizures; Sodium Selenite; Xanthenes; Xanthones

Prostaglandins (PGs) of the E series are known to exert anticonvulsant action in experimental animals. Earlier studies from this laboratory have indicated that PGE1 inhibits pentylenetetrazole (PTZ)-induced convulsions in rats through a serotonin-mediated mechanism. PGD2, the major PG in the rodent brain, shares a number of central pharmacological actions of the PGEs, and like the latter it potentiates the anticonvulsant action of phenobarbitone and phenytoin in rats. The present study was undertaken to investigate the putative anticonvulsant action of PGD2 against PTZ-induced convulsions in rats and to evaluate the role of serotonin in the anticonvulsant action of PGD2. PGD2 (5, 10, and 20 micrograms, icv) produced a dose-related inhibition of PTZ-induced clonic convulsions in rats. The anticonvulsant action of PGD2 (20 micrograms, icv) was significantly attenuated following pretreatment of the rats with pharmacologic agents known to reduce central serotonergic activity, including 5,6-dihydroxytryptamine, a selective neurotoxin for serotonergic neurons, p-chlorophenylalanine, a specific inhibitor of serotonin biosynthesis, metergoline, a serotonin postsynaptic receptor antagonist, and quipazine, which is known to inhibit neuronal release of serotonin. These findings, in conjunction with an earlier study from this laboratory indicating that PGD2 augments rat brain serotonergic activity, suggest that the anticonvulsant activity of PGD2 against PTZ-induced convulsions in rats is mediated through a serotonergic mechanism.

Topics: Animals; Dihydroxytryptamines; Dinoprost; Female; Fenclonine; Male; Metergoline; Pentylenetetrazole; Prostaglandin D2; Quipazine; Rats; Rats, Inbred Strains; Seizures; Serotonin

In view of the recent finding that prostaglandin D2 is stereospecifically converted to 9 alpha, 11 beta-prostaglandin F2, an isomer of prostaglandin F2 alpha, a highly specific and sensitive radioimmunoassay for 9 alpha, 11 beta-prostaglandin F2 was developed and applied to determine the content of this prostaglandin in various rat tissues. Antisera against 9 alpha, 11 beta-prostaglandin F2 were raised in rabbits immunized with the bovine serum albumin conjugate, and [3H]9 alpha, 11 beta-prostaglandin F2 was enzymatically prepared from [3H]prostaglandin D2. The assay detected 9 alpha, 11 beta-prostaglandin F2 over the range of 20 pg to 1 ng, and the antiserum showed less than 0.04% cross-reaction with prostaglandin F2 alpha, prostaglandin F2 beta and 9 beta, 11 beta-prostaglandin F2. To avoid postmortem changes, tissues were frozen in liquid nitrogen immediately after removal. The basal level of 9 alpha, 11 beta-prostaglandin F2 was hardly detectable in various tissues of the rat examined, including spleen, lung, liver and brain; although it was found to be 0.31 +/- 0.06 ng/g wet weight in the small intestine. During convulsion induced by pentylenetetrazole, enormous amounts of prostaglandin D2 (ca. 180 ng/g wet weight) and prostaglandin F2 alpha (ca. 70 ng/g) were produced in the brain; however, 9 alpha, 11 beta-prostaglandin F2 was detected neither there nor in the blood. This result demonstrates that the conversion to 9 alpha, 11 beta-prostaglandin F2 is a minor pathway, if one at all, of prostaglandin D2 metabolism in the rat brain.

Topics: Animals; Chromatography, High Pressure Liquid; Dinoprost; Immune Sera; Male; Pentylenetetrazole; Prostaglandin D2; Prostaglandins D; Prostaglandins F; Radioimmunoassay; Rats; Rats, Inbred Strains; Seizures; Tissue Distribution

The distribution of the two major cyclooxygenase products prostaglandin D2 (PGD2) and prostaglandin F2 alpha (PGF2 alpha) in 7 different regions of the brain (medulla, cerebellum, hypothalamus, striatum, midbrain, hippocampus and cerebral cortex) was studied. Basal levels were highest in hypothalamus and cortex. Following convulsions elicited by environmental stress prostaglandin concentrations increased in all areas, with largest increases (10-20-fold) in hippocampus and cortex, reaching 70 ng/g PGD2 in hippocampus and 115 ng/g PGD2 in cortex. These results demonstrate that, during spontaneous seizures, there is a greater increase in prostanoid production in those areas involved in the convulsive process.

Topics: Animals; Brain; Dinoprost; Female; Gerbillinae; Male; Prostaglandin D2; Prostaglandins D; Prostaglandins F; Radioimmunoassay; Seizures; Stress, Physiological; Time Factors

Basal levels of 5 cerebral prostanoids (PGD2, PGF2 alpha, PGE2, 6-keto-PGF1 alpha and thromboxane/TX/B2) were measured radioimmunologically in normal and convulsion-prone gerbils. Significantly less PGD2,PGE2 and 6-keto-PGF1 alpha was found in the brain of seizure-sensitive animals. After treatment with indomethacin, which reduced the amount of brain cyclo-oxygenase products, also normal gerbils exhibited convulsions following environmental stress. The results are in accordance with the hypothesis that endogenous prostanoids play a role in the regulation of seizure susceptibility.

Topics: Alprostadil; Animals; Brain; Brain Chemistry; Dinoprost; Dinoprostone; Disease Susceptibility; Female; Gerbillinae; Male; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Prostaglandins D; Prostaglandins E; Prostaglandins F; Seizures; Thromboxane B2

The present work examined some central nervous actions of prostaglandin D2 (PGD2), which is the most prevalent prostaglandin in rodent brain. The effects of PGD2 were compared with those of PGE2 and PGF2 alpha. The prostaglandins were administered intracerebroventricularly (ICV) to conscious rats using the method of Herman (1970). All three prostaglandins studied produced depressive behavioral effects, causing obvious sedation at doses of 2.0 micrograms and 20.0 micrograms ICV. PGD2 and PGE2 significantly reduced spontaneous motor activity at doses of 2.0 micrograms and 20.0 micrograms ICV. PGF2 alpha was less effective; only 20.0 micrograms significantly inhibited motor activity. At a dose of 20.0 micrograms ICV all three compounds were shown to block convulsions induced by pentylenetetrazol. PGD2, the most effective prostaglandin in this respect, was still slightly anticonvulsive at a dose of 2.0 micrograms ICV. PGF2 alpha hat the weakest anticonvulsive potency. PGE2 and PGF2 alpha (2.0 micrograms and 20.0 micrograms ICV) caused a marked hypertensive effect, whereas PGD2 at the same dose levels only produced a small increase in blood pressure. PGE2 and PGF2 alpha (2.0 micrograms and 20.0 micrograms) also exerted marked pyrogenic actions. The effects of PGD2 on body temperature were variable. When given at a dose of 20.0 micrograms ICV, it caused slight hyperthermia whereas a lower dose (2.0 micrograms ICV) induced a moderate fall in body temperature. These findings suggest a relationship between the actions of the different prostaglandins on blood pressure and body temperature.

Topics: Animals; Behavior, Animal; Blood Pressure; Body Temperature; Dinoprost; Dinoprostone; Injections, Intraventricular; Male; Motor Activity; Prostaglandin D2; Prostaglandins; Prostaglandins D; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains; Seizures