Potential anticonvulsive properties of endogenous prostaglandins formed in mouse brain

doi:10.1016/0006-8993(82)90225-6

Brain Research

Volume 240, Issue 2, 27 May 1982, Pages 303-310

https://doi.org/10.1016/0006-8993(82)90225-6 Get rights and content

Abstract

The levels of 5 different prostanoids (PGD₂, PGF₂α, PGE₂, TXB₂ and 6-keto-PGF₁α) formed in whole mouse brain in vivo were measured by specific radioimmunoassays. Basal concentrations were found to be very low (few ng/g wet weight). A marked increase occurred during convulsions induced by either pentylenetetrazole or by electroconvulsive shock. Under both conditions the major cyclooxygenase product detected was PGD₂, followed by PGF₂α and lower concentrations of the other prostanoids.

The non-steroidal anti-inflammatory drugs flurbiprofen, indomethacin, and diclofenac dose-dependently inhibited the pentylenetetrazole-induced formation of prostaglandins. Concomitantly these 3 compounds dose-dependently increased the acute toxicity of pentylenetetrazole (decrease in LD₅₀).

Conversely, if levels of cerebral prostaglandins were enhanced by a preceding electroshock, the toxicity of pentylenetetrazole was significantly reduced (increase in LD₅₀), and the time of onset of clonic seizures was markedly prolonged. Both the effect on the latency time and the LD₅₀ could be reversed if the cerebral prostaglandin synthesis was prevented by indomethacin, or if the time interval between the electroshock and pentylenetetrazole administration was extended, so that the electroshock-stimulated prostaglandin concentrations had declined to basal levels again. These findings indicate that endogenous prostanoids formed in mouse brain during convulsions might possess anticonvulsive properties.

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Thus, TIA-1 does not appear to influence the sensitivity of mice to acute PTZ-induced seizures. Results from several studies employing various animal models showed that inhibitors of COX-2 activity enhanced the susceptibility for convulsions (Steinhauser and Hertting, 1981; Förstermann et al., 1982; Forstermann et al., 1984; Baik et al., 1999; Sanchez-Hernandez et al., 1999; Kunz and Oliw, 2001; Claycomb et al., 2012; Arnao et al., 2017). This is consistent with observations in human cases as well (Sanchez-Hernandez et al., 1999; Arnao et al., 2017).
Activity of neuronal cyclooxygenase-2 (COX-2), a primary source of PG synthesis in the normal brain, is enhanced by excitatory neurotransmission and this is thought to be involved in seizure suppression. Results herein showing that the incidence of pentylenetetrazole (PTZ)-induced convulsions is suppressed in transgenic mice overexpressing COX-2 in neurons support this notion. T-cell intracellular antigen-1 (TIA-1) is an mRNA binding protein that is known to bind to COX-2 mRNA and repress its translation in non-neuronal cell types. An examination of the expression profile of TIA-1 protein in the normal brain indicated that it is expressed broadly by neurons, including those that express COX-2. However, whether TIA-1 regulates COX-2 protein levels in neurons is not known. The purpose of this study was to test the possibility that deletion of TIA-1 increases basal COX-2 expression in neurons and consequently raises the seizure threshold. Results demonstrate that neither the basal nor seizure-induced expression profiles of COX-2 were altered in mice lacking a functional TIA-1 gene suggesting that TIA-1 does not contribute to regulation of COX-2 protein expression in neurons. The acute PTZ-induced seizure threshold was also unchanged in mice lacking TIA-1 protein, indicating that this RNA binding protein does not influence the innate seizure threshold. Nevertheless, the results raise the possibility that the level of neuronal COX-2 expression may be a determinant of the innate seizure threshold and suggest that a better understanding of the regulation of COX-2 expression in the brain could provide new insight into the molecular mechanisms that suppress seizure induction.
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Decreased expression of HDACs may be one mechanism facilitating expression of these genes. The respective gene products may support pro-convulsive (Forstermann et al., 1982) or endogenous anticonvulsive mechanisms (Sperk et al., 1992; Esclapez and Houser, 1999; Szabo et al., 2000). Thus, increased expression of the T-type calcium channel α1-subunit Cav3.2 after pilocarpine-induced status epilepticus leads to increased cellular T-type Ca++ currents and an increase in intrinsic burst firing.
A prominent role of epigenetic mechanisms in manifestation of epilepsy has been proposed. Thus altered histone H3 and H4 acetylation has been demonstrated in experimental models of temporal lobe epilepsy (TLE). We now investigated changes in the expression of the class I and class IV histone deacetylases (HDAC) in two complementary mouse TLE models. Unilateral intrahippocampal injection of kainic acid (KA) induced a status epilepticus lasting 6 to 24 h, development of spontaneous limbic seizures (2 to 3 days after KA injection) and chronic epilepsy, as revealed by telemetric recordings of the EEGs. Mice were killed at different intervals after KA injection and expression of HDAC mRNAs was investigated by in situ hybridization. We observed marked decreases in the expression of HDACs 1, 2 and 11 (by up to 75%) in the granule cell and pyramidal cell layers of the hippocampus during the acute status epilepticus (2 to 6 h after KA injection). This was followed by increased expression of all class I HDAC mRNAs in all principal cell layers of the hippocampus after 12 to 48 h. In the chronic phase, 14 and 28 days after KA, only modest increases in the expression of HDAC1 mRNA were observed in granule and pyramidal cells. Immunohistochemistry using an antibody detecting HDAC2 revealed results consistent with the mRNA data and indicates also expression in glial cells on the injection side. Similar changes as seen in the KA model were observed after a pilocarpine-induced status epilepticus except that decreases in HDACs 2, 3 and 8 were also seen at the chronic 28 day interval.
The prominent decreases in HDAC expression during status epilepticus are consistent with the previously demonstrated increased expression of numerous proteins and with the augmented acetylation of histone H4. It is suggested that respective putative gene products could facilitate proconvulsive as well as anticonvulsive mechanisms. The increased expression of all class I HDACs during the “silent phase”, on the other hand, may be related to decreased histone acetylation, which could cause a decrease in expression of certain proteins, a mechanism that could also promote epileptogenesis. Thus, addressing HDAC expression may have a therapeutic potential in interfering with a status epilepticus and with the manifestation of TLE.
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An effector role of COX-2 in the anti-epileptic actions of IL-1β in the PTZ model presupposes that COX-2 activity is rapidly augmented in the CNS by acute seizure activity and that metabolites of COX-2 possess anti-convulsive properties. Unlike most cells outside of the CNS, COX-2 is constitutively expressed by excitatory neurons (Adams et al., 1996; Breder et al., 1995; Joseph et al., 2006; Yamagata et al., 1993), particularly within the cerebral cortex and hippocampus, and prostaglandin production is indeed augmented in these brain regions following PTZ exposure (Berchtold-Kanz et al., 1981; Engelhardt et al., 1996; Forstermann et al., 1982). Moreover, a time-course analysis indicated that this increase precedes convulsive seizure behavior and studies with KA and electrical stimulation demonstrated that elevated brain prostaglandin levels can persist for tens of minutes following the convulsive stimulus (Baran et al., 1987; Forstermann et al., 1982; Kim et al., 2008; Yoshikawa et al., 2006).
The function of endogenous interleukin-1β (IL-1β) signaling in acute seizure activity was examined using transgenic mice harboring targeted deletions in the genes for either IL-1β (Il1b) or its signaling receptor (Il1r1). Acute epileptic seizure activity was modeled using two mechanistically distinct chemoconvulsants, kainic acid (KA) and pentylenetetrazole (PTZ). KA-induced seizure activity was more severe in homozygous null (−/−) Il1b mice compared to their wild-type (+/+) littermate controls, as indicated by an increase in the incidence of sustained generalized convulsive seizure activity. In the PTZ seizure model, the incidence of acute convulsive seizures was increased in both Il1b and Il1r1−/− mice compared to their respective +/+ littermate controls. Interestingly, the selective cyclooxygenase (COX)-2 inhibitor, rofecoxib, mimicked the effect of IL-1β deficiency on PTZ-induced convulsions in Il1r1+/+ but not −/− mice. Together, these results suggest that endogenous IL-1β possesses anticonvulsive properties that may be mediated by arachidonic acid metabolites derived from the catalytic action of COX-2.
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Further establishing the COX selectivity in learning and memory, Sang and Chen (2006) referred to unpublished data which showed that LTP is normal in COX-1 knockout mice. ECS has been shown to upregulate COX-2 in the dentate gyrus and amygdala (Lipsky, 1999; Newton et al., 2003) and release prostaglandins in the brain (Berchtold-Kanz et al., 1981; Forstermann et al., 1982; Mathe et al., 1987). How does ECS upregulate COX-2?
We sought to explore nonselective vs. selective COX mechanisms in ECS-induced retrograde amnesia using indomethacin and celecoxib as in vivo probes. Adult Wistar rats (n = 72) which showed adequate learning on a passive avoidance task received 5 once-daily 30 mC true or sham ECS. During the learning and ECS periods, indomethacin (4 mg/kg/day), celecoxib (15 mg/kg/day), or vehicle were orally administered. One day after the fifth ECS, recall of pre-ECS learning was tested. There were no baseline or pre-ECS differences in learning between groups. ECS seizure duration did not differ across groups. ECS-treated rats showed impaired recall in the vehicle but not indomethacin and celecoxib groups. Celecoxib but not indomethacin significantly protected against ECS-induced retrograde amnesia. We interpret these results as follows: ECS may impair cognition by pathologically upregulating glutmatergic signalling, thereby causing cation and water influx, oxidative stress, and saturation of hippocampal LTP. These may result from glutamatergic disinhibition through COX-2-mediated removal of endogenous cannabinoids, and by ECS-activated, NMDA-mediated upregulation of platelet activating factor and COX-2 signalling pathways. Thus, indomethacin and celecoxib, by inhibiting COX-2, may protect against ECS-induced amnesia. Furthermore, COX-2 mediated increase in hippocampal kynurenic acid may impair glutamate-dependent learning and memory processes at ionotropic glutamatergic receptor sites; the inhibition of kynurenic acid synthesis by celecoxib and its induction by indomethacin may explain the greater benefits with celecoxib. These findings suggest new avenues for the study of the neurobiology of ECT-induced amnesia and the attenuation thereof.
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The parameters of pentylenetetrazol (PTZ)-induced seizures have been evaluated at various time intervals after lipopolysaccharide (LPS; Escherichia coli O111:B4, 100 μg/kg, i.p.) administration in mice. A proconvulsant effect occurred 4 h after LPS injection with decreased seizure latency and enhanced seizure intensity. In contrast, the incidence of seizures was reduced 18 h after LPS injection. There were no significant alterations on seizure parameters 2, 8, 12, and 24 h after LPS treatment. SC-58236, a selective cyclooxygenase (COX)-2 inhibitor (20 or 40 mg/kg, s.c.) treatment alone had no effect on PTZ-induced seizures, but reversed the antiseizure activity observed 18 h after LPS injection. However, SC-58236 treatment partially restored the proconvulsant changes that were observed 4 h after LPS administration. On the other hand, COX-1-selective inhibitor valeryl salicylate (20 or 40 mg/kg, s.c.) itself facilitated PTZ-induced seizures. Thus, it was not possible to evaluate the effects of valeryl salicylate on the excitability changes after LPS injection. These results indicate that the parameters of PTZ-induced seizures change time-dependently after LPS treatment, in which proconvulsant and anticonvulsant states could be seen in a sequence. It seems that COX-2 isoenzyme may be involved in the neuronal excitability changes due to LPS.

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Potential anticonvulsive properties of endogenous prostaglandins formed in mouse brain

Abstract

Identification of prostaglandin D2 as a major prostaglandin in homogenates of rat brain

Prostaglandins

Regional and species differences in endogenous prostaglandin biosynthesis by brain homogenates

Prostaglandins

Prostaglandin profiles in nervous tissue and blood vessels of the brain of various animals

Prostaglandins

Radioimmunological determination of prostaglandin D2 synthesis in human thrombocytes

Experientia

Effects of ischemia and electroconvulsive shock on free fatty acid pool in the brain

Biochim. biophys. Acta

Regional distribution of arachidonic acid metabolites in rat brain following convulsive stimuli

Prostaglandins

Inhibition of pentylenetrazol-induced convulsions in rats by prostaglandin E1: role of brain monoamines

Psychopharmacology

Correlation between release of free arachidonic acid and prostaglandin formation in brain cortex and cerebellum

Prostaglandins

Convulsions in a breast-fed infant after maternal indomethacin

Lancet

Vergleich biologischer Wirkungen mittels programmierter Probitanalyse

Meth. Inform. Med.

Probit Analysis, a Statistical Treatment of Sigmoid Response Curves

Relations between prostaglandin E2, F2α, and cyclic nucleotides levels in rat brain and induction of convulsions

Prostaglandins

Factors affecting brain prostaglandin formation

Accumulation of cyclooxygenase products of arachidonic acid metabolism in gerbil brain during reperfusion after bilateral common carotid artery occlusion

J. Neurochem.

Modulation of autonomic neurotransmission by PGD2: comparison with effects of other prostaglandins in anesthetized cats

Prostaglandins

Actions of prostaglandins E1, E2 and E3 on the central nervous system

Brit. J. Pharmacol.

Identification of prostaglandin D₂ as a major prostaglandin in homogenates of rat brain

Radioimmunological determination of prostaglandin D₂ synthesis in human thrombocytes

Inhibition of pentylenetrazol-induced convulsions in rats by prostaglandin E₁: role of brain monoamines

Relations between prostaglandin E₂, F₂α, and cyclic nucleotides levels in rat brain and induction of convulsions

Modulation of autonomic neurotransmission by PGD₂: comparison with effects of other prostaglandins in anesthetized cats

Actions of prostaglandins E₁, E₂ and E₃ on the central nervous system