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Relation between prostaglandin E2, F2α, and cyclic nucleotides levels in rat brain and induction of convilsions
PROSTAGLANDINS
RELATIONS
BETWEEN
LEVELS
PROSTAGLANDIN
Folco G.C., Longiave Institute University
E 2, F2«, AND CYCLIC NUCLEOTIDES
IN RAT BRAIN AND INDUCTION
of Pharmacology of Milan,
D.
OF CONVULSIONS.
and Bosisio E.
and Pharmacognosy,
20129 Milan,
School of Pharmacy,
Italy.
ABSTRACT Fully convulsant doses of pentamethylenetetrazole cause marked increase in rat brain cortical PGFù , PGE2, cGMP and cAMP during seizures, whereas subconvulsant do~~s cause an increase of rat brain cortical PGFù without affecting the other biochemical parametersconsidered. Rat cerebellar prostaglandlns were not modified by the convulsant agent at either dosage.
ACKNOWLEDGEMENTS The Authors are grateful to Dr. J. Pike of the Upjohn Company, Kalamazoo, Michigan, and to Dr. K. Sano, ONO Pharmaceutical, Osaka, Japan, for generous supply of prostaglandins and deuterated standards. The experimental results were partly supported by a grant of the C.N.R. (Consiglio Nazionale delle Ricerche, Roma) No. 75.00522. We are also indebted to Mr. Aurelio Toia for his excellent technical assistance and to Dr. V. Mandelli for statistical advice.
INTRODUCTION The presence of prostaglandins (PGs) in mammalian brain is well documented (i), and several groups have demonstrated that PGF2« is the predominant prostaglandin identified (2). Biosynthesis of PGs occurs in rat brain cortex from arachidonic acid released from phospholipids (3) by a phospholipase A, which is considered to be the triggering and also rate limiting step enzyme. Conflicting reports have appeared on the existence of brain degradative enzymes: a very low activity of these enzymes is found in cerebral cortex of cat and dog (4, 5). Probably prostaglandins synthetized in brain "in vivo" are released in the venous circulation and metabolized in other tissues.
MAY 1977 VOL. 13 NO. 5
893
PROSTAGLANDINS
The regulatory role of PGs on intracellular concentrations of cyclic nucleotides at peripheral level (6, 7), as well as in the CNS, is also well established. Several laboratories have demonstrated an "in vitro" stimulation of 3',5'cyclic Adenosin Monophosphate (cAMP) formation by PGs of the E type in cultured neural tissue and in slices of cerebral cortex (8, 9): responses varied with the species examined and PGs of the F type were completely ineffective in this respect, although PGF2« is the major prostaglandin present in the brain. In addition to this, neurophysiological studies using microiontophoretic techniques have shown that PGE], and PGE 2 consistently antagonize the reduction in discharg~ rate of 9at Purkinje cells caused by norepinephrine (NE) but not by cAMP (10, ii). These Authors, placing the inhlbitory action of PGs at the level of cAMP formation, indicate a possible feed-back regulatory role of these compounds in central neurotransmission. From the behavioural point of view, E prostaglandins administered to the intact animal exert a sedative-tranquillizing action (12). Furthermore, PGE I shows marked anticonvulsant properties which are dependen£ on the experimental model : animals are protected against seizures produced by pentamethylenetetrazole, strychnine but not against picrotoxin induced convulsions. PGs of the F type are on the contrary, completely inactive (13). It has been recently reported that changes in cerebellar cyclic 3',5'-guanosine monophosphate (cGMP) play a primary role in experimental convulsions and several investigators have been able to correlate the anticonvulsant properties of several drugs with their ability to interfere selectively with the increase of cerebellar cGMP elicited by the stimulating agent (14). Studies carried out in this laboratory have recently demonstrated tbat PGs of the E type do exert the anticonvulsant effect by preventing the cerebellar cGMP increase induced by pentamethylenetetrazole (PMT) which may trigger the convulsive phase (15). Experiments designed by using harmaline, a drug which induces tremors by specifically increasing cerebellar cGMP, have given similar results (15). Although the behavioural effects of exogenous PGEs are well established, very little is known on the fate of endogenous PGs in the CNS during experimental convulsions: Wolfe (16) has reported an increase of PGF« in cerebrospinal fluid of patients with seizures, and La TorreZ~nd Patrono (17) have obtained similar results and found high levels of PGF2~ in patients with subarachnoid hemorrage and following braln damage. Furthermore Zaz and Roth (18) have demonstrated an increase of PGF2« in rat cerebral cortex following electroconvulsive shock. These results are of interest, but the absolute values of PGF« found by these Authors should be considered with caution, bec~~se of the well known stimulation in PGs synthesis by trauma, anoxia, and tissue manipulation.
894
MAY 1977 VOL. 13 NO. 5
PROSTAGLANDINS The possibility that brain PGs might be involved in the induction of convulsions, prompted us to investigate the existence of a causal relationship between modifications in endogenous PGs and convulsions, together with their possible interference with cyclic nucleotides. METHODS AND MATERIALS Animals. Male Sprague Dawley rats (Charles River) weighing approximately 120-150 gr were used after housing for 7 days under conditions of controlled temperature (22°C) and light (14 hours light, i0 hours dark). Sacrifice of. the animals. Rats were sacrificed by exposure of their head for 5 seconds to a high intensity focussed microwave radiation (70 mW/cm2), generated by a magnetron (2.4 Kw, 2.49 GHg), in order to avoid post mortem changes in PGs and cyclic ~ucleotides levels (19, 20). Determination of PGs and cyclic nucleotides. ~l Determination of PGs content in rat cortex: extraction, purification, preparation of PG derivatives and mass-fragmentographic analysis were performed as previously reported (2, 21). ~l Determination of cAMP and cGMP content in rat cortex: cAMP and cGMP were assayed after extraction and purification by column chromatography and separation of the nucleotides fD~owing the procedure described by Mao and Guidotti (22). cAMP was measured according to the method of Gilman (23), using a binding protein from rabbit skeletal muscle isolated in our laboratory. cGMP was determined using the radioassay technique described by Steiner (24). Commercially available kit for cGMP were purchased from Collaborative Research Inc., Boston, Mass., USA. Dru~s. Pentamethylenetetrazole (PMT) was purchased from Aldrich Europe, Beerse, Belgium. cAMP (3',5'-adenosine cyc~ic monophosphate) was purchased from Boehringer Mannheim, and ~HcAMP from Sorin, Saluggia, Italy.
RESULTS The intraperitoneal administration of PMT, at the fully convulsant dose of iOO mg/kg has a profound effect on cortical prostaglandins as well as on cortical cyclic nucleotides. Cortical PGF« is increased from the basal value of 126 pg/mg prot. to values as high as 1425 pg/mg prot. (Table i). A remarkable increase is also seen with PGE», although not as high as with PGF2 : PGE 2 values average 148 pg/mg prot. in normal conditions, ana undergo a 4 fold increase during the convulsive phase, reaching a value of 579 pg/mg prot (Table i).
MAY 1977 VOL. 13 NO. 5
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PROSTAGLANDINS The a n i m a l s w e r e k i l l e d 90" after t r e a t m e n t w i t h the PMT, a time at w h i c h the seizures are fully present. In these e x p e r i m e n t a l conditions, also c o r t i c a l cyclic nucleotides u n d e r g o striking variations. C o r t i c a l cGMP is increased three-fold, changing from a basal v a l u e of 0.24 + 0.05 pmoles/mg prot. to values as high as 0.69 + 0.05 (during convulsions) (Table i). C o r t i c a l cAMP is i~creased after t r e a t m e n t w i t h PMT (iOO mg/kg, i.p.) reaching values of 18.2 + 1 pmoles/mg prot., from a basal v a l u e of 7.9 + 1.2 pmole~/mg prot. (Table i). In o r d e r to a s c e r t a i n w h a t is the sequence of b i o c h e m i c a l events following the a d m i n i s t r a t i o n of PMT and p o s s i b l y triggering the p h a r m a c o l o g i c a l phenomena, further e x p e r i m e n t s have b e e n c a r r i e d out using a s u b c o n v u l s a n t dose of PMT (50 m g / k g i.p.). Even w i t h o u t d e t e c t a b l e convulsions, there is a d e f i n i t e rise in PGFù from the basal values to 396 pg/mg prot. w i t h a h i g h l y s t ~ ~ i s t i c a l s i g n i f i c a n c e (p
DISCUSSION The a n a l y s i s of our e x p e r i m e n t a l data c l e a r l y indicate that in rat cortex v a r i a t i o n s in cGMP levels induced by PMT are not the p r i m a r y b i o c h e m i c a l event detected, as in the case of the rat c e r e b e l l u m (15) but an increase of P G F 2 « levels is the first p a r a m e t e r to be modified. At the light of these e x p e r i m e n t a l results, the m e a n i n g of the increased levels of P G F 2 e . i n rat cortex is d i f f i c u l t to interpret, since PGF^ g i v e n l.p. does not induce c o n v u l s i o n s in the rat. This m i g h t ~ ~ due to the e x t r e m e l y s~all concent r a t i o n of the s u b s t a n c e a c t u a l l y r e a c h i n g the proper b r a i n area after an i n t r a p e r i t o n e a l i n j e c t i o n (25). H o w e v e r PGF~ injected i n t r a v e n o u s l y in young chicks • Z w h i c h are d e v o l d o 9 b l o o d b r a i n barrier, causes an immediate and extreme e x t e n s i o n of the limbs w i t h some d o r s i f l e c t i o n of the neck, an e f f e c t w h i c h is b l o c k e d by deep a n e s t h e s i a (26).
MAY 1977 VOL. 13 NO. 5
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In addition to this one should consider that PGF_« injected intravenously in mice potentiates like amphet~mine, and unlike PGE 2, the effect of subthreshold convulsant doses of PMT. Recent clinical studies have been reported by Lyneham et al. (27) on epileptic seizures and atypical electroencephalograms (E.E.G.) occurring in patients aborted by intraamniotic instillation of PGFA . This report has casted considerable concern on the potential use of prostaglandins as oxy-tocic, but reports by other laboratories (28, 29) are at variance with this statement. Draw definite conclusions about the role of PGs in convulsive state from the above cited observations is definitely overoptimistic. Further studies are necessary in order to elucidate the complex nature of the events leading to a convulsive state and the possible relationships between PGs and brain neurotransmitters.
REFERENCES i. Samuelsson, B. Identification of a smooth muscle-stimulating factor in bovine brain. Prostaglandin and related factors 25. Biochim. Biophys. Acta 84:218, 1964 2. Nicosia, S., G. Galli. A mass fragmentographic method for the quantitative evaluation of brain prostaglandin biosynthesis. Prostaglandins, 9:397, 1975 3. Schoen, M.W., J.M. Iacono. In: Advances in Prostaglandins and Thromboxanes Research.(B. Samuelsson and R. Paoletti, eds.), vol. i, Raven Press, N.Y., 1976, p. 763 4. Pappius, H.M., K. Rostworowski, and L.S. Wolfe. Biosynthesis of prostaglandin F?« and E 9 by brain tissue in vitro. Trans. Amer. Soc. Neurocheß., 5:119 (abstract) and unpublished results. 5. Nakano, J., A.V. Prancan, and S.E. Moore. Metabolism of prostaglandin E r in the cerebral cortex and cerebellum of the dog and rat. Bräin Res. 39:545, 1972 6. Kuehl, I.A. Jr. Prostaglandins, cyclic nucleotides functions. Prostaglandins, 5:325, 1974
and cell
7. Shaw, J.E., S.J. Jessup and P.V. Ramwell. In: Advances in Cyclic Nucleotides Research (P. Greengard and G.A. Robison, vol. i, Raven Press, N.Y., 1972, p. 479
eds.)
8. Berti, F., M. Trabucchi, V. Bernareggi and R. Fumagalli. Prostaglandins on cyclic AMP formation in cerebral cortex of different m a m a l i a n species. Adv. Biosc. 9:475, 1972 9. Gilman, A.G., and M. Niremberg. Regulation of adenosine 3',5'cyclic monophosphate metabolism in cultured neuroblastoma cells. Nature 234:356, 1971 iO. Siggins, G.R., B.J. Hoffer and F.E. Bloom. Studies on norepinephrine-containing afferents to Purkinje cells of rat cerebellum. III. Evidence for mediation of norepinephrine effects by cyclic 3',5'-adenosine monophosphate. Brain Res. 25:535, 1971
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PROSTAGLANDINS ii. Siggins, G.R., B.J. Hoffer, and F.E. Bloom. Prostaglandinnorepinephrine interactions in brain: micro-electrophoretic and histochemical correlates. Ann. N.Y. Acad. Sci. 180:302, 1971 12. Horton,
E.W., Br. J. Pharmac.
22:189,
1964
13. Horton, E.W. Prostaglandins, Monographs on endocrinology. Springer-Verlag, N.Y., 7:117, 1972 14. Mao, C.C., A. Guidotti and E. Costa. Inhibition by diazepam of the tremor and the increase of cerebellar cGMP content elicited by harmaline. Brain Res. 83:516, 1975 15. Folco, G.C., D. Longiave, F. Berti, R. Fu~agalli and R. Paoletti. In: Advances in Prostaglandins and Thromboxane Research. (B. Samuelsson and R. Paoletti, eds.), Raven Press, N.Y., vol. I, 305, 1976 16. Wolfe, L.S. In: Advances in Neurochemistry (B.W. Agranoff, and N.H. Aprison, eds.), Plenum Press, N.Y., vol. i, 1975, p.l 17. La Torre-Patrono, C., A. Fortuna and D. Grossi Belloni. Role of prostaglandin Fg« in human cerebral vasospasm. J. Neurosurg., 41:293, I974 18. Zatz, M., and R.H. Roth. Electroconvulsive shock raiser prostaglandins F in rat cerebral cortex. Biochem. Pharmacol. 24:2101, 1975 19. Bosisio, E., Galli C., G. Galli, S. Nicosia, C. Spagnuolo and L. Tosi. Correlation between release of free arachidonic acid and prostaglandin formation in brain cortex and cerebellum. Prostaglandins, 11:773, 1976 20. Guidotti, A., D.L. Cheney, M. Trabucchi, M. Doteuchi and C. Wang. Focussed microwave radiation: a technique to minimize post-mortem changes of cyclic nucleotides, dopa and choline and to preserve brain morphology. Neuropharmacol. 13:1115, 1974 21. Nicosia, S., G. Galli. A rapid gas-chromatographic-mass spectrometric method for prostaglandin analysis at picomole levels. Anal. Biochem. 61:192, 1974 22. Mao, C.C., A. Guidotti. Simultaneous isolation of adenosine3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) in small tissue samples. Anal. Bioch. 59:63, 1974 23. Gilman, A. A protein binding assay of adenosine 3',5'-cyclic monophosphate. Proc. Nat. Acad. S~i. 67:305, 1970 24. Steiner, A.L., R.E. Wehmann, C.W. Parker and D.M. Kipnis, In: Advances in Cyclic Nucleotides Research (P. Greengard and G.A. Robison, eds.), vol. 2, Raven Press, 1972, p. 51 25. Holmes, S.W. and E.W. Horton, The distribution of tritiumlabelled prostaglandin E 1 injected in amounts sufficient to produce central nervous effects in cats and chicks. Br. J. Pharmac. 34:32, 1962 26. Horton, E.W. and I.H.M. Main. Further observations on the central nervous actions of prostaglandins F2~ and E 1. Br. J. Pharm. 30:568, 1967 27. Lyneham, R.C., J.G. McLeod, I.D. Smith, P.A. Low, R.P. Shearman and A.R. Korda. Convulsions and electroencephalogram abnormalities after intraamniotic prostaglandin F2«. The Lancet, II:lO03, 1973 28. Craft, I. Prostaglandins and convulsions. The Lancet, December 15th, 1389, 1973 29. Thiery, M., J.J. Amy, D. De Hemptinne and A. Yo Le Sian. The Lancet, February 9th, 9 1 8 , 1 9 7 4 Received Ii/24/76 - Approved'i/19/77
900
MAY 1977 VOL. 13 NO. 5
RELATIONS
BETWEEN
LEVELS
PROSTAGLANDIN
Folco G.C., Longiave Institute University
E 2, F2«, AND CYCLIC NUCLEOTIDES
IN RAT BRAIN AND INDUCTION
of Pharmacology of Milan,
D.
OF CONVULSIONS.
and Bosisio E.
and Pharmacognosy,
20129 Milan,
School of Pharmacy,
Italy.
ABSTRACT Fully convulsant doses of pentamethylenetetrazole cause marked increase in rat brain cortical PGFù , PGE2, cGMP and cAMP during seizures, whereas subconvulsant do~~s cause an increase of rat brain cortical PGFù without affecting the other biochemical parametersconsidered. Rat cerebellar prostaglandlns were not modified by the convulsant agent at either dosage.
ACKNOWLEDGEMENTS The Authors are grateful to Dr. J. Pike of the Upjohn Company, Kalamazoo, Michigan, and to Dr. K. Sano, ONO Pharmaceutical, Osaka, Japan, for generous supply of prostaglandins and deuterated standards. The experimental results were partly supported by a grant of the C.N.R. (Consiglio Nazionale delle Ricerche, Roma) No. 75.00522. We are also indebted to Mr. Aurelio Toia for his excellent technical assistance and to Dr. V. Mandelli for statistical advice.
INTRODUCTION The presence of prostaglandins (PGs) in mammalian brain is well documented (i), and several groups have demonstrated that PGF2« is the predominant prostaglandin identified (2). Biosynthesis of PGs occurs in rat brain cortex from arachidonic acid released from phospholipids (3) by a phospholipase A, which is considered to be the triggering and also rate limiting step enzyme. Conflicting reports have appeared on the existence of brain degradative enzymes: a very low activity of these enzymes is found in cerebral cortex of cat and dog (4, 5). Probably prostaglandins synthetized in brain "in vivo" are released in the venous circulation and metabolized in other tissues.
MAY 1977 VOL. 13 NO. 5
893
PROSTAGLANDINS
The regulatory role of PGs on intracellular concentrations of cyclic nucleotides at peripheral level (6, 7), as well as in the CNS, is also well established. Several laboratories have demonstrated an "in vitro" stimulation of 3',5'cyclic Adenosin Monophosphate (cAMP) formation by PGs of the E type in cultured neural tissue and in slices of cerebral cortex (8, 9): responses varied with the species examined and PGs of the F type were completely ineffective in this respect, although PGF2« is the major prostaglandin present in the brain. In addition to this, neurophysiological studies using microiontophoretic techniques have shown that PGE], and PGE 2 consistently antagonize the reduction in discharg~ rate of 9at Purkinje cells caused by norepinephrine (NE) but not by cAMP (10, ii). These Authors, placing the inhlbitory action of PGs at the level of cAMP formation, indicate a possible feed-back regulatory role of these compounds in central neurotransmission. From the behavioural point of view, E prostaglandins administered to the intact animal exert a sedative-tranquillizing action (12). Furthermore, PGE I shows marked anticonvulsant properties which are dependen£ on the experimental model : animals are protected against seizures produced by pentamethylenetetrazole, strychnine but not against picrotoxin induced convulsions. PGs of the F type are on the contrary, completely inactive (13). It has been recently reported that changes in cerebellar cyclic 3',5'-guanosine monophosphate (cGMP) play a primary role in experimental convulsions and several investigators have been able to correlate the anticonvulsant properties of several drugs with their ability to interfere selectively with the increase of cerebellar cGMP elicited by the stimulating agent (14). Studies carried out in this laboratory have recently demonstrated tbat PGs of the E type do exert the anticonvulsant effect by preventing the cerebellar cGMP increase induced by pentamethylenetetrazole (PMT) which may trigger the convulsive phase (15). Experiments designed by using harmaline, a drug which induces tremors by specifically increasing cerebellar cGMP, have given similar results (15). Although the behavioural effects of exogenous PGEs are well established, very little is known on the fate of endogenous PGs in the CNS during experimental convulsions: Wolfe (16) has reported an increase of PGF« in cerebrospinal fluid of patients with seizures, and La TorreZ~nd Patrono (17) have obtained similar results and found high levels of PGF2~ in patients with subarachnoid hemorrage and following braln damage. Furthermore Zaz and Roth (18) have demonstrated an increase of PGF2« in rat cerebral cortex following electroconvulsive shock. These results are of interest, but the absolute values of PGF« found by these Authors should be considered with caution, bec~~se of the well known stimulation in PGs synthesis by trauma, anoxia, and tissue manipulation.
894
MAY 1977 VOL. 13 NO. 5
PROSTAGLANDINS The possibility that brain PGs might be involved in the induction of convulsions, prompted us to investigate the existence of a causal relationship between modifications in endogenous PGs and convulsions, together with their possible interference with cyclic nucleotides. METHODS AND MATERIALS Animals. Male Sprague Dawley rats (Charles River) weighing approximately 120-150 gr were used after housing for 7 days under conditions of controlled temperature (22°C) and light (14 hours light, i0 hours dark). Sacrifice of. the animals. Rats were sacrificed by exposure of their head for 5 seconds to a high intensity focussed microwave radiation (70 mW/cm2), generated by a magnetron (2.4 Kw, 2.49 GHg), in order to avoid post mortem changes in PGs and cyclic ~ucleotides levels (19, 20). Determination of PGs and cyclic nucleotides. ~l Determination of PGs content in rat cortex: extraction, purification, preparation of PG derivatives and mass-fragmentographic analysis were performed as previously reported (2, 21). ~l Determination of cAMP and cGMP content in rat cortex: cAMP and cGMP were assayed after extraction and purification by column chromatography and separation of the nucleotides fD~owing the procedure described by Mao and Guidotti (22). cAMP was measured according to the method of Gilman (23), using a binding protein from rabbit skeletal muscle isolated in our laboratory. cGMP was determined using the radioassay technique described by Steiner (24). Commercially available kit for cGMP were purchased from Collaborative Research Inc., Boston, Mass., USA. Dru~s. Pentamethylenetetrazole (PMT) was purchased from Aldrich Europe, Beerse, Belgium. cAMP (3',5'-adenosine cyc~ic monophosphate) was purchased from Boehringer Mannheim, and ~HcAMP from Sorin, Saluggia, Italy.
RESULTS The intraperitoneal administration of PMT, at the fully convulsant dose of iOO mg/kg has a profound effect on cortical prostaglandins as well as on cortical cyclic nucleotides. Cortical PGF« is increased from the basal value of 126 pg/mg prot. to values as high as 1425 pg/mg prot. (Table i). A remarkable increase is also seen with PGE», although not as high as with PGF2 : PGE 2 values average 148 pg/mg prot. in normal conditions, ana undergo a 4 fold increase during the convulsive phase, reaching a value of 579 pg/mg prot (Table i).
MAY 1977 VOL. 13 NO. 5
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PROSTAGLANDINS The a n i m a l s w e r e k i l l e d 90" after t r e a t m e n t w i t h the PMT, a time at w h i c h the seizures are fully present. In these e x p e r i m e n t a l conditions, also c o r t i c a l cyclic nucleotides u n d e r g o striking variations. C o r t i c a l cGMP is increased three-fold, changing from a basal v a l u e of 0.24 + 0.05 pmoles/mg prot. to values as high as 0.69 + 0.05 (during convulsions) (Table i). C o r t i c a l cAMP is i~creased after t r e a t m e n t w i t h PMT (iOO mg/kg, i.p.) reaching values of 18.2 + 1 pmoles/mg prot., from a basal v a l u e of 7.9 + 1.2 pmole~/mg prot. (Table i). In o r d e r to a s c e r t a i n w h a t is the sequence of b i o c h e m i c a l events following the a d m i n i s t r a t i o n of PMT and p o s s i b l y triggering the p h a r m a c o l o g i c a l phenomena, further e x p e r i m e n t s have b e e n c a r r i e d out using a s u b c o n v u l s a n t dose of PMT (50 m g / k g i.p.). Even w i t h o u t d e t e c t a b l e convulsions, there is a d e f i n i t e rise in PGFù from the basal values to 396 pg/mg prot. w i t h a h i g h l y s t ~ ~ i s t i c a l s i g n i f i c a n c e (p
DISCUSSION The a n a l y s i s of our e x p e r i m e n t a l data c l e a r l y indicate that in rat cortex v a r i a t i o n s in cGMP levels induced by PMT are not the p r i m a r y b i o c h e m i c a l event detected, as in the case of the rat c e r e b e l l u m (15) but an increase of P G F 2 « levels is the first p a r a m e t e r to be modified. At the light of these e x p e r i m e n t a l results, the m e a n i n g of the increased levels of P G F 2 e . i n rat cortex is d i f f i c u l t to interpret, since PGF^ g i v e n l.p. does not induce c o n v u l s i o n s in the rat. This m i g h t ~ ~ due to the e x t r e m e l y s~all concent r a t i o n of the s u b s t a n c e a c t u a l l y r e a c h i n g the proper b r a i n area after an i n t r a p e r i t o n e a l i n j e c t i o n (25). H o w e v e r PGF~ injected i n t r a v e n o u s l y in young chicks • Z w h i c h are d e v o l d o 9 b l o o d b r a i n barrier, causes an immediate and extreme e x t e n s i o n of the limbs w i t h some d o r s i f l e c t i o n of the neck, an e f f e c t w h i c h is b l o c k e d by deep a n e s t h e s i a (26).
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MAY 1977 VOL. 13 NO. 5
PROSTAGLANDINS
In addition to this one should consider that PGF_« injected intravenously in mice potentiates like amphet~mine, and unlike PGE 2, the effect of subthreshold convulsant doses of PMT. Recent clinical studies have been reported by Lyneham et al. (27) on epileptic seizures and atypical electroencephalograms (E.E.G.) occurring in patients aborted by intraamniotic instillation of PGFA . This report has casted considerable concern on the potential use of prostaglandins as oxy-tocic, but reports by other laboratories (28, 29) are at variance with this statement. Draw definite conclusions about the role of PGs in convulsive state from the above cited observations is definitely overoptimistic. Further studies are necessary in order to elucidate the complex nature of the events leading to a convulsive state and the possible relationships between PGs and brain neurotransmitters.
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