- Email: [email protected]
Effect of quinolinic acid administered during pregnancy on the brain of offspring
Exp Toxic Patho11994; 46: 323-327 Gustav Fischer Verlag Jena
Medical Centre of Postgraduate Education, Laboratory of Histochemistry, Warsaw, Poland
Effect of quinolinic acid administered during pregnancy on the brain of offspring M. BESKlD With 5 figures Received: September 20,1993; Accepted: October 18, 1993 Address for correspondence: Prof. M. BESKID, M.D., D.Sc., Laboratory of Histochemistry, ul. Marymoncka 99,01-813 Warsaw, Poland. Key words: Quinolinic acid; Brain, foetus; Pregnancy
Summary
Material and Methods
The brains of rat offspring were histologically and histochemically examined after quinolinic acid administration to mothers during the gestation period. Quinolinic acid was administered intraperitoneally in a dose of 30 or 60 mmol, once daily, throughout the entire gestation period. Brain specimens were taken on days 1,5, and 21 after birth from experimental and control animals. The neuronal cell body injury was detected in the selected brain formations. More profound alterations were seen in the substantia nigra and cerebral cortex, especially within the entorhinal area, whereas much less damage was noted in the striatum and hippocampus. Strongly pronounced symptoms of cerebral edema were seen. Histochemically, an increased activity of NADPH-reductase within neuronal cell bodies of the pyramidallayer in the hippocampus, striatum and cerebral cortex was demonstrated. The decrease of activity of succinic and alpha-glycerophosphate dehydrogenases within areas of tissue spongiosis was noted. The weak overall activity of MAO made it impossible to register changes in its intensity. No changes in the Ca-ATP-ase activity in brain formations after quinolinic acid treatment were observed. It has been reported that excitotoxic brain injury caused by quinolinic acid displays a selective pattern of neuronal degeneration that affects neuronal cell bodies but spares axons at the site of intracerebral in jections (SCHWARCZ et al. 1983; LEHMANN et al. 1985; VEZZANI et al. 1986), as well as following systemic administration (BESKID and MARKIEWICZ 1988; BESKID and FINKIEWICZ-MuRAWIEJSKA 1992). The excitotoxic activity of this compound can be detected by making use of the properties of the N-methyl-D-aspartate (NMDA) receptor agonist (STONE et al. 1987). It is to be noted that brain injury caused by quinolinic acid has been explored in detail in adult, but much less in developing animals. Hence, this supports our explanation of the quinolinic acid effect on the brain of rat offsprings, when this compound was administered to the mother throughout the gestation period.
Studies were carried out on the brains of rat offspring. Two groups of rats, 30 animals each, were taken. Quinolinic acid was administered intraperitoneally in a dose of 30 or 60 mmol once daily throughout the entire gestation period (experimental group). Animals from the control group were untreated. Brain specimens were taken on days 1, 5, and 21 after birth from both experimental and control groups. Serial paraffin sections were stained with cresyl violet and with hematoxylin and eosin. In the unfixed material cut on a cryostat the presence of succinic and alpha-glycerophosphate dehydrogenases were studied after PEARSE, NADPH-reductase after FARBER, monoamino-oxidase after GLENNER, and the calcium method for adenosine triphosphatase after PADYKULA and HERMAN.
Results Under normal conditions as well as after administration of quinolinic acid in a dose of 30 mmol the brain formations of the rat offspring present a characteristic picture. In the experimental material, when quinolinic acid in a dose of 60 mmol was administered, the neurotoxic effects were more profound and developed selectively in the substantia nigra and cortex tissue, whereas in the striatum and hippocampus they were much less intense. In such cases, in jury of neuronal cell bodies accompanied by strong symptoms of cerebral edema, was detected. In the substantia nigra of 1 and 5 day-old rats the density of neuronal cell bodies was either strongly increased, and the bodies were condensate and dark or, on the contrary, were pale, indicating severe losses in neuronal peExp Toxic Patho146 (1994) 4-5
323
Fig. 1. Substantia nigra of a 1 day-old rat. Quinolinie acid administration. Degenerated neuron cell bodies and tissue spongiosis. HE, x300.
Fig. 2. Substantia nigra of a 21 day-old rat. Quinolinic acid administration. Degenerated neuron cell bodies. HE, x300.
Fig. 3. Hippocampus of a 21 day-old rat. Quinolinie • acid administration. Focal loss of neuronal cell bodies within the pyramidal cell layer. HE, x120.
324
Exp Toxic Pathol46 (1994) 4--5
4
5
Fig. 4. Hippocampus of a 21 day-old rat. Quinolinic acid administration. Tissue spongiosis at the border of the granular layer of the hilus. HE, x300. Fig. 5. Entorhinal cortex of a 5 day-old rat. Quinolinic acid administration. Decreased content of cell bodies and tissue spongiosis. HE, x160. rikarya (fig. 1). In the substantia nigra of 21 day-old rats the neuronal cell bodies, which were pale and deprived of perikarya, resembled cell shadows. Moreover, the symptoms of focal tissue spongiosis, accompanied by neuronal injury, were strongly marked (fig. 2). In the striatum, dispersed neuronal cell bodies were pale, characterized by the loss of neuronal perikarya. These neuronal cell bodies were present in all experimental animals. In such cases the tissue spongiosis was of focal character, its intensity varied, being usually insignificant. In the nigro-striatal complex the glial cells had a moderately increased density. In the hippocampal formation of 1 and 5 day-old rats neuronal cell bodies within the pyramidal layer showed losses of neuronal perikarya and looked pale. In the hippocampus of 21 day-old rats the focal loss of neuronal cell bodies within the pyramidal cell layer at different levels of this formation was visible. Then the architectonic composition of the pyramidal cell layer was irregularly arranged (fig. 3). Signs of tissue spongiosis at the granular layer were invariably observed independent of the age of rats. As a rule, a more intense tissue spongiosis was seen within the hilus (fig. 4).
In the cortex of 1 and 5 day-old rats tissue spongiosis was observed to be more intense within entorhinal areas (fig. 5). This was accompanied by a decreased content of cell bodies. A less intense tissue spongiosis was shown in the cortex tissue of 21 day -old rats, and in this case the cerebral cortex within the entorhinal area was deficient in neuronal cells. Histochemical investigations revealed a variable intensity of the reaction of succinic and alpha-glycerophosphate dehydrogenases. A decrease in their activity was seen in areas where the tissue spongiosis was histologically demonstrated. The mapping of mono amino-oxidase (MAO) reaction was unsatisfactory. The weak activity of this enzyme made it impossible to investigate the intensity of its changes. The reaction of NADPH-reductase was more intense in certain brain formations after quinolinic acid treatment than in the control group. The increase of enzymatic activity was usually observed within the pyramidal cell layer of the hippocampus, and within the neuronal cell bodies ofthe striatum and cerebral cortex. No changes of Ca-ATP-ase activity in brain formations after quinolinic acid treatment were observed.
Exp Toxic Pathol46 (1994) 4-5
325
Discussion Qur results demonstrated that alterations in the brain of the rat offspring after the administration of quinolinic acid to mothers throughout the gestation period took place. Selective neuronal cell body injuries and symptoms of cerebral edema were the typical effects of that treatment. As a rule, neuronal injuries were accompanied by edema symptoms in the brain of 1 and 5 day-old rats, whereas in the 21 day-old ones neuronal alterations predominated. Tissue spongiosis in such cases was limited to the border of the granular layer of the hippocampus. It may be noted that quinolinic acid in a dose of 30 mmol was ineffective. The alterations detected in the brain of 1 day-old rats suggested that quinolinic acid can diffuse into foetal tissues during pregnancy. The results obtained have shown, though, that more profound alterations took place both in the substantia nigra and cerebral cortex; especially within the entorhinal area, whereas symptoms of the damage of the striatum and hippocampus were much less pronounced. Regional distribution of the selectively damaged neuronal cell bodies is indicative of the neuronal susceptibility to quinolinic acid. Quinolinic acid is a potent excitatory compound when applied to mammalian neurons, acting by activating NMDA-receptors (PERKINS and STONE 1983; STONE et al. 1987), which leads to neuronal cell body injury (COYLE and SCHWARCZ 1976; SCHWARCZ et al. 1983; STONE et al. 1987). The proposed mechanism is the ability to depolarize neurons (OLNEY 1974). It has been reported that the neurotoxicity of various excitatory compound varies with age (GREENAMYRE et al. 1987; MACDONALD et al. 1988; SILVERSTEIN et al. 1986). It has been further demonstrated that the immature rat brain is more susceptible to N-methyl-D-aspartate (NMDA) and quisquilate, and resistant to kainate. It was described that the neonatal striatum is resistant to kainate toxicity but this resistance vanishes after the second postnatal week (CAMPOCHIASO and COYLE, 1987). On the other hand, the response of the rat's hippocampus to N-methyl-D-asparartate (NMDA) depends on age and on the specific hippocampal region. Neuronal cells of the pyramidal layer show maximal response during the second postnatal week, whereas the susceptibility of the stratum radiatum appears only after the third week (HAMON and HEINEMANN 1988). It has been shown that in certain brain formations neuronal cell bodies exist which are resistant to the toxicity of N-methyl-D-aspartate (NMDA), but not to that of either quisqualate or kainate (KOH et al. 1964). These neuronal cell bodies were selectively spared also due to quinolinic acid treatment (BOEGMAN et al. 1987; DAVIES and ROBERTS 1987), and characterized by NADPH-diaphorase activity (FERRIERO et al. 1988a; 1990b). The persistence of NADPH-diaphorase-reactive neurons is considered to be a marker for the NMDA-receptor-mediated neurotoxicity (FERRIERO et al. 1988). As follows from the presented experiments, these neuronal cell bodies are 326
Exp Toxic Pathol46 (1994) 4-5
situated within the striatum, hippocampus, and cerebral cortex, and are characterized by strong NADPH-reductase activity. The cerebral edema may be considereded as a more general symptom of quinolinic acid toxicity. In neonates this may be related to hypoxia-ischemia, and mediated through excitatory transmitters acting at the level of NMDA-receptors (FERRIERO et al. 1988a; 1990b; CHAN et al. 1979). A series of experiments has demonstrated that administration ofNMDA-receptor antagonists resulted in an inhibition of the ischemic damage (SIMON et al. 1986; GERMANO et al. 1987). The alterations in neuronal cell bodies detected in the substantia nigra and entorhinal cortex, may serve as an argument that binding sites for quinolinic acid developed before birth. On the other hand, much less intense lesions observed in the striatum and hippocampus may be due to a lack of quinolinic acid binding sites in tissues of these animals. Since, on the other hand, injuries of neuronal cell bodies both in the striatum and hippocampus occur, a possibility of quinolinic acid accumulation in the tissues cannot be ruled out (GHOLSON et al. 1964). Hence, a prolonged toxic effect may take place. Moreover, in immature tissues a low activity of enzymes specifically catabolizing quinolinic acid (quinolinic acid phosphori-bosyltransferase - QPRT), may occur in spite of the fact that it may increase in response to elevated tissue levels of quinolinic acid (FOSTER et al. 1985). In conclusion, quinolinic acid which is a natural metabolite of tryptophan can under abnormal conditions produce neuronal cell body injury in the brain of the foetus which may be revealed after birth.
References BESKID M, MARKIEWICZ D: Morphological changes in brain of rats after intracardiac and intraperitoneal administration of quinolinic acid. Neuropat Pol 1988; 26: 61-68. BESKID M, FINKIEWICZ-MuRAWIEJSKA L: Quinolinic acid: effects on brain catecholamine and c-AMP content during L-dopa and reserpine administration. Exp Toxic Patholl992; 44: 66-69. BOEGMAN RJ, SMITH Y, PARENT A: Quinolinic acid does not spare striatal neuropeptide Y -immunoreactive neurons. Brain Res 1987; 415: 178-182. CAMPOCHIARO P, COYLE JT: Ontogenetic development of kainate neurotoxicity: correlates with glutamatergic innervation. Proc natn Acad Sci USA 1987; 75: 2025-2029. CHAN PH, FISHMAN RA, LEE JL, et al.: Effects of excitory neurotransmitter amino acids on swelling of rat brain cortical slices. J Neurochem 1979; 33: 1309-1315. COYLE JT, SCHWARCZ R: Lesions of striatal neurones with kainic acid provides a model for Huntington's chorea. Nature (Lond) 1976; 263: 244-246. DAVIES S, ROBERTS PJ: No evidence for preservation of somatostatin containing neurons after intrastriatal injections of quinolinic acid. Nature 1987; 327: 326-329. FOSTER AC, WHETSELL WOo Bird E, et al.: Quinolinic acid
phosphoribosyltransferase in human and rat brain: activity in Huntington's disease and quinolinate-Iesioned rat striatum. Brain Res 1985; 336: 207-214. GERMANO 1M, PITTS LH, MELDRUM BS: Kynurenate inhibition of cell excitation decreases stroke size and deficits. Ann Neuro11987; 22: 730-734. GHOLSON RK, UEDA L, OGASAWARA N, et al.: The enzymatic conversion of quinolinate to nicotinic acid mononucleotide in mammalian liver. J bioI chern 1964; 239: 1208-1214. GREENAMYRE T, PENNEY J, YOUNG AB, et al.: Evidence for transient perinatal glutamatergic innervation of globus pallidus. J Neurosci 1987; 7: 1022-1030. HAMON B, HEINEMANN U: Developmental changes in neuronal sensitivity to excitatory amino acids in area CAl of the rat hippocampus. Devl Brain Res 1988; 38: 286-290. KOH JY, PETERS S, CHOI DW: Neurons containing NADPH-diaphorase are selectiveley resistant to quinolate toxicity. Science 1986; 234: 73-76. LEHMANN J, FERKANY JW, SCHAEFFER P, et al.: Dissociation between the excitatory and "excitotoxic" effects of quinolinic acid analogs on the striatal cholinergic interneuron. J Pharmacol Exp Therap 1985; 232: 873-882. McDONALD JW, SILVERSTEIN FS, JOHNSTON MV: Neurotoxicity of N-methyl-D-aspartate is markedly enhanced in developing rat central nervous system. Brain Res 1988; 459: 200-203. OLNEY JW, Excitotoxic mechanism of neurotoxicity. In:
SPENCER PS, SCHAUMBURG HH (Eds.): Experimental and clinical neurotoxicology. Wiliams and Wilkins Baltimore, MD pp. 272-294. PERKINS MN, STONE TW: Quinolinic acid: regional variations in neuronal sensitivity. Brain Res. 1983; 259: 172-176. SCHWARCZ R, WHETSELL WO, MANGANO RM: Quinolinic acid: an endogenous metabolite that produces axonsparing lesion in rat brain. Science (Wash DC) 1983; 219: 316-318. SILVERSTEIN FS, CHEN R, JOHNSTON MV: The glutamate analogue quisqualic acid is neurotoxic in striatum and hippocampus of immature rat brain. Neurosci Lett 1986; 71: 13-18. SIMON RP, YOUNG RSK, STOUT S, et al.: Inhibition of excitatory neurotransmission with kynurenate reduces brain edema in neonatal anoxia. Neurosci Lett 1986; 71: 361-364. STONE TW, CONNICK JH, WINN P, et al.: Endogenous excitotoxic agents. In: Selective neuronal death. Wiley, Chichester (Ciba Foundation Symposium 126) 1987 pp. 204---220. VEZZANI A, HUI-Qru Wu, TULL! T, et al.: Anticonvulsant drugs effective against human temporal lobe epilepsy prevent seizures but not neurotoxicity induced in rats by quinolinic acid: electroencephalographic, behavioral assessments. J Pharmacol Exp Ther 1986; 239: 256-263.
Exp Toxic Patho146 (1994) 4-5
327
Medical Centre of Postgraduate Education, Laboratory of Histochemistry, Warsaw, Poland
Effect of quinolinic acid administered during pregnancy on the brain of offspring M. BESKlD With 5 figures Received: September 20,1993; Accepted: October 18, 1993 Address for correspondence: Prof. M. BESKID, M.D., D.Sc., Laboratory of Histochemistry, ul. Marymoncka 99,01-813 Warsaw, Poland. Key words: Quinolinic acid; Brain, foetus; Pregnancy
Summary
Material and Methods
The brains of rat offspring were histologically and histochemically examined after quinolinic acid administration to mothers during the gestation period. Quinolinic acid was administered intraperitoneally in a dose of 30 or 60 mmol, once daily, throughout the entire gestation period. Brain specimens were taken on days 1,5, and 21 after birth from experimental and control animals. The neuronal cell body injury was detected in the selected brain formations. More profound alterations were seen in the substantia nigra and cerebral cortex, especially within the entorhinal area, whereas much less damage was noted in the striatum and hippocampus. Strongly pronounced symptoms of cerebral edema were seen. Histochemically, an increased activity of NADPH-reductase within neuronal cell bodies of the pyramidallayer in the hippocampus, striatum and cerebral cortex was demonstrated. The decrease of activity of succinic and alpha-glycerophosphate dehydrogenases within areas of tissue spongiosis was noted. The weak overall activity of MAO made it impossible to register changes in its intensity. No changes in the Ca-ATP-ase activity in brain formations after quinolinic acid treatment were observed. It has been reported that excitotoxic brain injury caused by quinolinic acid displays a selective pattern of neuronal degeneration that affects neuronal cell bodies but spares axons at the site of intracerebral in jections (SCHWARCZ et al. 1983; LEHMANN et al. 1985; VEZZANI et al. 1986), as well as following systemic administration (BESKID and MARKIEWICZ 1988; BESKID and FINKIEWICZ-MuRAWIEJSKA 1992). The excitotoxic activity of this compound can be detected by making use of the properties of the N-methyl-D-aspartate (NMDA) receptor agonist (STONE et al. 1987). It is to be noted that brain injury caused by quinolinic acid has been explored in detail in adult, but much less in developing animals. Hence, this supports our explanation of the quinolinic acid effect on the brain of rat offsprings, when this compound was administered to the mother throughout the gestation period.
Studies were carried out on the brains of rat offspring. Two groups of rats, 30 animals each, were taken. Quinolinic acid was administered intraperitoneally in a dose of 30 or 60 mmol once daily throughout the entire gestation period (experimental group). Animals from the control group were untreated. Brain specimens were taken on days 1, 5, and 21 after birth from both experimental and control groups. Serial paraffin sections were stained with cresyl violet and with hematoxylin and eosin. In the unfixed material cut on a cryostat the presence of succinic and alpha-glycerophosphate dehydrogenases were studied after PEARSE, NADPH-reductase after FARBER, monoamino-oxidase after GLENNER, and the calcium method for adenosine triphosphatase after PADYKULA and HERMAN.
Results Under normal conditions as well as after administration of quinolinic acid in a dose of 30 mmol the brain formations of the rat offspring present a characteristic picture. In the experimental material, when quinolinic acid in a dose of 60 mmol was administered, the neurotoxic effects were more profound and developed selectively in the substantia nigra and cortex tissue, whereas in the striatum and hippocampus they were much less intense. In such cases, in jury of neuronal cell bodies accompanied by strong symptoms of cerebral edema, was detected. In the substantia nigra of 1 and 5 day-old rats the density of neuronal cell bodies was either strongly increased, and the bodies were condensate and dark or, on the contrary, were pale, indicating severe losses in neuronal peExp Toxic Patho146 (1994) 4-5
323
Fig. 1. Substantia nigra of a 1 day-old rat. Quinolinie acid administration. Degenerated neuron cell bodies and tissue spongiosis. HE, x300.
Fig. 2. Substantia nigra of a 21 day-old rat. Quinolinic acid administration. Degenerated neuron cell bodies. HE, x300.
Fig. 3. Hippocampus of a 21 day-old rat. Quinolinie • acid administration. Focal loss of neuronal cell bodies within the pyramidal cell layer. HE, x120.
324
Exp Toxic Pathol46 (1994) 4--5
4
5
Fig. 4. Hippocampus of a 21 day-old rat. Quinolinic acid administration. Tissue spongiosis at the border of the granular layer of the hilus. HE, x300. Fig. 5. Entorhinal cortex of a 5 day-old rat. Quinolinic acid administration. Decreased content of cell bodies and tissue spongiosis. HE, x160. rikarya (fig. 1). In the substantia nigra of 21 day-old rats the neuronal cell bodies, which were pale and deprived of perikarya, resembled cell shadows. Moreover, the symptoms of focal tissue spongiosis, accompanied by neuronal injury, were strongly marked (fig. 2). In the striatum, dispersed neuronal cell bodies were pale, characterized by the loss of neuronal perikarya. These neuronal cell bodies were present in all experimental animals. In such cases the tissue spongiosis was of focal character, its intensity varied, being usually insignificant. In the nigro-striatal complex the glial cells had a moderately increased density. In the hippocampal formation of 1 and 5 day-old rats neuronal cell bodies within the pyramidal layer showed losses of neuronal perikarya and looked pale. In the hippocampus of 21 day-old rats the focal loss of neuronal cell bodies within the pyramidal cell layer at different levels of this formation was visible. Then the architectonic composition of the pyramidal cell layer was irregularly arranged (fig. 3). Signs of tissue spongiosis at the granular layer were invariably observed independent of the age of rats. As a rule, a more intense tissue spongiosis was seen within the hilus (fig. 4).
In the cortex of 1 and 5 day-old rats tissue spongiosis was observed to be more intense within entorhinal areas (fig. 5). This was accompanied by a decreased content of cell bodies. A less intense tissue spongiosis was shown in the cortex tissue of 21 day -old rats, and in this case the cerebral cortex within the entorhinal area was deficient in neuronal cells. Histochemical investigations revealed a variable intensity of the reaction of succinic and alpha-glycerophosphate dehydrogenases. A decrease in their activity was seen in areas where the tissue spongiosis was histologically demonstrated. The mapping of mono amino-oxidase (MAO) reaction was unsatisfactory. The weak activity of this enzyme made it impossible to investigate the intensity of its changes. The reaction of NADPH-reductase was more intense in certain brain formations after quinolinic acid treatment than in the control group. The increase of enzymatic activity was usually observed within the pyramidal cell layer of the hippocampus, and within the neuronal cell bodies ofthe striatum and cerebral cortex. No changes of Ca-ATP-ase activity in brain formations after quinolinic acid treatment were observed.
Exp Toxic Pathol46 (1994) 4-5
325
Discussion Qur results demonstrated that alterations in the brain of the rat offspring after the administration of quinolinic acid to mothers throughout the gestation period took place. Selective neuronal cell body injuries and symptoms of cerebral edema were the typical effects of that treatment. As a rule, neuronal injuries were accompanied by edema symptoms in the brain of 1 and 5 day-old rats, whereas in the 21 day-old ones neuronal alterations predominated. Tissue spongiosis in such cases was limited to the border of the granular layer of the hippocampus. It may be noted that quinolinic acid in a dose of 30 mmol was ineffective. The alterations detected in the brain of 1 day-old rats suggested that quinolinic acid can diffuse into foetal tissues during pregnancy. The results obtained have shown, though, that more profound alterations took place both in the substantia nigra and cerebral cortex; especially within the entorhinal area, whereas symptoms of the damage of the striatum and hippocampus were much less pronounced. Regional distribution of the selectively damaged neuronal cell bodies is indicative of the neuronal susceptibility to quinolinic acid. Quinolinic acid is a potent excitatory compound when applied to mammalian neurons, acting by activating NMDA-receptors (PERKINS and STONE 1983; STONE et al. 1987), which leads to neuronal cell body injury (COYLE and SCHWARCZ 1976; SCHWARCZ et al. 1983; STONE et al. 1987). The proposed mechanism is the ability to depolarize neurons (OLNEY 1974). It has been reported that the neurotoxicity of various excitatory compound varies with age (GREENAMYRE et al. 1987; MACDONALD et al. 1988; SILVERSTEIN et al. 1986). It has been further demonstrated that the immature rat brain is more susceptible to N-methyl-D-aspartate (NMDA) and quisquilate, and resistant to kainate. It was described that the neonatal striatum is resistant to kainate toxicity but this resistance vanishes after the second postnatal week (CAMPOCHIASO and COYLE, 1987). On the other hand, the response of the rat's hippocampus to N-methyl-D-asparartate (NMDA) depends on age and on the specific hippocampal region. Neuronal cells of the pyramidal layer show maximal response during the second postnatal week, whereas the susceptibility of the stratum radiatum appears only after the third week (HAMON and HEINEMANN 1988). It has been shown that in certain brain formations neuronal cell bodies exist which are resistant to the toxicity of N-methyl-D-aspartate (NMDA), but not to that of either quisqualate or kainate (KOH et al. 1964). These neuronal cell bodies were selectively spared also due to quinolinic acid treatment (BOEGMAN et al. 1987; DAVIES and ROBERTS 1987), and characterized by NADPH-diaphorase activity (FERRIERO et al. 1988a; 1990b). The persistence of NADPH-diaphorase-reactive neurons is considered to be a marker for the NMDA-receptor-mediated neurotoxicity (FERRIERO et al. 1988). As follows from the presented experiments, these neuronal cell bodies are 326
Exp Toxic Pathol46 (1994) 4-5
situated within the striatum, hippocampus, and cerebral cortex, and are characterized by strong NADPH-reductase activity. The cerebral edema may be considereded as a more general symptom of quinolinic acid toxicity. In neonates this may be related to hypoxia-ischemia, and mediated through excitatory transmitters acting at the level of NMDA-receptors (FERRIERO et al. 1988a; 1990b; CHAN et al. 1979). A series of experiments has demonstrated that administration ofNMDA-receptor antagonists resulted in an inhibition of the ischemic damage (SIMON et al. 1986; GERMANO et al. 1987). The alterations in neuronal cell bodies detected in the substantia nigra and entorhinal cortex, may serve as an argument that binding sites for quinolinic acid developed before birth. On the other hand, much less intense lesions observed in the striatum and hippocampus may be due to a lack of quinolinic acid binding sites in tissues of these animals. Since, on the other hand, injuries of neuronal cell bodies both in the striatum and hippocampus occur, a possibility of quinolinic acid accumulation in the tissues cannot be ruled out (GHOLSON et al. 1964). Hence, a prolonged toxic effect may take place. Moreover, in immature tissues a low activity of enzymes specifically catabolizing quinolinic acid (quinolinic acid phosphori-bosyltransferase - QPRT), may occur in spite of the fact that it may increase in response to elevated tissue levels of quinolinic acid (FOSTER et al. 1985). In conclusion, quinolinic acid which is a natural metabolite of tryptophan can under abnormal conditions produce neuronal cell body injury in the brain of the foetus which may be revealed after birth.
References BESKID M, MARKIEWICZ D: Morphological changes in brain of rats after intracardiac and intraperitoneal administration of quinolinic acid. Neuropat Pol 1988; 26: 61-68. BESKID M, FINKIEWICZ-MuRAWIEJSKA L: Quinolinic acid: effects on brain catecholamine and c-AMP content during L-dopa and reserpine administration. Exp Toxic Patholl992; 44: 66-69. BOEGMAN RJ, SMITH Y, PARENT A: Quinolinic acid does not spare striatal neuropeptide Y -immunoreactive neurons. Brain Res 1987; 415: 178-182. CAMPOCHIARO P, COYLE JT: Ontogenetic development of kainate neurotoxicity: correlates with glutamatergic innervation. Proc natn Acad Sci USA 1987; 75: 2025-2029. CHAN PH, FISHMAN RA, LEE JL, et al.: Effects of excitory neurotransmitter amino acids on swelling of rat brain cortical slices. J Neurochem 1979; 33: 1309-1315. COYLE JT, SCHWARCZ R: Lesions of striatal neurones with kainic acid provides a model for Huntington's chorea. Nature (Lond) 1976; 263: 244-246. DAVIES S, ROBERTS PJ: No evidence for preservation of somatostatin containing neurons after intrastriatal injections of quinolinic acid. Nature 1987; 327: 326-329. FOSTER AC, WHETSELL WOo Bird E, et al.: Quinolinic acid
phosphoribosyltransferase in human and rat brain: activity in Huntington's disease and quinolinate-Iesioned rat striatum. Brain Res 1985; 336: 207-214. GERMANO 1M, PITTS LH, MELDRUM BS: Kynurenate inhibition of cell excitation decreases stroke size and deficits. Ann Neuro11987; 22: 730-734. GHOLSON RK, UEDA L, OGASAWARA N, et al.: The enzymatic conversion of quinolinate to nicotinic acid mononucleotide in mammalian liver. J bioI chern 1964; 239: 1208-1214. GREENAMYRE T, PENNEY J, YOUNG AB, et al.: Evidence for transient perinatal glutamatergic innervation of globus pallidus. J Neurosci 1987; 7: 1022-1030. HAMON B, HEINEMANN U: Developmental changes in neuronal sensitivity to excitatory amino acids in area CAl of the rat hippocampus. Devl Brain Res 1988; 38: 286-290. KOH JY, PETERS S, CHOI DW: Neurons containing NADPH-diaphorase are selectiveley resistant to quinolate toxicity. Science 1986; 234: 73-76. LEHMANN J, FERKANY JW, SCHAEFFER P, et al.: Dissociation between the excitatory and "excitotoxic" effects of quinolinic acid analogs on the striatal cholinergic interneuron. J Pharmacol Exp Therap 1985; 232: 873-882. McDONALD JW, SILVERSTEIN FS, JOHNSTON MV: Neurotoxicity of N-methyl-D-aspartate is markedly enhanced in developing rat central nervous system. Brain Res 1988; 459: 200-203. OLNEY JW, Excitotoxic mechanism of neurotoxicity. In:
SPENCER PS, SCHAUMBURG HH (Eds.): Experimental and clinical neurotoxicology. Wiliams and Wilkins Baltimore, MD pp. 272-294. PERKINS MN, STONE TW: Quinolinic acid: regional variations in neuronal sensitivity. Brain Res. 1983; 259: 172-176. SCHWARCZ R, WHETSELL WO, MANGANO RM: Quinolinic acid: an endogenous metabolite that produces axonsparing lesion in rat brain. Science (Wash DC) 1983; 219: 316-318. SILVERSTEIN FS, CHEN R, JOHNSTON MV: The glutamate analogue quisqualic acid is neurotoxic in striatum and hippocampus of immature rat brain. Neurosci Lett 1986; 71: 13-18. SIMON RP, YOUNG RSK, STOUT S, et al.: Inhibition of excitatory neurotransmission with kynurenate reduces brain edema in neonatal anoxia. Neurosci Lett 1986; 71: 361-364. STONE TW, CONNICK JH, WINN P, et al.: Endogenous excitotoxic agents. In: Selective neuronal death. Wiley, Chichester (Ciba Foundation Symposium 126) 1987 pp. 204---220. VEZZANI A, HUI-Qru Wu, TULL! T, et al.: Anticonvulsant drugs effective against human temporal lobe epilepsy prevent seizures but not neurotoxicity induced in rats by quinolinic acid: electroencephalographic, behavioral assessments. J Pharmacol Exp Ther 1986; 239: 256-263.
Exp Toxic Patho146 (1994) 4-5
327