Quinolinic acid and GABA-B receptor ligand: effect on pyramidal neurons of the CA1 sector of rat's dorsal hippocampus following peripheral administration.

In this study we evaluated the effect of baclofen on excitotoxic action of quinolinic acid in hippocampus following its prolonged systemic administration in rats. Male Wistar rats, weighing 200-220 g, were used in the study. Quinolinic acid and baclofen were administered alone or together. Quinolinic acid was administered intraperitoneally (i.p.) in a dose of 60 mmol, baclofen in a dose of 2 mg/kg, by gastric tube, once daily for 8 days. The control group received 1 ml of saline i.p. once daily for 8 days. Quinolinic acid alone produced neurotoxic effect in the CA1 area of the hippocampal formation. The presence of the dark-degenerated pyramidal cells was a common sign of a delayed excitotoxic effect. Baclofen added to quinolinic acid markedly attenuated the neurotoxic effect of quinolinic acid. In such cases, only some dark degenerated cells were seen. Baclofen alone resulted in alterations in some pyramidal cells in the hippocampal formation.

Quinolinic acid and sigma receptor ligand: effect on pyramidal neurons of the CA1 sector of dorsal hippocampus following peripheral administration in rats.

Male Wistar rats, weighing 200-220 g, were used in the study. Quinolinic acid and racemic pentazocine were administered alone or together. Quinolinic acid was administered intraperitoneally (i.p.) in a dose of 60 mmol, racemic pentazocine intramuscularly in a dose of 2 mg/kg, once every 24 h for 8 days. The control group received 1 ml of saline i.p. once daily for 8 days. Pentazocine alone produced no signs of alteration in the hippocampal formation. Quinolinic acid produced neurotoxic effect in the CA1 area of the hippocampal formation. The presence of the dark-degenerated pyramidal cells was a common sign of a delayed excitotoxic effect. Pentazocine added to quinolinic acid markedly attenuated the neurotoxic effect of quinolinic acid. In such cases, only single dark degenerated cells were seen.

Quinolinic acid: effect on the nucleus arcuatus of the hypothalamus in the rat (ultrastructural evidence).

Quinolinic acid was administered intraperitoneally to male Wistar rats in a dose of 60 mmol, once daily for 8 days. By electron microscopy, in quinolinic acid-treated rats, the neuronal cell bodies in the arcuate nucleus had features of increased cellular activity, but some damage of neuronal cell bodies was also evident.

Quinolinic acid: effect on neurons of the paraventricular nucleus of the hypothalamus.

Quinolinic acid was administered intraperitoneally to male Wistar rats in a dose of 60 mmol, once daily for 8 days. The neuronal cell bodies in the paraventricular nucleus of the hypothalamus of quinolinic acid-treated rats exhibited electron microscopic features of increased cellular activity but some damage of neuronal cell bodies was also present. After quinolinic acid treatment, damaged cells predominated within the parvocellular division of the nucleus. The cells varied with respect to the degree of their damage. Besides, the cells exhibiting an increased activity, as well as those looking normally, were also present. In the magnocellular division of the nucleus, the cells exhibiting an increased activity predominated, although some forms of damage could also be distinguished.

The effect of quinolinic acid administered during pregnancy on liver cells of rat offspring (ultrastructural investigation).

Liver cells of rat's offspring were ultrastructurally examined after administering quinolinic acid to mothers intraperitoneally in a dose of 60 mmol or 100 mmol, once daily, throughout the entire gestation period. Liver tissue specimens were taken on day 5 after birth from experimental and control animals. Administration of quinolinic acid resulted in a marked proliferation of smooth elements of endoplasmic reticulum in liver cells of their offspring, which indicated microsomal enzymatic induction. Simultaneously, injuries of liver cells of varying intensity were observed, which were dose-dependent on quinolinic acid administration, the injured cells being more frequent at higher doses of the drug.

The effect of quinolinic acid administered during pregnancy on the nigro-striatal complex of rat's offspring: ultrastructural investigation.

The nigro-striatal complex of rat's offspring was ultrastructurally examined after quinolinic acid administration to mothers during the gestation period, in order to mimick the congenital metabolic disturbances, resulting from an excess of quinolinic acid within foetal tissues. Hence, quinolinic acid was administered to mothers intraperitoneally in a dose of 60 mmol, once daily, throughout the entire gestation period. Brain specimens were taken on day 5 after birth, from experimental and control animals. Within the nigro-striatal complex there can be distinguished the more characteristic neuronal cell body alterations, and the more toxic effect as the edema signs and the retardment of the neuronal cell body maturity. In the substantia nigra, both swollen and dark-degenerated neuronal cell bodies have been identified, while in the striatum the latter forms predominated. The maturation of neuronal cell bodies was retarded, mainly within the striatum.

Effect of quinolinic acid administration on rat liver: ultrastructural investigation.

Quinolinic acid was administered intraperitoneally in a dose of 30 or 60 mmol, once every 24 h for 8 days. Its result in the dose of 30 mmol was the proliferation of smooth elements of the endoplasmic reticulum. The use of quinolinic acid in a dose of 60 mmol was characterized by the presence of more profound damage of organelles, among them the distinct decrease of the rough elements of the endoplasmic reticulum and polyribosomal structures was seen, and moreover, wide areas devoid of organelles were observed.

Histological and ultrastructural changes in the rat brain following systemic administration of picolinic acid.

Picolinic acid was administered intraperitoneally in a dose of 30, 60, or 100 mmol, once every 24 h for 8 days. Histologically, under normal conditions as well as when picolinic acid was administered in a dose of 30 mmol the brain formations exhibited characteristic features. When picolinic acid was administered in a dose of 60 mmol or 100 mmol, the alterations were profound and developed selectively in hippocampus, being much less intense in the substantia nigra and striatum. In such cases, injuries of neuronal cell bodies were accompanied by symptoms of spongiosis. Within the hippocampus, the neuronal cell body injury was selectively restricted to the hilar and CA3 regions of stratum pyramidale. Tissue spongiosis was more intense at the granular layer, particularly within the hilus and in the mossy fiber area at CA3. Histochemically, a variable intensity of the reaction of succinic and alpha-glycerophosphate dehydrogenases was demonstrated. A decrease in their activities was observed in areas where the neuronal cell body injuries and spongiosis took place. No changes in the Ca-ATP-ase activity in brain formation after picolinic acid treatment were observed. Ultrastructurally, the changes within substantia nigra were manifested by neuronal cell bodies of the dark type and dendritic degenerations. Also less damaged neuronal cell bodies were seen. They were swollen, depleted of polyribosomes with dilated elements of RER and altered mitochondria. Some of the dendritic profiles were swollen with lucent cytoplasm. Most of the boutons in synaptic contact zones were unchanged. Most presynaptic terminals which were in junction with dark dendrites were swollen with or without crystal-like aggregates of synaptic vesicles.

The effect of quinolinic acid administered during pregnancy on the hippocampal formation of rat's offspring (ultrastructural investigation).

The pyramidal cells of CA1 hippocampal area of rat's offspring was ultrastructurally examined after quinolinic acid administration to mothers during the gestational period, in order to mimic the congenital metabolic disturbances resulting from an endogenous excess of quinolinic acid within foetal tissues. Hence, quinolinic acid was administered to mothers intraperitoneally in a dose of 60 mmol, once daily, throughout the entire gestation period. Brain specimens were taken on Day 5 after birth, from experimental and control animals. The only observed change within the pyramidal cells was swelling of both neuronal somata and dendrites, as well as a distinct swelling of astroglia cytoplasm and processes. Besides this, toxic effects, like edema signs, were observed. Neurons of the hippocampal formation were found to be particularly susceptible to quinolinic acid toxicity. The highly vulnerable neurons were located within the CA1-area. The neuronal vulnerability correlates remarkably well with those responding to the excitatory effects of quinolinic acid in electrophysiological experiments (Perkins and Stone 1983 a,b). This region was shown to be rich in NMDA receptors (Cotman et al. 1987; Greenamyre et al. 1984). The susceptibility of neuronal cell bodies of the hippocampal formation of an adult mammalian to the quinolinic acid toxicity, has been investigated with great interest (Schwarcz et al. 1984; Taraszewska et al. 1991; Kida and Matyja 1990; Speciale et al. 1987). Yet there is little information on the course of the foetal development. Hence, in our experiments, quinolinic acid was administered to the mother throughout the gestation period in order to mimic the congenital metabolic disturbances resulting from an excess of quinolinic acid within foetal tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of quinolinic acid administered during pregnancy on the brain of offspring.

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 pyramidal layer 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 injections (Schwarcz et al. 1983; Lehmann et al. 1985; Vezzani et al. 1986), as well as following systemic administration (Beskid and Markiewicz 1988; Beskid and Finiewicz-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).(ABSTRACT TRUNCATED AT 250 WORDS)

Toxic effect of quinolinic acid administered during pregnancy on the cerebral cortex of rat's offspring: an ultrastructural study.

The cerebral cortex of rat's offspring was ultrastructurally examined after quinolinic acid administration to mothers during the gestation period. Quinolinic acid was administered intraperitoneally in a dose of 60 mmol, once daily, throughout the entire gestation period. Brain specimens were taken on day 5 after birth, from experimental and control animals. Ultrastructural analysis of the cortex tissue revealed maturing neuronal cell bodies and immaturelike cells. The distinguishing feature of altered maturing neuronal cell bodies was the presence of vacuoles and/or swollen cytoplasm. The vacuoles were present in the perikaryon as well as in the processes. As a rule, the organelles within swollen cytoplasm were scarce, and the cytoplasm itself had a distinctly lower electron density. In some cases a loss of chromatin grains was noted. The nuclear envelope was distended, forming perinuclearly situated channels and vacuoles. The most frequently observed change in the immature-like cells was a marked swelling of the cytoplasm, hence only few organelles could be seen. Only few synaptic complexes were present and their contact was weakly marked. The axon endings contained sometimes few vesicles. The postsynaptic dendritic processes were frequently significantly swollen. Astrocytes were swollen.

Quinolinic acid: effects on brain catecholamine and c-AMP content during L-dopa and reserpine administration.

The catecholamine content in rat brain tissue was determined following the administration of quinolinic acid alone or combined either with L-dopa and decarboxylase inhibitor or reserpine. Quinolinic acid alone decreased the levels of dopamine and noradrenaline, as well as those of c-AMP, and increased those of adrenaline. Treatment with L-dopa/decarboxylase inhibitor reversed the suppressing effect of quinolinic acid on dopamine, but not on noradrenaline. Reserpine alone depleted the contents of dopamine, noradrenaline and adrenaline. It could be concluded from the effects of quinolinic acid and reserpine given together that quinolinic acid suppresses the depletion of amines induced by reserpine. It has been demonstrated that quinolinic acid leads to injuries of nerve-cell bodies in pars compacta of the substantia nigra and in the striatum. Quinolinic acid is a natural metabolite of tryptophan, normally occurring in the liver, kidney and brain (Wolfensberger et al. 1983; Moroni et al. 1984). This compound exhibits convulsant and neuron excitant properties (Stone et al. 1987). It induces a selective pattern of neuronal degeneration both at the site of intracerebral injection (Schwarcz et al. 1983; Stone et al. 1987) and after general (intracardiac) administration (Beskid and Markiewicz 1988). The ability of quinolinic acid to produce neurotoxicity was greater in the striatum than in other parts of the brain. This prompted us to study catecholamine and c-AMP levels in rat brain tissue following quinolinic acid and L-dopa administration, as well as the influence of reserpine on quinolinic acid action.

Quinolinic acid: effect on 45Ca content in perfused rat heart preparations and its calcium ion binding property in Krebs-Henseleit medium and blood serum.

In the experiment it was found that quinolinic acid perfusion was accompanied with the increase in calcium 45Ca content in myocardium tissue. The increase in calcium content was associated with a decrease in heart contractility. Moreover, it was shown that quinolinic acid can form complexes with calcium ions in Krebs-Henseleit medium as well as in blood serum but only to a small degree.

Quinolinic acid: a modulator of the heart calcium channel in the rat and a binder of calcium ions.

When rat heart preparations were perfused with quinolinic acid at a slow constant rate, a decrease in contractility was observed. A higher rate of perfusion resulted in a biphasic response, thus both a positive inotropic effect and then a decrease in heart contractility were visible. Using a polarographic method, the association constant of quinolinic acid with calcium ions (Ka) was found to be equal to 220. By combining the values from heart perfusion experiments with the calculated ones of free calcium ions, a linear correlation was obtained between the decreases of contractility and of calcium ions (r = 0.94).

Quinolinic acid as calcium channel modulator in isolated rat heart preparations.

The effect of quinolinic acid perfusion on isolated rat hearts according to the procedure of Langendorff was studied. In the experiments when the final concentration range of quinolinic acid decreased from 10(-1) to 10(-7) mol/l through intermediate concentrations, a negative inotropic response with the enhancement of the coronary flow was stated. When an isolated heart preparation was perfused with 4 x 10(-3) and 4 x 10(-4) mol/l of a quinolinic acid, a biphasic response of the contractility was visible. In the experiments initial increase and then decrease in the contractility were demonstrated. Therefore, these effects of quinolinic acid were similar to those of the well-known action of the classical calcium channel modulators and may remain the basis of quinolinic acid neuro-excitotoxing activity after intracerebral and general treatment.

Ultrastructural and histochemical assessment of proximal renal tubule in rats during administration of lithium carbonate.

Rat kidney was studied histochemically and in electron microscope during administration of lithium carbonate for 14 days in doses of 4 mmol/l. Morphological examination demonstrated signs of damage exclusively to the epithelial cells in the proximal tubule. Histochemical examination demonstrated a major reduction of the reactions for succinate dehydrogenase and cytochrome oxidase. No difference was found in the intensity of the reaction for alkaline phosphatase and Ca-ATPase during lithium treatment as compared to controls. Additional observation demonstrated, only in histological examination, an increased number of cells of the macula densa.

[Morphological picture of lesions to substantia nigra of rats following intracardial administration of quinolinic acid]. / Obraz morfologiczny uszkodzenia istoty czarnej mózgu szczurów po dosercowym podaniu kwasu chinolinowego.

Quinolinic acid is tryptophan metabolite and one of the known endogenous substance of selective neurotoxic properties. Morphological studies on noxious effect of quinolinic acid on the black substance of the brain of rats following intracardial administration of this acid were carried out. Dependence of the lesions on the dose and time of use were analysed. No lesions to the black substance were noted following a series of everyday injections of quinolinic acid in the dose of 30 mol/ml for 4 and 8 days. Degenerative changes in the neurons of black substance appeared after a dose of 60 mol/ml injected everyday for 4 days. These changes exacerbated significantly after 8 days. Generalized neuronal defects and intensive degenerative lesions in the preserved neurons with signs of decomposition of fibrous elements of tissular basis followed an administration of quinolinic acid in the dose of 100 mol/ml for 4 and 8 consecutive days.