[Analysis of psychotic disorders in patients with refractory partial epilepsy, psychiatric diagnoses and clinical aspects]. / Análisis de los trastornos psicóticos en pacientes con epilepsia parcialrefractaria, diagnóstico psiquiátrico y características clínicas.

INTRODUCTION: The association between psychotic disorders and epilepsy has been controversial. Different subtypes of psychotic disorders in epilepsy patients have been described according to temporal relationship with seizures-postictal (PIP), interictal (IIP) and bimodal (BP) psychoses are described in literature. OBJECTIVES: Determine clinical characteristics of patients with refractory partial epilepsy and psychoses and compare the results with a control group of patients with refractory partial epilepsy without psychoses. METHODS: A total of 57 patients with refractory partial epilepsy and psychotic disorders (psychotic group [PG]) and 56 patients with refractory partial epilepsy and without psychoses (control group, CG) were evaluated according to DSM-IV criteria and SCID-I. All patients underwent complete neurological, neuroimaging, neuropsychological, and psychiatric assessment. Clinical, demographic and neuroimaging data were compared between patients in CG and PG. RESULTS: In PG 15 patients (26 %) had criteria for PIP, 29 patients (51%) for IIP and 13 patients (23%) for BP. Epilepsy time duration and bilateral hippocampal sclerosis were significantly more frequent in patients with psichosis. PG patients had a longer evolution time of epilepsy and greater frequency of bilateral hippocampal sclerosis (p < 0.05). No differences were found between psychoses subtypes. CONCLUSIONS: Longer evolution of seizures and the presence of bilateral hippocampal sclerosis may increase propensity to develop psychoses in patients with refractory partial epilepsy.

Sensitivity of cerebellar glutathione system to neonatal ionizing radiation exposure.

Reactive oxygen species (ROS) are relevant components of living organisms that, besides their role in the regulation of different important physiological functions, when present in excess are capable to affect cell oxidative status, leading to damage of cellular molecules and disturbance of normal cell function. ROS accumulation has been associated with a variety of conditions such as neurodegenerative diseases and ionizing radiation exposure. Cell ability to counteract ROS overproduction depends on the capacity of the endogenous antioxidant defenses--which includes the glutathione (GSH) system--to cope with. Since developing central nervous system (CNS) is especially sensitive to ROS-induced damage, the aim of the present work was to evaluate ROS, reduced GSH and oxidized glutathione (GSSG) levels in the cerebellum at different developmental ages after irradiation, in order to test if any changes were induced on these key oxidative stress-related cellular markers that might explain the high cerebellar vulnerability to radiation-induced injury. Since intracellular levels of GSH are maintained by glutathione reductase (GSHr), this enzymatic activity was also evaluated. Newborn Wistar rats were irradiated in their cephalic ends and the different parameters were measured, from 1h to 90 days post-irradiation. Results showed that an early transient increase in ROS levels followed by a decrease in cerebellar weight at 3-5 days post-irradiation were induced. An increase in cerebellar GSH levels was induced at 30 days after irradiation, together with a decrease in GSHr activity. These results support the hypothesis that ROS may represent a marker of damage prior to radiation-induced cell death. In contrast, it would be suggested that GSH system might play a role in the compensatory mechanisms triggered to counteract radiation-induced cerebellar damage.

Impaired T-cell dependent humoral response and its relationship with T lymphocyte sensitivity to stress hormones in a chronic mild stress model of depression.

The humoral response and the role of catecholamines and corticosterone were analyzed in a chronic mild stress (CMS) model of depression. Mice subjected for more than 6 weeks to CMS showed a significant decrease in T-cell dependent antibody production. However, T-cell independent humoral response was not altered. Serum corticosterone levels and splenic norepinephrine (NE) contents showed an early increase but they were not altered after prolonged CMS exposure. Nevertheless, hormonal inhibitory effect on T lymphocyte reactivity was higher in 6-week CMS mice compared to non-exposed animals. Thus, our results suggest that the impaired T-cell dependent humoral response in a CMS model of depression is neither related to changes in glucocorticoids nor in NE levels but is correlated with an increment of T-cell sensitivity to stress hormones. These findings would underlie the involvement of catecholamines and glucocorticoid lymphocyte receptors in the immune alterations observed in stress and depression.

WR-2721 (amifostine, ethyol) prevents motor and morphological changes induced by neonatal X-irradiation.

Neonatal X-irradiation induces permanent abnormalities in cerebellar cortex cytoarchitecture and neurochemistry, as well as impairment in motor gait. The aim of the present work was to examine the potential protective properties of WR-2721 (Amifostine, Ethyol), a free radical scavenger, against the above mentioned alterations by using a previously described neuroprotection assessment protocol. Pre-irradiation treatment with amifostine was effective in partially preventing the cerebellar morphological damage and the motor gait impairment induced by ionizing radiation. No changes in cerebellar noradrenaline (NA) levels were detected in amifostine-treated irradiated animals. These results suggest that it is possible to counteract radiation-induced damage in the cerebella and motor gait of neonatal rats through oxygen free radical scavenger administration prior to irradiation. The presence of the agent before the injury occurs, favors the efficacy of amifostine neuroprotective activity. Clinical implications of this model are related to the daily exposure of many people to different sources of radiation (accidental, diagnostical or therapeutical).

Motor, cytoarchitectural and biochemical assessment of pharmacological neuroprotection against CNS damage induced by neonatal exposure to ionizing radiation.

Exposure of neonatal rats to a 5 Gy single dose of X-irradiation induces permanent abnormalities in cerebellar cortex cytoarchitecture and neurochemistry and motor function. This rodent model constitutes an useful tool to evaluate morphological, neurochemical and motor changes induced by ionizing radiation and the possible restorative effects of potential or clearly established neuroprotective drugs. After selection and administration of a neuroprotective agent to neonatally irradiated rats, quantitative evaluations of motor behavior (gait), cerebellar cortex cytoarchitecture and cerebellar monoamine levels are performed. Data are compared to those of both saline-injected, X-irradiated, and saline-injected, sham-irradiated controls. Evaluation of data from the different experimental groups is performed at postnatal days 30 and 90. After this postnatal interval, radiation-induced damage of cerebellar function in nonprotected rodents is considered to be permanent. The longitudinal evaluation of various parameters in the different experimental groups through a multidisciplinary approach, allows determination of the variables that are more sensitive to X-irradiation-induced damage and/or neuroprotective agent-induced restoration. Given the well-known correspondence in cerebellar developmental stages between rodents and humans, this model and related studies bring health-related implications, considering the accidental or therapeutic exposure of developing human beings to ionizing radiation.

Chronic corticosterone impairs inhibitory avoidance in rats: possible link with atrophy of hippocampal CA3 neurons.

The aim of our work was to evaluate the effect of a chronic (22 days) administration of corticosterone, which induces supraphysiological serum levels of the hormone, on an inhibitory avoidance learning in rats (one-trial step-through learning task, footshock: 0.5 mA, 2 s). We also studied hippocampal markers of neuroanatomical CA3 pyramidal neuron atrophy by using the Golgi staining method. Chronic exposure to high CORT serum levels induced a significant impairment of inhibitory avoidance learning. The CORT group also showed hippocampal glucocorticoid receptor (GR) downregulation and the decrease of hippocampal CA3 branch points and total dendritic length in the apical tree that would be causally related with the learning impairment.

GM1 ganglioside treatment protects against long-term neurotoxic effects of neonatal X-irradiation on cerebellar cortex cytoarchitecture and motor function.

Exposure of neonatal rats to a 5 Gy dose of X-irradiation induces permanent abnormalities in cerebellar cortex cytoarchitecture (disarrangement of Purkinje cells, reduction of thickness of granular cortex) and neurochemistry (late increase in noradrenaline levels), and motor function (ataxic gait). The neuroprotective effects of gangliosides have been demonstrated using a variety of CNS injuries, including mechanical, electrolytic, neurotoxic, ischemic, and surgical lesions. Here, we evaluated whether systemically administered GM1 ganglioside protects against the long-term CNS abnormalities induced by a single exposure to ionizing radiation in the early post-natal period. Thus, neonatal rats were exposed to 5 Gy X-irradiation, and subcutaneously injected with one dose (30 mg/kg weight) of GM1 on h after exposure followed by three daily doses. Both at post-natal days 30 and 90, gait and cerebellar cytoarchitecture in X-irradiated rats were significantly impaired when compared to age-matched controls. By contrast, both at post-natal days 30 and 90, gait in X-irradiated rats that were treated with GM1 was not significantly different from that in non-irradiated animals. Furthermore, at post-natal day 90, cerebellar cytoarchitecture was still well preserved in GM1-treated, X-irradiated animals. GM1 failed to modify the radiation-induced increase in cerebellar noradrenaline levels. Present data indicate that exogenous GM1, repeatedly administered after neonatal X-irradiation, produces a long-term radioprotection, demonstrated at both cytoarchitectural and motor levels.

The effect of X-radiation on cerebellar granule cells grown in culture. Ganglioside GM1 neuroprotective activity.

In this paper we describe the effects of X-radiation on the viability of cerebellar granule cells grown in culture. Cell cultures were exposed to X-rays 2 h after plating and then grown for 1-7 days. Two days after X-ray exposure with a dose-range of 0.1-2 Gy (acute effect), a significant decrease in neuronal number was observed. The magnitude of the lethal effect was directly correlated to the dose of X-ray applied. When the interval between plating and irradiation was increased, the acute lethal effect of X-rays decreased. 3H-thymidine incorporation was maximal during the first 24 h in vitro and decreased to nearly blank levels, after 72 h. In some experiments, cells present in each culture dish were counted at day 2 and at day 7. We observed that the number of cells present in sham-irradiated cultures decreased from day 2 to day 7, reflecting cell death after several days in vitro. The cell loss observed in X-irradiated cultures was significantly greater as compared with sham-irradiated cultures, confirming the deleterious effect of X-ray on cell survival. This effect was completely prevented by GM1 (6.5, 10 and 30 microM) added 48 h after X-ray exposure, but not 1 h after plating. We conclude that X-rays induce two different effects: an acute effect related to impaired DNA synthesis which is very active during the first 24 h in vitro, and a long-term effect owing to a sublethal damage in the surviving neuronal population.

Activities of monoamine oxidase-A and -B in adult rat cerebellum following neonatal X-irradiation.

The activities of monoamine oxidases, MAO-A and MAO-B, were separately determined in the cerebellum (CE) from adult rats neonatally exposed to 5 Gy X-irradiation. They were found to be markedly reduced: 58% and 66% of values from nonirradiated, littermate controls. Since the specific activities of both isoenzymes (per mg tissue weight) were not significantly different from controls, the reduction of activity per CE is basically explained by the irradiation-induced cerebellar atrophy. The unmodified MAO-A specific activity makes it highly improbable that the increase in the cerebellar noradrenaline content, characteristic of neonatally X-irradiated rats, could be due to a decreased neuronal metabolism of noradrenaline by this enzyme.

Motor abnormalities and changes in the noradrenaline content and the cytoarchitecture of developing cerebellum following X-irradiation at birth.

We have studied the developmental time-course of changes in the noradrenaline (NA) content of cerebellum (CE), cytoarchitecture of the cerebellar cortex, and motor abnormalities induced by the exposure of the cephalic end of rats to a single dose (5 Gy) of X-irradiation immediately after birth. At all ages examined, i.e., from postnatal (PN) d 5 to 90, CE from exposed animals show a marked atrophy, with an agranular cortex that has lost its layered structure. Purkinje cells are scattered at all depths in the cortex, and their primary dendrite is randomly oriented. The motor syndrome includes dystonia-like movements, a fine tremor, and an ataxic gait. Being progressive, the abnormal movements are evident from PN d 10, and fully developed by d 30. On the other hand, no differences in cerebellar NA content between X-irradiated rats and age-matched nonirradiated controls were detected from PN d 5 to 60. However, at PN d 90 a significant increase in NA content of CE from exposed animals is found when compared to either age-matched controls (+36%, p < 0.01), or data from irradiated rats obtained at PN d 5 to 60 (p < 0.01). These results indicate a temporal dissociation between the motor and cytoarchitectural abnormalities and the increase in cerebellar NA content produced by a single dose of X-rays at birth. The late increase in cerebellar NA content might represent a compensatory response of noradrenergic terminals to an altered information flow out of the cerebellar cortex induced by the ionizing noxa.

Neurochemical characterization of the alterations in the noradrenergic afferents to the cerebellum of adult rats exposed to X-irradiation at birth.

A single dose of x-irradiation was applied on the cephalic end of newborn rats, and the alterations in the noradrenergic afferents to the cerebellum were studied 180 days later. A net increase in the noradrenaline content of cerebellum was found (122% of nonirradiated controls). The response of noradrenaline content to reserpine injection (0.9 mg/kg, i.p.) was similar in exposed and control rats. Likewise, the 3H release induced by Ro 4-1284 from cerebellar cortex slices labeled with [3H]noradrenaline was unmodified by x-rays, although a mild increase in the spontaneous efflux of 3H was found. The retention of 3H by the slices was reduced in exposed animals (58% of controls). Both the in vitro activity of tyrosine hydroxylase and the accumulation of L-3,4-dihydroxyphenylalanine (L-DOPA) were not significantly different between x-treated rats and controls. In contrast, monoamine oxidase activity was markedly reduced in x-irradiated cerebellum (38% of controls). The x-ray-induced decrease in cerebellar weight (-60%) resulted in marked increases in noradrenaline concentration (223%), tyrosine hydroxylase activity per milligram of protein (206%), and 3H retention (50%). The accumulation of L-DOPA per gram of tissue was also increased at every time considered. These data indicate that x-irradiation at birth produces a cerebellar loss not completely shared by the noradrenergic afferents, and a permanent imbalance between the noradrenergic afferent input and its target cells might eventually result.(ABSTRACT TRUNCATED AT 250 WORDS)

Down regulation of cerebral cortical 3H imipramine binding sites during chronic antidepressant treatment is independent of the central serotonergic innervation.

The effects of chronic antidepressant (AD) administration (amitryptiline 12 mg/Kg i.p., 20 days) on cerebral cortical [3H] imipramine binding sites were examined in control rats and in serotonergic denervated animals. Both treatments independently reduced the density of [3H] imipramine binding sites by 33-40%. Animals submitted to both treatments showed a slightly higher decrease in the Bmax (-50%). No alterations were observed in the apparent dissociation constant. Preincubation of cerebral cortical synaptosomal membranes with Triton X-100 (0.2% v/v), which preferentially dissolves the presynaptic component of the synaptosomes, reduced by 40% the maximal number of [3H] imipramine binding sites in control rats. In chronic AD treated rats or in serotonergic lesioned rats, membranes preincubated with Triton X-100 showed a 30% decrease in the number of [3H] imipramine sites in comparison to the sham group. The combination of both treatments produced an even larger decrease in the density of [3H] imipramine binding sites in Triton X-100 treated membranes (-55%) compared to the sham group. Taken together, these results strongly suggest that cerebral cortical [3H] imipramine binding sites located both pre- and postsynaptically, are down regulated by the long term AD administration independently of the integrity of the central serotonergic system.

Interactions of phospholipids and free fatty acids with antidepressant recognition binding sites in rat brain.

The lipid microenvironment of cell membranes has been shown to regulate both neurotransmitter and hormone receptors. Preincubation of cortical synaptosomal membranes of rat brain with phospholipase A2 (PLA2) increases the number of [3H]imipramine ([3H]IMI) high affinity binding sites without altering Kd (Bmax control: 2.53 +/- 0.28 pmol/mg protein vs Bmax PLA2: 3.66 +/- 0.26 pmol/mg protein). The displacement curves of [3H]IMI binding in synaptosomal membranes with other tricyclic antidepressants are not affected by the presence of PLA2. The effect of PLA2 was prevented by incubation with EGTA (2 x 10(-3)) or bovine serum albumin (BSA; 1:1). In addition, end products of catalytic activity of PLA2 such as unsaturated fatty acids (arachidonic or oleic acids) mimicked the effect of PLA2. These effects were entirely prevented by preincubation with BSA. The in vitro addition of the acidic phospholipid phosphatidylserine isolated from bovine brain (BC-PS) produced a similar increase in Bmax. This action was also blocked by addition of BSA. On the other hand, palmitic acid, a saturated fatty acid, and lysophosphatidylserine (lysoPS) or lysophosphatidylethanolamine (lysoPE) failed to modify [3H]IMI binding sites. The chronic administration of tricyclic antidepressant (AD) resulted in a 25% decrease in [3H]IMI binding sites in synaptosomal membranes. Preincubation of these AD-treated membranes with PLA2 did not alter [3H]IMI binding, whereas the addition of unsaturated free fatty acids (FFA) produced a greater increase in the density of [3H]IMI binding sites in comparison with control membranes. Taken together, these findings suggest that unsaturated free fatty acids could play an important role in the regulation of the number of [3H]IMI high affinity binding sites in the mammalian brain.

Increased activity of tyrosine hydroxylase in the cerebellum of the X-irradiated dystonic rat.

The exposure of the cephalic end of rats to repeated doses of X-irradiation (150 rad) immediately after birth induces a long-term increase in the noradrenaline (NA) content of cerebellum (CE) (+ 37.8%), and a decrease in cerebellar weight (65.2% of controls), which results in an increased NA concentration (+ 109%). This increase in the neurotransmitter level is accompanied by a dystonic syndrome and histological abnormalities: Purkinje cells (the target cells for NA afferents to CE) fail to arrange in a characteristic monolayer, and their primary dendritic tree appears randomly oriented. The injection of reserpine 0.9 and 1.2 mg/kg ip to adult rats for 18 h depletes cerebellar NA content in both controls (15.7 +/- 4 ng/CE and 2.8 +/- 1.5 ng/CE, respectively) and X-irradiated rats (17.1 +/- 1 ng/CE and 8.3 +/- 2 ng/CE, respectively). The activity of tyrosine hydroxylase (TH) in CE of adult rats, measured by an in vitro assay, is significantly increased in neonatally X-irradiated animals when compared to age-matched controls (16.4 +/- 1.4 vs 6.32 +/- 0.6 nmol CO2/h/mg prot., p less than 0.01). As observed for NA levels, a net increase in TH activity induced by the ionizing radiation is also measured: 308.9 +/- 23.8 vs 408.2 +/- 21.5 nmol CO2/h/CE, p less than 0.01 (controls and X-treated, respectively). These results suggest that X-irradiation at birth may induce an abnormal sprouting of noradrenergic afferents to CE. The possibility that these changes represent a response of the NA system to the dystonic syndrome is discussed.

Long-term changes in noradrenaline (NA) and dopamine (DA) contents of rat cerebellum following neonatal X-irradiation.

The effects of neonatal X-irradiation on cerebellar cathecholamine levels in rats were studied at different postnatal intervals. Since synaptogenesis in the cerebellar cortex is basically a postnatal phenomenon, changes in noradrenaline (NA) and dopamine (DA) levels induced by X-rays on the cerebella (CE) of adult rats (60 days old) were also studied. With 200 rad at birth there was an increase in both NA (+ 75%) and DA (+ 40%) levels at day 30, with a return to control values by day 90. CE weight did not change with this dose. Both 500 and 700 rad given at birth induced a persistent increase in NA levels, even when studied at day 390 (+ 127%) and a long-term decrease in DA levels. A marked atrophy of CE was found, even at day 390 (a 61% decrease in weight). Histologic analysis showed that the cerebellar cortex lacked its interneurons (agranular cerebellar cortex) and that Purkinje cells were randomly arranged. Rats showed dystonia, fine tremor, posterior train ataxia and microcephalia. On the other hand, X-irradiation of adult rats did not change cerebellar catecholamine levels or produced cerebellar atrophy. These animals did not show motor deficits or microcephalia. Taken together, these results suggest that the long-term changes in cerebellar catecholamine levels induced by neonatal X-irradiation may be somehow related to the loss of cerebellar interneurons which develop early in the postnatal period, although a primary change(s) in the activity of noradrenergic neurons can not be excluded.

Catecholamine metabolizing enzymes and synthesis of dopamine in normal and grafted pituitary partes distales.

The presence of enzymatic activity (tyrosine hydroxylase, dopa-decarboxylase, dopamine-beta-hydroxylase, monoamine oxydase and catechol-O-methyl transferase), as well as dopamine (DA) content and DA synthesis from tyrosine and dopa, were investigated in intact rats partes distales and in grafts (both estrogenized and nonestrogenized). Counts of prolactin cells showed the following regression in the number of these cells: estrogenized grafts greater than nonestrogenized grafts greater than intrasellar intact glands. Tyrosine hydroxylase activity was not found in intact glands, but this enzyme was detected in the two types of grafts. An approximate correlation could be established between the number of prolactin cells and the diverse enzyme activities. Dopamine was not synthesized from tyrosine in intact glands, but it occurred in the transplants. However, when dopa was used, both intact and grafted glands produced dopamine. Estrogen administration decreased dopamine content in all the glands investigated. The significance of these results in relation to the physiology of the pars distalis is discussed.

Different effects of neonatal vinblastine on peripheral and central noradrenaline neurons.

The systemic injection of newborn rats of the mitotic inhibitor vinblastine sulfate (0.25 microgram/s.c. 48 h after birth), produces marked and persistent changes in peripheral sympathetic neurons. Approximately half the neuronal population of the superior cervical ganglia was destroyed already at 16 days of age and this was accompanied by a partial but persistent depletion of noradrenaline (NA) from peripheral organs receiving a rich sympathetic nerve supply such as the heart, salivary glands and spleen. After the systemic injection of vinblastine to newborn rats, the content of NA in several brain regions remained unaltered at 45-60 days of age. To overcome the obstacle that the blood-brain barrier could represent to vinblastine penetration into the brain, the compound was injected directly into the brain of rat pups at 2 days of age (0.25-1.0 microgram). When these animals were killed 45-60 days later, no changes were found in the concentration of NA in the cerebral cortex, the spinal cord or the cerebellum but NA levels were increased in the brain stem. Besides producing a partial but persistent peripheral sympathectomy, vinblastine injected either systemically or intracerebrally to newborn rats, provides a useful tool for the analysis of similarities and differences between the ontogenesis of central and peripheral NA neurons.

Ultrastructural evidence for monoamine uptake by vesicles of pineal sympathetic nerves immediately after their stimulation.

Bilateral electrical stimulation of the preganglionic fibers to the superior cervical ganglia of the rat markedly reduces the number of osmiophilic dense cores present in the nerve vesicles of the sympathetic fibers in the pineal gland. These cores owe their density to the presence of noradrenaline and serotonin in the vesicles. When sympathetic nerves of the pineal organ are exposed immediately after stimulation for a brief period to the false neurotransmitter 5-hydroxydopamine, either in vitro or in vivo, dense precipitates reappear in the electron-lucent vesicles. On the basis of these observations, it is concluded that the vesicles remaining in the nerves after releasing their neurotransmitter content have the capacity to take up and store monoamines. This provides a morphological correlate for the recent biochemical evidence suggesting that the vesicles in sympathetic nerves are reused after neurotransmitter release.

Los transmisores catecolaminicos (noradrenalina, adrenalina, dopamina). / The catecholamine transmitters (noradrenaline, adrenaline, dopamine)

Los transmisores catecolaminicos de importancia fisiologica son dopamina, noradrenalina, y adrenalina. Sirven como neurotransmisores en el sistema nervioso central y el sistema nervioso simpatico. Se discuten la distribucion central y periferica, biosintesis y el almacenamiento de estas vitalmente importantes sustancias. La forma en que son liberadas y como se controla esta liberacion, tambien esta sujeta a discusion. Se describen sus varios receptores adrenergicos y se explican los efectos de su estimulacion. Lo mismo se describe de los neurotransmisores AMP ciclico y GMP ciclico y sus antagonistas. Y finalmente se definen el metabolismo, la degradacion y comprension de las catecolaminas.Se presentan tablas, diagramas y la ruta de la sintesis a partir de la materia prima hasta los productos catecolaminicos terminados