Morphometric analysis of brain lesions in rat fetuses prenatally exposed to low-level lead acetate: correlation with lipid peroxidation.

The effect of prenatal lead acetate exposure was studied microscopically together with the concentration of lead and lipid fluorescent products (LFP) in the brain of rat fetuses. Wistar rats were intoxicated with a lead solution containing either 160 or 320 ppm of lead acetate solution during 21 days through drinking water. The control group (ten rats) received deionized water for the same period. The rats were killed on gestation day 21 and fetuses were obtained; the placenta, umbilical cord and parietal cortex (Cx), striatum (St), thalamus (Th) and cerebellum (Ce) were collected for measuring tissue lead concentration, LFP as an index of lipid peroxidation and histopathologic examination. Lead contents were increased in placenta, umbilical cord, St, Th and Cx in both lead-exposed groups. Lead exposure increased (LFP) in placenta and umbilical cord, St, Th and Ce as compared to the control group. Histopathological examination showed severe vascular congestion in placenta, the Cx, St, Th and Ce with hyperchromatic and shrunken cells. Interstitial oedema was found in all regions studied of both lead exposed groups. The morphometric evaluation of the studied brain regions showed an absolute decrease in total cell number and increased number of damaged cells and interstitial oedema. Our results show that morphological changes in rat brain are correlated with increased lipid peroxidation, and the lead levels of the umbilical cord, however it is not clear whether oxidative stress is the cause or the consequence of these neurotoxic effects of lead.

Enhanced brain regional lipid peroxidation in developing rats exposed to low level lead acetate.

Neurotoxicity associated with lead exposure may be the result of a series of small perturbations in brain metabolism, and, in particular, of oxidative stress. Some studies have suggested a lead-induced enhancement on lipid peroxidation as a possible mechanism for some toxic effects of lead. However, there are no reports about the association between lipid peroxidation enhancement and brain lead content. In this study, we determined the concentration of lead and the formation of lipid fluorescence products in the blood, as well as in the parietal cortex, striatum, hippocampus, thalamus, and cerebellum of rats exposed prenatally and postnatally to variable concentrations of lead acetate through drinking water. Pregnant Wistar rats were intoxicated throughout gestation with solutions containing either 320 or 160 ppm of lead. The pups were treated after birth in the same way until 45 days of age. Control animals received deionized water for the same period of time. The developing rats were sacrificed at postnatal day 45 and lead level was assessed biochemically in the blood and different brain regions. Results showed that blood lead levels were increased in a dose-dependent manner. In the brain, lead accumulated preferentially in the parietal cortex, striatum, and thalamus as compared to the control group, while lipid fluorescence products were significantly increased in the striatum, thalamus, and hippocampus of the treated animals. These data suggest that in the brain of rats exposed to lead acetate, lead produces a neurotoxic effect with a complex correlation with both lead regional content and lipid peroxidation.

Histopathological alterations in the brain regions of rats after perinatal combined treatment with cadmium and dexamethasone.

Industrial and environmental exposure to cadmium (Cd) is well known to produce multiorgan toxicity in humans. Metallothionein (MT) is a cellular ligand for Cd. MT has been shown to protect against Cd-induced toxicity in many organs, including brain. In this study, we described the histopathological alterations in parietal cortex, striatum, hippocampus and cerebellum of rats following perinatal combined exposure to cadmium and dexamethasone (Dx), a drug known to induce MT synthesis in brain. Wistar rats of 13 days of age were treated for 5 days, as follows; (1) saline solution, (2) CdCl(2) 1 mg/kg per day, (3) Dx 2 mg/kg per day, (4) CdCl(2) 1 mg/kg per day + Dx 2 mg/kg/day. Rats were killed on either 18 or 28 days of age. The content of Cd in parietal cortex, striatum, hippocampus and cerebellum at 18 days old age increased 58.3-, 9.4-, 18.3- and 11.3-fold, while at 28 days of age in the same regions the increases were 6.6-, 5.8-, 25.3- and 11.3-fold in the Cd treated rats, respectively. No lesions were observed in the brain of control rats. Rats treated with Dx at 28 days of age showed interstitial edema in the four regions. Cd-treated rats at 28 days of age showed lesions in the four studied regions. In general, Dx treatment attenuated all Cd-induced lesions.

Alveolar lesions induced by systemic administration of cocaine to rats.

In this work, alveolar lesions induced after systemic administration of cocaine (30 mg/kg per day, i.p.) to rats were evaluated both by light microscope analysis for morphological assessment as well as by measurement of the alveolar area as a quantitative index of the alveolar damage. Rats were examined after different times of exposure: 7, 15, 30, 45, 60 and 75 days. The histopathological evaluation of cocaine-treated rats revealed a remarkable thickening in some interalveolar septa, with interstitial hemorrhages, progressive thrombosis and transformation of reticular and elastic fibers into diffuse fibrosis. A significant decrease of the alveolar area was also observed. These findings are indicative of severe changes in capillaries, alveoli and bronchiole after cocaine exposure, which in turn may progressively disrupt the general function of the lungs. Differential mechanisms of systemic toxicity after cocaine exposure are discussed.

Dapsone prevents morphological lesions and lipid peroxidation induced by quinolinic acid in rat corpus striatum.

Increasing doses of dapsone were tested on rats administered intrastriatally with quinolinic acid in order to evaluate a possible protective action of this drug on the striatal lesions produced after the excessive activation of N-methyl-D-aspartate receptors. Morphological lesions were evaluated 7 days after the intrastriatal injection of quinolinate (240 nmol/microl) by light microscopy, and the ratio of neuronal damage per field was also estimated as a quantitative index of the striatal toxicity. Quinolinate alone produced extensive necrosis and loss of striatal neurons. No protective effects on the striatal tissue from quinolinate-treated rats were observed at lower doses of dapsone (6.25 and 9.375 mg/kg). However, at higher doses (12.5 and 25 mg/kg), dapsone prevented significantly the striatum from quinolinate toxicity. Dapsone alone had no effect on the striatal tissue from control rats. A single dose of dapsone (12.5 mg/kg) was tested also on the index of lipid peroxidation 2 h after the striatal injection of quinolinate, resulting in a significant protection (78% vs. QUIN). Findings of this study, in accordance with our previous reports, demonstrate the ability of dapsone to prevent the neuronal damage associated with the excitatory action of quinolinate via overactivation of NMDA receptors, and provide evidences to support the hypothesis that this drug is acting against the pattern of toxicity elicited by agonists of glutamate receptors.

Brain capillary lesions produced by cocaine in rats.

In the last 20 years, acute and chronic cocaine addiction has increased among young and adult people. The effects of cocaine on brain vasculature of young animals have not been histologically studied in depth. In the present study, we report the lesions of brain capillaries, including the choroid plexus, produced by chronic cocaine administration, in adult Wistar rats receiving i.p., 30 mg/kg/day of aqueous cocaine hydrochloride solution. Rats were sacrificed after several days of treatment. Histopathological examination of capillaries from different brain regions and cerebellum was performed using light microscopy. At 7 days, there were initial signs of dilatation, rupture and thrombosis of capillaries. At 15 days of treatment small interstitial oedema and hemorrhages by rupture of the basal membrane of the capillaries was found. At 30 days of treatment, many capillaries from different areas showed fibroid endothelial thickening, and wall fibrosis become evident after 60 days of daily cocaine. In numerous places (cortex, gray nucleus: thalamus, caudate, hippocampus and cerebellum) we observed capillaries with an occluded lumen probably due to fibrosis or thrombi after 90 days of treatment. In the latter treatment, capillaries from the choroid plexuses had their lumen dilated and the epithelial cells vacuolated or necrotic. We hypothesize that the chronic administration of cocaine in rats induced brain lesions in part as a result of capillary disruption and subsequent extravasation of erythrocytes to brain parenchyma.

Retinal lesions in rat fetuses prenatally exposed to cocaine.

The increased use of cocaine in the United States and worldwide has created great concern about its effects on fetuses and neonates of pregnant cocaine abusers. The effects on neonates are varied: fetal growth delay, microcephaly, abnormal neurological functions, microphthalmia, and maternal obstetric complications. In this study, the effect of prenatal cocaine administration was studied microscopically in the retina of rat fetuses. Twenty-five pregnant Wistar rats were injected i.p. with an aqueous cocaine solution using a 30 mg/kg daily dose for 45 days. Control group rats (15 pregnant animals) received saline solution for the same period. Day 0 of gestation was the day after mating. Dosing began on this day. The rats were killed on gestation day 21 and fetuses were obtained for examination. The histopathological light and electron microscope studies of the retinas showed interstitial oedema, areas depleted of cells, necrosis, and hyperchromatic ganglion cells. There also was a significantly lower number of retinal cells compared to control fetuses. In four cases, teratogenic lesions of the retina were observed whereas no changes were present in control fetuses. Results indicate that development of retina in fetuses prenatally exposed to cocaine was altered by cocaine exposure.

Experimental neuromyopathy induced by thallium in rats.

A histopathological study, with a light microscope, of experimental neuromyopathy produced by thallotoxicosis was undertaken in 40 newborn Wistar rats. Treatment consisted of a single i.p. injection of an aqueous solution of 16 mg kg-1 thallium(I) acetate 1 day after birth. Groups of ten animals were euthanized at either 8 or 50 days of age. Sural nerves, as well as peroneus muscle, were fixed in 10% formaldehyde solution for 15 days and then prepared for histopathological observation. At 8 days of age sural nerves of thallium-treated animals showed a moderate reduction in the large- and medium-sized fibres and several of the myelin sheaths had initial degeneration along the course of the axon. Interstitial oedema was found in both neural and muscular tissues. Distinct features of focal necrosis as well as small haemorrhages were seen in peroneus muscle. At 50 days of age, the lesions were more diffuse. Large and small myelinated fibres were found to be sinuous, fragmented and scanty. Alterations in the large- and medium-sized axons were seen and the myelin sheaths were altered along the course of the axon, suggesting a progressive distal axonopathy. Additionally, muscle fibres had myopathic changes with abnormal central nucleoli and the striated transverse fibres had disappeared in many areas of the sample. Several interstitial foci of muscular necrosis accompanied by phagocytosis and fibrosis were also present.

Experimental nephropathy by chronic administration of cocaine in rats.

The recent and significant increase of cocaine abuse has emerged as a major public health problems. Cocaine abuse is frequently associated with multiorganic lesions, including renal failure. We report the light-microscopic features of the progression of renal lesions produced by chronic cocaine administration in rats. Male Wistar rats weighing 225-250 g were used. Twenty eight rats received an aqueous solution of cocaine hydrochloride (30 mg/kg/day i.p.) daily, while 28 control rats were injected i.p. daily with a saline solution. Rats from both groups were sacrificed after 7, 15, 30, 45, 60, 75 and 90 days of treatment. The histopathological study showed early changes on day 15, with damage to glomerular capillary walls and swelling of tubular epithelium, and lesions progressed to 90 days with development of glomerular atrophy and sclerosis. The tubular epithelial cells were necrotic and sloughed, and the lumen of papillary ducts contained destroyed red blood cell (RBC) casts. The interstitium had numerous foci of necrosis and haemorrhage. The results show that chronic treatment with cocaine in rats produce severe lesions both to glomerular, interstitium and tubular cells.

Combined D-penicillamine and prussian blue as antidotal treatment against thallotoxicosis in rats: evaluation of cerebellar lesions.

Rats were treated with a single dose of thallium acetate (32 mg/kg i.p.) and the antidotal effect of D-penicillamine and prussian blue given alone or in combination was assessed by means of evaluation of the thallium-induced cerebellar histological lesions. After thallium poisoning (24 h), antidotes were administered for 4 days as follows: D-penicillamine (DP) 25 mg/kg, i.p. twice daily; prussian blue (PB), 50 mg/kg p.o., twice daily. Mortality among the treatment groups was as follows: control, 87.5%; DP, 100%; PB, 56.25%; DP+PB, 25%. Three days after these treatments, rats treated with the combination DP+PB presented a significantly lower number of altered Purkinje cells in cerebellum as compared with those of the thallium alone treated animals, indicating adequate protection by this antidote treatment against thallium neurotoxicity. Prussian blue protected against thallium-induced neurotoxicity to a lesser extent as compared with the effects obtained by the DP+PB protection. DP did not protect against thallium-induced alterations of Purkinje cells. These results confirm the efficacy of the combined antidotal treatment of DP and PB against thallium toxicity in rats, and support the possible application in human cases of thallotoxicosis.

Testicular lesions by chronic administration of cocaine in rats.

Although cocaine is a common drug of abuse, its effects on the testicular structure have not been studied in depth. We report here the testicular lesions produced by chronic cocaine administration to rats. Twenty-eight male Wistar rats weighing 225-250 g were used throughout. Fourteen of them (controls) were injected i.p. with saline solution and the remaining 14 received 30 mg kg-1 day-1 i.p. of aqueous cocaine hydrochloride solution. Animals from both groups were sacrificed at variable times: 7, 15, 30, 45, 60, 75 and 90 days of treatment. Histopathological examination of the testes showed initial alterations at day 15: capillary dilatation; interstitial oedema with lipoid drops due to incipient necrosis of interstitial cells; and necrosis of the cells of the seminiferous tubules. Lesions progressed until 90 days of treatment, showing atrophic and necrotic cells and terminal tubule fibrosis. At this time, the testes were found to be diminished in size. The seminiferous tubules were shrunken, of small diameter and contained necrotic spermatogenic cells and fibrosis. These lesions may produce testosterone diminution and thus sterility due to the disappearance of spermatogenesis.

[Clinico-pathologic correlation of dementia produced by thinner and cocaine]. / Correlación clínico-patológica de las demencias producidas por thinner y cocaína.

Industrial solvents mixed from thinner, used in paints, leathers, rubber, varnishes, have neurotoxic action. By laboral inhalation or spontaneously these are absorbed from the lungs, transported by blood and because of this high lipophilic section are retained within the lipid rich nervous system. Euphoric effects appear accompanied with visual and additive halucinations. In chronic abusers it produce schizophrenic-paranoid consequences with encephalic and peripheral neuronal and nervous fibers destruction, accompanied of blindness and paralysis. Cocaine is another neurotoxic drug. At first it produces euphoria, arterial hypertension and symptoms suggestive of underlying psychiatric diseases. The cocaine addicts often suffer depression, paranoia, hallucinations, seizures and suicidal ideation. The morphological base of the symptomatology is the encephalic and peripheral neuronal and nerve fibers destruction.

Osteochondral lesions in developing rats intoxicated with thallium twenty four hours after birth.

An i.p. injection of a solution of thallium acetate in deionized water at a dose of 32 mg/kg, in 24-h-old rats, produces morphological and biochemical alterations in both cartilaginous and osseous tissues. From the beginning, there are alterations in the cartilaginous cell as well as in chrondrine, osteoblasts, osseous tissue and bone marrow. Rats were sacrificed at 24, 48, and 72 h and also at 7 days. Two animals survived for 50 days. One showed total irreversible alopecia while the other one had partial alopecia with discrete recovery. Both showed a low weight and a size of 8 cm. Microscopically, degenerative changes were produced consisting of alteration and death of many cartilaginous cells, uneven metachromasia and the chondrine and decrease of the growth cartilage, scanty bone trabeculae with few osteoblasts. The bone marrow showed few myeloblasts and megakaryocytes. Progressive cellular damage throughout the 50 days of survival represents a response of the thallium ionic accumulation and recycling in cellular mitochondria of all the body's cells. This appeared in our study as irreversible and progressive osteochondral alterations with atrophy of the skin and its adnexa, hyalinization of elastic and collagenous fibers with intense interstitial edema.

[Teratologic cranio-encephalic effects of chronic thinner inhalation in progenitors, in rats and humans]. / Efectos teratológicos cráneo-encefálicos por inhalación crónica con thinner de los progenitores, en ratas y humanos.

Inhalation of thinner by youngsters and adolescents is an increasing drug abuse problem in Mexico. It presents serious repercussions upon socio-economic, cultural, legal and health (neurologic and psychiatric) problems. We report a comparative study in humans and rats which demonstrate the embryotoxic and craneo encephalic teratologic effects in the children and brood of progenitors who have chronically inhaled thinner (in the case of pregnant women, before, at the beginning and throughout pregnancy). Inhaled thinner passes directly to the blood stream and crosses the placentary barrier freely reaching the embryo. It may cause craneal bone and partial or total encephalon agenesia, added to macro and microscopic lesions secondary to direct aggression to the neuroepithelial germ cells. Abortions and premature labor with weight and size underdeveloped products and placentary hemorrhages occur. Usually these die, but if they survive they show trascendental mental retardation, as well as neurologic and psychiatric sequels.

Medical causes and effects of cocaine abuse.

Historical data concerning the use of cocaine, its epidemiology, chemistry and pharmacology, as well as its medical complications and treatment, in both acute intoxication and chronic addiction is reported. Its repercussion and damage upon the nervous system with neurologic and psychiatric alterations is also reported. The frequency of cerebral hemorrhages and myocardial, and other visceral infarctions due to vascular lesions are discussed. Various pulmonary lesions produced by the different routes used and the multiple obstetric problems during pregnancy, such as abnormal labour with products showing cerebral damage and teratogenic lesions due to the use of cocaine are presented. Finally, the present prophylactic campaigns against the use of cocaine and other drugs are mentioned.

[Causes and medical effects of cocaine abuse]. / Causas y efectos médicos por abuso de cocaína.

Historical data concerning the use of cocaine, its epidemiology, chemistry and pharmacology, as well as its medical complications and treatment, in both acute intoxication and chronic addiction is reported. Its repercussion and damage upon the nervous system with neurologic and psychiatric alterations is also reported. The frequency of cerebral hemorrhages and myocardial, and other visceral, infarctions due to vascular lesions are discussed. Various pulmonary lesions produced by the different routes used and the multiple obstetric problems during pregnancy, such as abnormal labour with products showing cerebral damage and teratogenic lesions due to the use of cocaine are presented. Lastly, the present prophylactic campaigns against the use of cocaine and other drugs is mentioned.

Neurotoxicity of thallium: biochemical and morphological study of organic lesions.

A biochemical study of experimental thallium intoxication in newborn rats and its morphological consequences upon the brain of developing animals was undertaken. The thallium content was analyzed in the following encephalic regions: hippocampus, hypothalamus, mesencephalon, cerebellum, and cortex. One day after application of the toxic substance, a homogeneous distribution of the metal in the brain was found. Thallium concentrations in the mentioned regions were twice as high as those found in an adult rat, at the same dosage, 20 newborn Wistar rats were used for the histopathological study. 5 remained as witnesses, the rest received a single injection of thallium of .07 ml. of a solution with a concentration of .32 mg/Kg. 3 rats were sacrificed at 24, 48 and 72 hours; 3 at 7 days and 3 at 51 days. The brain , sciatic and crural nerves were fixated in 10% formaldehyde for 15 days. Cuts in paraffin and frozen sections measuring between 5 and 7 microns were taken from the fragments of different areas. These were stained with aniline methods (Masson, Gallego and H-E) and silver-gold impregnation as modified by Río-Hortega.

Experimental neuropathy produced in rats with industrial solvents (thinner).

Thinner is a very potent neurotoxic compound which damages both the central and peripheric nervous system, as well as the rest of the organism, when it is used or inhaled spontaneously chronically. 20 Wistar rats were used. They inhaled 1.5 ml of thinner per day and were sacrificed by pairs upon days 7, 15, 30, 45, 60, 75, and 90. Four of them were sacrificed after suspending the inhalation 15, 30, 60 and 90 days later so as to study the process of recuperation. The hind legs were fixated in 10% formaldehyde for 15 days. Fragments of sciatic and crural nerves were included in paraffin and histological cuts were performed both in transversal and longitudinal sections of 5 to 7 micra. Techniques for myelin and argento-auric ones were performed. Incipient lesions are described as well as intermediate and terminal ones produced after having inhaled 45 ml of thinner for 30 days. The myelin sheath shows edema, ballooning and destruction due to lysis after inhaling 135 ml in 90 days. In a parallel manner the nerve fibers show edema, irregular thickening and after inhaling 135 ml in 90 days there is atrophy or disintegration. A partial regeneration is produced if inhalation is suspended after 30 days and 30 more days are allowed for recuperation, when some Schwann cells are still active. We believe that the lesions which begin to appear on the myelin sheath occur because thinner is a fat solvent, fats being important elements in their structure and the nerve fiber injury may be secondary to the demyelinization, or due to destruction of the central neuron from which they originate.