New polymorphisms associated with response to anti-TNF drugs in patients with moderate-to-severe plaque psoriasis.

Anti-tumor necrosis factor (anti-TNF) drugs are effective against psoriasis, although 20-30% of patients are nonresponders. Few pharmacogenomic studies have been performed to predict the response to anti-TNF drugs in psoriasis. We studied 173 polymorphisms to establish an association with the response to anti-TNF drugs in patients with moderate-to-severe plaque psoriasis (N=144). We evaluated the response using PASI75 at 3, 6 and 12 months. The results of the multivariate analysis showed an association between polymorphisms in PGLYR4, ZNF816A, CTNNA2, IL12B, MAP3K1 and HLA-C genes and the response at 3 months. Besides, the results for polymorphisms in IL12B and MAP3K1 were replicated at 6 months. We also obtained significant results for IL12B polymorphism at 1 year. Moreover, polymorphisms in FCGR2A, HTR2A and CDKAL1 were significant at 6 months. This is the first study to show an association with these polymorphisms. However, these biomarkers should be validated in large-scale studies before implementation in clinical practice.

Paradoxical psoriasiform reactions to anti-TNFα drugs are associated with genetic polymorphisms in patients with psoriasis.

Paradoxical psoriasiform reactions to anti-tumor necrosis factor α (TNFα) agents have been described. We aimed to study the association between these reactions and polymorphisms in genes previously associated with psoriasis or other autoimmune diseases. A total of 161 patients with plaque-type psoriasis treated with anti-TNFα drugs were genotyped for 173 single-nucleotide polymorphisms (SNPs) using the Illumina Veracode genotyping platform. Among the 161 patients, 25 patients developed a paradoxical psoriasiform reaction consisting of a change in morphology, mostly to guttate psoriasis (88%). These lesions developed 9.20±13.52 months after initiating treatment, mainly with etanercept (72%). Psoriasis type and a Psoriasis Area and Severity Index (PASI) 75 response to treatment were not associated with lesions. Multivariate logistic regression revealed that five SNPs (rs11209026 in IL23R, rs10782001 in FBXL19, rs3087243 in CTLA4, rs651630 in SLC12A8 and rs1800453 in TAP1) were associated with paradoxical reactions. This is the first study to show an association between genetic polymorphisms and paradoxical reactions in patients with psoriasis treated with anti-TNFα drugs.The Pharmacogenomics Journal advance online publication, 21 July 2015; doi:10.1038/tpj.2015.53.

The relationship between tumour necrosis factor (TNF)-α promoter and IL12B/IL-23R genes polymorphisms and the efficacy of anti-TNF-α therapy in psoriasis: a case-control study.

BACKGROUND: Antitumour necrosis factor (anti-TNF)-α agents can be used successfully to treat patients with psoriasis and other inflammatory diseases. However, very few studies have examined the relationship between TNF-α polymorphisms and the response to anti-TNF-α agents. OBJECTIVES: To study the association of single nucleotide polymorphisms (SNPs) of the TNF-α promoter and IL12B/IL23R genes with the response to anti-TNF-α in patients with psoriasis. METHODS: SNPs for the TNF-α promoter and IL12B/IL23R genes, and the presence of the HLA-Cw6 haplotype were genotyped for 109 patients. We studied the association between these SNPs and the efficacy of treatment at 3 and 6 months [Psoriasis Area and Severity Index (PASI) and body surface area (BSA)]. RESULTS: Patients with the TNF-α-238GG genotype more frequently achieved a PASI75 at 6 months (82·5% vs. 58·8%, P = 0·049). At 6 months, patients with the TNF-α-857CT/TT genotypes showed greater improvements in PASI score and BSA (83·1% vs. 92·7%, P = 0·004; 82·7% vs. 92·6%, P = 0·009) and more frequently achieved PASI75 (71·4% vs. 96·3%, P = 0·006). More patients with the TNF-α-1031TT genotype achieved PASI75 at 3 months (90·8 vs. 75·7, P = 0·047) and 6 months (85·5% vs. 65·7%, P = 0·038) and demonstrated superior improvements in PASI at 6 months (89·9% vs. 78·7%, P = 0·041). Patients with the IL23R-GG genotype (rs11209026) achieved PASI90 at 6 months more frequently (66·3% vs. 0, P = 0·006) and the improvement of the PASI score was also greater (86·8% vs. 67·8%, P = 0·013). Patients with the HLA-Cw6 haplotype showed poorer response than those without this haplotype. CONCLUSION: This study identified a relationship between certain TNF-α and IL12B/IL23R polymorphisms and the short-term response to anti-TNF-α drugs. If these results are confirmed, this information will allow for stratified consent with more accurate prediction of response/personalized choice of treatment hierarchy for the patient.

Gene polymorphisms that can predict response to anti-TNF therapy in patients with psoriasis and related autoimmune diseases.

Psoriasis (Ps) is a chronic inflammatory disease with an important genetic component. It shares pathophysiological mechanisms with other autoimmune diseases such as psoriatic arthritis (PsA), rheumatoid arthritis (RA) and Crohn's disease (CD). These conditions can be treated using biological drugs such as infliximab, adalimumab and etanercept, which selectively block the proinflammatory cytokine tumor necrosis factor (TNF)-α. Although these agents have greatly improved the prognosis of Ps, PsA, RA and CD, they do not cure the disease and are expensive; in addition, significant proportions of patients do not respond or develop serious adverse effects. Therefore, it is important to investigate biomarkers, such as gene polymorphisms, that can predict which patients will respond best to a specific drug. Some polymorphisms in genes TNF, TNF receptor superfamily 1B (TNFR1B) and TNFα-induced protein 3 gene (TNFAIP3) have been associated with response to anti-TNF therapy in patients with Ps. The present article reviews other polymorphisms that could also play a role in prediction of response to these treatments.

Estudio de los polimorfismos genéticos de la región promotora del TNF-alfa en pacientes españoles afectos de psoriasis / Study of Genetic Polymorphisms in the Tumor Necrosis Factor alfa Promoter Region in Spanish Patients With Psoriasis

Introducción: En diversos estudios se ha descrito la asociación de los polimorfismos del factor de necrosis tumoral α (TNF-Alfa) y patologías inflamatorias como la psoriasis vulgar y la artritis psoriásica, aunque los resultados son variables según la población de origen de la muestra. No se han realizado estudios previamente en población española. Objetivo: Analizar los polimorfismos de la región promotora del gen del TNF-Alfa en pacientes con psoriasis moderada-grave y establecer las posibles diferencias genotípicas con los hallados en un grupo de voluntarios sanos. Material y métodos: Se seleccionaron 89 pacientes con psoriasis moderada-grave y 76 controles sin antecedentes familiares ni personales de psoriasis. Se genotiparon los polimorfismos de la región promotora del gen del TNF-Alfa en ambos grupos. Resultados: Observamos una mayor prevalencia de genotipo con ambos alelos en estado silvestre en posición -238 (GG, 86,5% vs 70,4% respectivamente) y -1031 (TT, 80,2% vs 45,8% respectivamente) en el grupo de pacientes con psoriasis al compararlo con el grupo control. Las diferencias halladas en posición -308 y -857 no fueron significativas. Conclusión: Existen diferencias en los polimorfismos en las posiciones -238 y -1031 entre pacientes con psoriasis moderada-grave y voluntarios sanos, lo cual apoya la importancia del papel del TNF-Alfa en la fisiopatología de esta entidad (AU)

Background: Several studies have reported an association between tumor necrosis factor α (TNF-Alfa) polymorphisms and inflammatory diseases such as psoriasis vulgaris and psoriatic arthritis, although the results vary according to the population studied. No studies have been performed in the Spanish population. Objective: To analyze the polymorphisms of the promoter region of the TNF-Alfa gene in patients with moderate to severe psorasis and to identify potential differences in genotype compared to a group of healthy volunteers. Material and methods: Eighty-nine patients with moderate to severe psoriasis and 76 healthy controls with no personal or family history of psoriasis were selected. Polymorphisms of the TNF-Alfa promoter region of both groups were genotyped. Results: We observed a higher prevalence of the genotype with both wild-type alleles at positions -238 (GG genotype, 86.5% vs 70.4%, respectively) and -1031 (TT genotype, 80.2% vs 45.8%, respectively) in patients compared to the healthy control group. The differences at positions -308 and -857 were not significant. Conclusion: There are differences in polymorphisms at positions -238 and -1031 in patients with moderate to severe psoriasis compared to healthy volunteers. This observation provides further support for the importance of the part that TNF-Alfa plays in the pathophysiology of this disease (AU)

[Study of genetic polymorphisms in the tumor necrosis factor α promoter region in Spanish patients with psoriasis]. / Estudio de los polimorfismos genéticos de la región promotora del TNF-α en pacientes españoles afectos de psoriasis.

BACKGROUND: Several studies have reported an association between tumor necrosis factor α (TNF-α) polymorphisms and inflammatory diseases such as psoriasis vulgaris and psoriatic arthritis, although the results vary according to the population studied. No studies have been performed in the Spanish population. OBJECTIVE: To analyze the polymorphisms of the promoter region of the TNF-α gene in patients with moderate to severe psorasis and to identify potential differences in genotype compared to a group of healthy volunteers. MATERIAL AND METHODS: Eighty-nine patients with moderate to severe psoriasis and 76 healthy controls with no personal or family history of psoriasis were selected. Polymorphisms of the TNF-α promoter region of both groups were genotyped. RESULTS: We observed a higher prevalence of the genotype with both wild-type alleles at positions -238 (GG genotype, 86.5% vs 70.4%, respectively) and -1031 (TT genotype, 80.2% vs 45.8%, respectively) in patients compared to the healthy control group. The differences at positions -308 and -857 were not significant. CONCLUSION: There are differences in polymorphisms at positions -238 and -1031 in patients with moderate to severe psoriasis compared to healthy volunteers. This observation provides further support for the importance of the part that TNF-α plays in the pathophysiology of this disease.

Cadmium effects on 24h changes in glutamate, aspartate, glutamine, GABA and taurine content of rat striatum.

This work evaluates the possible changes in 24 h variations of striatal aspartate, glutamate, glutamine, gamma-aminobutyric acid (GABA) and taurine content after oral cadmium treatment. Male rats were submitted to cadmium exposure at two doses (25 and 50 mg/L of cadmium chloride (CdCl(2))) in the drinking water for 30 days. Control rats received cadmium-free water. After the treatment, rats were killed at six different time intervals throughout a 24 h cycle. Differential effects of cadmium on 24 h amino acid fluctuations were observed. Metal exposure modified the daily pattern of the amino acids concentration found in control animals, except for GABA and taurine with the lowest dose used. Exposure to 25 mg/L of CdCl(2) decreased mean content of aspartate, as well as GABA concentration. These results suggest that cadmium exposure affects 24 h changes of the studied amino acids concentration in the striatum, and those changes may be related to alterations in striatal function.

Endosulfan effects on pituitary hormone and both nitrosative and oxidative stress in pubertal male rats.

The present study was undertaken to investigate in pubertal male rats possible effects of endosulfan administered throughout lactation and gestation on: (a) pituitary gene expression of prolactin, luteinizing hormone (LH), growth hormone (GH) and thyroid stimulating hormone (TSH); (b) circulating levels of these hormones; and (c) expression of nitric oxide synthase 1 and 2 (NOS1 and NOS2), and heme oxygenase-1 (HO-1) at pituitary level. Endosulfan was administered orally at the doses of 0.61 mg/kg/day or 6.12 mg/kg/day, and possible toxic effects were studied in pubertal male pups (at postnatal day 30). Gene expression was evaluated by RT-PCR and plasma hormone levels by RIA. Exposure to both administered doses down-regulated LH, GH and TSH. Treatment with 0.61 mg endosulfan/kg/day decreased prolactin expression, although its plasmatic concentration was decreased by both administered doses. LH secretion was stimulated by both doses, whereas the highest dose increased GH levels and decreased plasma TSH concentration. Endosulfan up-regulated NOS1 and NOS2. We can conclude that in pubertal male rat, prenatal and lactational exposure to endosulfan modifies expression and release of prolactin, LH, GH and TSH, and pituitary NOS1 and NOS2 mRNA levels, suggesting that nitrosative stress can be implicated in the endocrine toxicity of endosulfan at pituitary level.

Cadmium chloride exposure modifies amino acid daily pattern in the mediobasal hypothalamus in adult male rat.

The present study was conducted to investigate the possible effects of cadmium exposure on the daily pattern of aspartate, glutamate, glutamine, gamma-aminobutyric acid (GABA) and taurine levels in the mediobasal hypothalamus of adult male rats. For this purpose, animals were treated with cadmium at two different exposure doses (25 and 50 mg l(-1) of cadmium chloride, CdCl(2)) in the drinking water for 30 days. Control age-matched rats received CdCl(2)-free water. After the treatment, rats were killed at six different time intervals throughout a 24 h cycle. CdCl(2) exposure modified the amino acid daily pattern, as it decreased aspartate, glutamate, GABA and taurine levels at 12:00 h with both exposure doses employed. In addition, the treatment with 25 mg l(-1) of CdCl(2) induced the appearance of minimal values at 16:00 h and maximal values between 04:00 and 08:00 h for glutamate, and a peak of glutamine content at 20:00 h. The heavy metal also decreased GABA medium levels around the clock in the mediobasal hypothalamus. However, CdCl(2) did not alter the metabolic correlation between glutamate, aspartate, glutamine and GABA observed in control animals. These results suggest that CdCl(2) induced several alterations in aspartate, glutamate, glutamine, GABA and taurine daily pattern in the mediobasal hypothalamus and those changes may be related to alterations in hypothalamic function.

Cadmium exposure disrupts GABA and taurine regulation of prolactin secretion in adult male rats.

This work was undertaken to evaluate the possible effects of cadmium exposure on 24 h changes of gamma-aminobutyric acid (GABA) and taurine median eminence and pituitary contents. Also the possible alterations of the regulatory mechanisms of GABA and taurine on prolactin secretion were evaluated. Adult male rats were given cadmium at a dose of 25 mg/l of cadmium chloride in the drinking water for 30 days. Control age-matched rats received cadmium free water. Metal exposure induced the appearance of a maximal value of prolactin at 08:00 h. In median eminence, cadmium abolished the GABA and taurine maximal values and decreased GABA and taurine mean levels. In the anterior pituitary, cadmium treatment phase advanced 12 h the peak observed in controls at 00:00 h for both amino acids. There was a positive correlation between GABA and taurine contents in median eminence and the anterior pituitary in both control and cadmium-exposed animals. However, the correlation between GABA or/and taurine with prolactin levels disappeared in cadmium-exposed animals. These results suggest that cadmium exposure affects GABA and taurine daily pattern in the median eminence and anterior pituitary, and those changes explain, at least in part, the modification in the regulatory pattern of prolactin secretion.

Toxic effects of methoxychlor administered subcutaneously on the hypothalamic-pituitary-testicular axis in adult rats.

This study was undertaken to evaluate the effects of methoxychlor MTX at the hypothalamic-pituitary-testicular axis in adult male rats. This global objective comprises three major aims: (1) to analyze the possible differential MTX effects in norepinephrine and serotonin concentration an in serotoninergic metabolism in anterior, mediobasal and posterior hypothalamus and median eminence; (2) to evaluate effects induced by MTX exposure on gonadotropins and testosterone; 93 to elucidate whether the regulatory interactions in the hypothalamic-pituitary-testicular axis are modified by this pesticide. Animals were administered subcutaneously 25mg/kg/day of MTX for 1 month. MTX increased norepinephrine and serotonin content in anterior hypothalamus (P < or = 0.05), but decreased serotonin concentration in posterior hypothalamus (P < or = 0.05). MTX diminished serotonin turnover in anterior hypothalamus (P < or = 0.01) and decreased plasma LH (P < or = 0.001) and testosterone (P < or = 0.05) levels but those of FSH remained unmodified. We can conclude that MTX exposure: (1) could exert differential effects in norepinephrine and serotonin concentration an in serotoninergic metabolism in anterior, mediobasal and posterior hypothalamus and median eminence, being the anterior hypothalamus the most sensitive region to the pesticide; (2) could inhibit LH and testosterone secretion without changing FSH; (3) four potential pathways might be involved in MTX effects on testosterone secretion (changing LH secretion; modifying serotonin and norepinephrine at the hypothalamic level; alterating the direct neural pathway between brain and testes; and/or by a direct effect in testes).

Posible papel protector de la melatonina frente a la toxicidad neuroendocrina inducida por cadmio / Possible protective role of melatonin in the neuroendocrine toxicity induced by cadmium

El cadmio es un agente químico tóxico importante debido a su creciente nivel en el medio ambiente como resultado de prácticas industriales y agrícolas. Como perturbador endocrino, el cadmio modifica la secreción de hormonas hipofisarias. Los efectos indirectos del cadmio provocan la generación de especies reactivas de oxígeno y reducen la actividad de las proteínas implicadas en las defensas antioxidantes. La melatonina es conocida como un potente antioxidante, scavenger de radicales libres y quelante de metales sintetizada en la glándula pineal. De esta manera, las acciones antioxidantes de esta indolamina protegen frente a la peroxidación lipídica y el daño oxidativo de los radicales y de sus productos tóxicos. Los trabajos recopilados en esta revisión ponen de manifiesto la capacidad antioxidante de la melatonina y, por lo tanto, su posible papel protector frente a la toxicidad del cadmio en lo que se refiere al estrés oxidativo y peroxidación lipídica inducidos por la exposición a este metal (AU)

Cadmium is one of the most important toxic chemicals due to its increasing level in the environmentas a result of industrial and agricultural practices. As an endocrine disruptor, cadmium modifies pituitary hormone release. Indirect effects of cadmium provoke generation of reactive oxygen species and reduce activities of proteins involved in antioxidant defenses. Melatonin is a well-known potent antioxidant, free radical scavenger and metal chelator synthesized in the pineal gland. Thus, antioxidative actions of this nature protect against lipid peroxidation and oxidative damage by radicals and their toxic products. This review collates evidence from many research laboratories who reported antioxidant effects of melatonin and this mechanism could counteract oxidative stress and lipid peroxidation induced by cadmium exposure (AU)

Toxic effects of methoxychlor in rat striatum: modifications in several neurotransmitters.

Neurotoxic effects of methoxychlor (MTX) are poorly understood at present. This study was undertaken to evaluate the possible effects of MTX in norepinephrine, dopamine and amino acid contents and serotonin turnover in rat striatum. For this purpose, adult male Sprague-Dawley rats were administered 25 mg/kg/day of MTX in sesame oil or vehicle only for 30 days. The neurotransmitters of interest were measured in the striatum by HPLC. MTX decreased norepinephrine and 5-hydroxyindole acetic acid (5-HIAA) content and serotonin turnover (measured as 5-HIAA/serotonin ratio), and increased glutamate and GABA concentrations. However, the content of serotonin, aspartate, glutamine and taurine was not modified by MTX exposure. These data suggest that MTX exposure inhibits norepinephrine synthesis and serotonin metabolism. The inhibitory effect on norepinephrine could be explained, at least in part, by the increase of both GABA and glutamate contents. Further studies are needed to understand the effects of MTX on serotonin. Also a disruptive effect of MTX on the metabolisms of glutamate, aspartate, glutamine and GABA emerges.

Toxic effects of methoxychlor in rat striatum: modifications in several neurotransmitters

Neurotoxic effects of methoxychlor (MTX) are poorly understood at present.This study was undertaken to evaluate the possible effects of MTX in norepinephrine,dopamine and amino acid contents and serotonin turnover in rat striatum. Forthis purpose, adult male Sprague-Dawley rats were administered 25 mg/kg/day ofMTX in sesame oil or vehicle only for 30 days. The neurotransmitters of interestwere measured in the striatum by HPLC. MTX decreased norepinephrine and 5-hydroxyindole acetic acid (5-HIAA) content and serotonin turnover (measured as 5-HIAA/serotonin ratio), and increased glutamate and GABA concentrations. However,the content of serotonin, aspartate, glutamine and taurine was not modified byMTX exposure. These data suggest that MTX exposure inhibits norepinephrine synthesisand serotonin metabolism. The inhibitory effect on norepinephrine could beexplained, at least in part, by the increase of both GABA and glutamate contents.Further studies are needed to understand the effects of MTX on serotonin. Also adisruptive effect of MTX on the metabolisms of glutamate, aspartate, glutamine andGABA emerges (AU)

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Toxic effects of methoxychlor in rat striatum: modifications in several neurotransmitters

Neurotoxic effects of methoxychlor (MTX) are poorly understood at present.This study was undertaken to evaluate the possible effects of MTX in norepinephrine,dopamine and amino acid contents and serotonin turnover in rat striatum. Forthis purpose, adult male Sprague-Dawley rats were administered 25 mg/kg/day ofMTX in sesame oil or vehicle only for 30 days. The neurotransmitters of interestwere measured in the striatum by HPLC. MTX decreased norepinephrine and 5-hydroxyindole acetic acid (5-HIAA) content and serotonin turnover (measured as 5-HIAA/serotonin ratio), and increased glutamate and GABA concentrations. However,the content of serotonin, aspartate, glutamine and taurine was not modified byMTX exposure. These data suggest that MTX exposure inhibits norepinephrine synthesisand serotonin metabolism. The inhibitory effect on norepinephrine could beexplained, at least in part, by the increase of both GABA and glutamate contents.Further studies are needed to understand the effects of MTX on serotonin. Also adisruptive effect of MTX on the metabolisms of glutamate, aspartate, glutamine andGABA emerges (AU)

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Toxic effects of cadmium on GABA and taurine content in different brain areas of adult male rats

This work assesses the possible changes in gamma amino butyric acid (GABA)and taurine content in the hypothalamus, the median eminence and striatum after theexposure to various doses of cadmium. Cadmium chloride (CdCl2) was administeredin the drinking water at the doses of 5, 10, 25, 50 or 100 ppm to adult male rats for 1month. In the anterior hypothalamus, taurine and GABA content decreased with thedose of 10 ppm of CdCl2 only. Cadmium exposure decreased both GABA and taurinecontent in mediobasal hypothalamus except for the 50 ppm dose. In posteriorhypothalamus GABA and taurine content was not affected by cadmium treatment.As far as the median eminence, 5 or 10 ppm of CdCl2 increased taurine concentration,and at a dose of 5 ppm enhanced GABA content. A significant decrease ofGABA and taurine concentration was seen in the striatum at any dose of cadmiumused. The concentration of cadmium increased in the hypothalamus and in the striatumin animals receiving CdCl2 in the drinking water at doses of 25, 50 or 100 ppm.The results indicate that cadmium globally decreased GABA and taurine content inthe brain areas studied through effects that were not dose dependent (AU)

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Toxic effects of cadmium on the regulatory mechanism of dopamine and serotonin on prolactin secretion in adult male rats.

This work was designed to analyze the effects of cadmium on the regulatory mechanism of prolactin in cadmium-exposed rats. Adult male rats were given cadmium at a dose of 25 ppm of cadmium chloride (CdCl2) in the drinking water for 1 month. At the end of the treatment, the rats were killed at six different time intervals throughout a 24 h cycle to measure circulating prolactin levels and dopamine and serotonin content in the median eminence and in both anterior and posterior pituitary. Control and cadmium-exposed animals exhibited significant time of day-dependent variations in plasma prolactin levels and in dopamine and serotonin concentration in all analyzed tissue. Cadmium exposure did not modify the mean values of the hormone around the clock but it modified the amplitude of the secretory peaks at 08:00 and 12:00 h. Cadmium decreased dopamine content in the median eminence, while increased its content in the posterior pituitary and induced a phase advanced peak at 20:00 h. On the other hand, serotonin content was not modified in the median eminence. Only differences in specific time points were observed, while serotonin concentration in anterior and posterior pituitary were increased in cadmium-treated rats. Differences in time peaks were also observed. The negative correlation between plasma prolactin and dopamine content in pituitary, and between plasma levels of the hormone and serotonin content in posterior pituitary, disappeared in cadmium-treated animals.

Toxic effects of cadmium on GABA and taurine content in different brain areas of adult male rats.

This work assesses the possible changes in gamma amino butyric acid (GABA) and taurine content in the hypothalamus, the median eminence and striatum after the exposure to various doses of cadmium. Cadmium chloride (CdCl2) was administered in the drinking water at the doses of 5, 10, 25, 50 or 100 ppm to adult male rats for 1 month. In the anterior hypothalamus, taurine and GABA content decreased with the dose of 10 ppm of CdCl2 only. Cadmium exposure decreased both GABA and taurine content in mediobasal hypothalamus except for the 50 ppm dose. In posterior hypothalamus GABA and taurine content was not affected by cadmium treatment. As far as the median eminence, 5 or 10 ppm of CdCl2 increased taurine concentration, and at a dose of 5 ppm enhanced GABA content. A significant decrease of GABA and taurine concentration was seen in the striatum at any dose of cadmium used. The concentration of cadmium increased in the hypothalamus and in the striatum in animals receiving CdCl2 in the drinking water at doses of 25, 50 or 100 ppm. The results indicate that cadmium globally decreased GABA and taurine content in the brain areas studied through effects that were not dose dependent.