Effects of maternal thyroid hormone deficiency on differentiation of mesenchymal stem cells in CSF-exposed neonatal Wistar rats.

Cerebrospinal fluid (CSF) contains growth and neurotrophic factors which regulate proliferation, differentiation, and neurogenesis. Thyroid hormones play a crucial role in the development of the nervous system and hypothyroidism during development of embryos leads to defects in the nervous system. This study aimed to survey the effects of rat neonatal CSF collected from induced hypothyroid mothers on differentiation of bone marrow mesenchymal stem cells (BM-MSCs). We hypothesized that hypothyroidism affected levels of growth factor in CSF. To induce hypothyroidism, pregnant Wistar rats received methimazole at the third day of gestation. BM-MSCs were obtained from rat femurs and tibias and cultured in medium. CSF was collected from the cisterna magna of newborn rats, and cells were subsequently exposed to CSF with concentrations of 5,7, and 10 /100 (v/v) for 72 h. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and real time polymerase chain reaction (RT-PCR) were used to quantify the cell viability and analyze the expression of neural markers, respectively. Our morphological studies showed that treatment with hypothyroidism CSF (HTH-CSF) resulted in a significant decrease in neurite growth and proliferation as compared to normal CSF (N-CSF). RT-PCR analysis also showed a significant decrease in expression of neural markers (i.e., Nestin, Neurod-1, NeuN) in cells treated with HTH-CSF as compared with the N-CSF group. The most effective concentration of CSF for BM-MSC differentiation was 5% (V/V). Our results showed a significant decrease in differentiation of BM-MSCs in the presence of neonatal CSF of hypothyroid mothers compared with neonatal CSF of healthy mothers. Thus, thyroid hormones are essential in neural development and hypothyroid defects can affect development of the neonatal brain.

Blood-brain-barrier disruption in chronic canine hypothyroidism.

BACKGROUND: Central nervous system (CNS) manifestations of hypothyroidism have been associated with cerebrovascular complications. Reports of cerebrospinal fluid (CSF) abnormalities are rare in hypothyroid dogs. OBJECTIVE: The aim of this study was to determine if chronic hypothyroidism causes blood-brain-barrier (BBB) abnormalities that are detectable using indirect CSF biomarkers. METHODS: The study included 18 normal, euthyroid, female mixed-breed dogs. Hypothyroidism was induced by (131) iodine administration in 9 dogs; 9 served as untreated controls. Evaluations included physical and neurologic examination, complete CSF analysis, serum and CSF protein electrophoresis, measurement of plasma vascular endothelial growth factor (VEGF) and serum S-100B concentrations, and calculation of CSF albumin quota (AQ) and were conducted at baseline and 6, 12, and 18 months after induction of hypothyroidism. Data were analyzed using repeated measures ANOVA. RESULTS: At baseline, differences between groups were not detected for any variable. Throughout the study, controls dogs remained free of neurologic disease and had test variables that remained within reference intervals. Two hypothyroid dogs developed CNS signs during the study, and evidence of cerebrovascular disease was found at necropsy. At 12 and 18 months, the CSF total protein, VEGF, S-100B, and fractional albumin concentrations, and AQ were significantly higher (P<.04) in hypothyroid dogs than controls. Among test variables assayed in serum or plasma, the only significant difference was a higher S-100B concentration in hypothyroid dogs (P=.003) at 18 months. CONCLUSIONS: BBB integrity is disrupted in chronic hypothyroidism. Significant increases in CSF concentrations of VEGF and S100-B in hypothyroid dogs indicate dysfunction in both endothelial and glial elements of the BBB.

Adipsic hypernatremia in a dog with antithyroid antibodies in cerebrospinal fluid and serum.

A 4-year-old, male Labrador retriever, weighing 27 kg, presented with abrupt clinical signs including mental retardation, circling and head pressing. The dog never ingested water by choice. An adipsia of the dog was persisted and developed to hypernatremia with artifactual hyperchloremia. Serial endocrine results and image findings were suggestive of a hypothyroidism. The dog revealed the presence of antithyroid antibodies in the cerebrospinal fluid and serum. With the administration of levothyroxine sodium, his neurologic signs were alleviated within the first week of treatment and adipsia was also resolved.

Depressive symptoms in hypothyroid disorder with some observations on biochemical correlates.

Lumbar punctures and ratings of depressive symptoms were done in hypothyroid patients before and during L-thyroxine therapy. Before treatment, the most prominent symptoms were concentration difficulties, lassitude, and reduced sexual interest. All patients suffered from sleep disturbances. Suicidal thoughts did not occur at all. Inner tension was negatively correlated with the anxiogenic cholecystokinin tetrapeptide (CCK-4) in the cerebrospinal fluid (CSF), while reduced sexual interest was negatively correlated with CSF tryptophan. Furthermore, failing memory correlated negatively with T3 as well as T4 in serum. A positive correlation was found between failing memory and serum TSH. All patients improved significantly during treatment. No biochemical correlates were found. In conclusion, hypothyroidism is associated with major depressive symptoms. CSF CCK-4 and tryptophan, as well as serum thyroid hormones, may constitute biochemical correlates for some of these symptoms.

Low levels of transthyretin in the CSF of depressed patients.

OBJECTIVE: Transthyretin plays an important role in the transport and distribution of thyroid hormone in the central nervous system (CNS). This study replicated and extended to patients with nonrefractory depressive illness a pilot study indicating that patients with refractory major depression have significantly lower levels of CSF transthyretin than do healthy comparison subjects. METHOD: Lumbar punctures were performed in drug-free subjects with DSM-III-R major depression (N = 18), DSM-III-R bipolar disorder, depressed phase (N = 1), and healthy comparison subjects (N = 24). CSF concentrations of transthyretin, determined by a quantitative dot-immunobinding assay, of the depressed patients and comparison subjects were compared by analysis of covariance (ANCOVA). The relationship between CSF transthyretin levels and Hamilton Depression Rating Scale scores was determined in a subset of the depressed patients. RESULTS: CSF concentrations of transthyretin were significantly lower in the depressed patients than in the comparison subjects by ANCOVA. Within the depressed group there was no significant overall correlation between CSF transthyretin levels and Hamilton depression scale scores, but there was a significant inverse correlation in male depressed patients (N = 8) between CSF transthyretin concentrations and Hamilton depression scores. CONCLUSIONS: Lower CSF transthyretin concentrations in depressed patients may reflect either a stable trait in this population or a state change secondary to depression or other factors. Lower CSF transthyretin concentrations may result in altered CNS thyroid hormone homeostasis. Such alteration could account for certain mood and neurovegetative symptoms of depression and might contribute to failure of standard antidepressant treatment.

L-thyroxine treatment and neurotransmitter levels in the cerebrospinal fluid of hypothyroid patients: a pilot study.

Monoamine precursors, neurotransmitters and their metabolites were studied in cerebrospinal fluid (CSF) obtained from nine newly diagnosed hypothyroid patients. Before treatment, the serum TSH correlated positively with the CSF concentrations of tyrosine and phenylalanine. During treatment, the levels of the precursors tryptophan, phenylalanine and tyrosine decreased significantly, as was also the case with dopamine and the noradrenaline metabolite 4-hydroxy-3-methoxyphenylglycol (HMPG), but not with serotonin, noradrenaline and the serotonin metabolite 5-hydroxyindoleacetic acid, nor the dopamine metabolites homovanilic acid and dihydroxyphenylacetic acid. The study provided some indication that the CSF levels of phenylalanine and tyrosine are related to thyroid function. Furthermore, we have found an indication that L-thyroxine treatment affects the CSF levels of the precursors as well as dopamine and HMPG. Our results support the notion that there is an interaction between thyroid function and CSF disposition of monoamine compounds.

Cerebrospinal fluid proteins in subclinical and overt hypothyroidism.

PATIENTS AND METHODS: We analysed cerebrospinal fluid (CSF) albumin and immunoglobulin G (IgG) concentrations and psychometric performance in subclinical (n = 6) and overt hypothyroidism (n = 9) before and after 6 months with L-thyroxine. RESULTS: In overt hypothyroidism, CSF albumin and IgG concentrations were increased before therapy [mean(SD): 328(156) mg/l and 69(27) mg/l], but within the reference interval [198(48) mg/l and 39(11) mg/l], P < 0.05, after therapy. In contrast, in subclinical hypothyroidism CSF protein concentrations were within the reference intervals before and after therapy. Psychometric testing indicated an improvement in performance in both groups. CONCLUSION: The increase in CSF proteins in overt hypothyroidism does not appear to be related to thyroid autoimmune disease per se, since we found no increase in CSF proteins in individuals with subclinical hypothyroidism and presence of thyroid antibodies. The increase might rather be caused by a blood-brain barrier dysfunction related to low thyroid hormone concentrations.

Free thyroxine and 3,3',5'-triiodothyronine levels in cerebrospinal fluid in patients with endogenous depression.

Total and free concentrations of T4 and rT3 in serum and cerebrospinal fluid were estimated by ultrafiltration in 12 patients with unipolar endogenous depression before and after electroconvulsive treatment. Recovery from depression resulted in a decrease in CSF concentrations of free T4 (median) (26.2 to 21.4 pmol/l, p less than 0.02) and free rT3 (14.1 to 12.3 pmol/l, p less than 0.05). Concentrations of free T4 in the cerebrospinal fluid were lower than those in serum (p less than 0.02), the ratio being 0.6. In contrast, levels of free rT3 in the cerebrospinal fluid were considerably higher than those found in serum (p less than 0.01), the ratio being 25. These ratios did not change following recovery from depression. In 9 patients with nonthyroidal somatic illness, concentrations of free T4 and rT3 in the cerebrospinal fluid were similar to those found in patients with endogenous depression, whereas 4 hypothyroid patients and one hyperthyroid patient had considerably lower and higher, respectively, concentrations of both free T4 and rT3. In conclusion, levels of free T4 and free rT3 in the cerebrospinal fluid are increased during depression compared with levels after recovery, probably reflecting an increased supply of T4 from serum and an increased production of rT3 from T4 in the brain. The data also suggest that the transport of iodothyronines between serum and the cerebrospinal fluid is restricted.

[L-thyroxine and triiodo-L-thyronine in the cerebrospinal fluid and hypothalamo-hypophyseal axis of hyper- or hypothyroid rats]. / L-tiroxina y triiodo-L-tironina en líquido cefalorraquídeo y eje hipotálamo hipofisario de ratas, hiper- e hipotiroideas.

L-thyroxine and triiodo-L-thyronine concentrations in cerebrospinal fluid (CSF), hypothalamus and pituitary gland are measured in male albino-Wistar rats under several experimental thyroid disfunction : including hyperthyroidism induced by L-T3 and L-T4 treatments and surgical hypothyroidism. Radioimmunoassay is carried out by Nejad's method modified in this work. The pattern of thyroid hormone concentrations in CSF is similar to that in serum, but the values obtained are lower. Thyroid hormone concentrations in adenohypophysis as opposed to hypothalamus or cerebral cortex, show an inverse change to functional thyroid status.