17ß-Estradiol/N-acetylcysteine interaction enhances the neuroprotective effect on dopaminergic neurons in the weaver model of dopamine deficiency.

The weaver mouse, is a phenocopy of Parkinson's disease (PD) in which dopaminergic neurons degenerate gradually during development, reaching at P21 a neurodegeneration of 55%. Thus, the weaver mouse constitutes an appropriate in vivo PD model for investigating the effect of neuroprotective agents. In the present study, long-term treatment (from P1 to P21) with 17ß-estradiol (17ß-estradiol) significantly protected the dopaminergic neurons in the substantia nigra (SN) of weaver mouse by 54%, as was detected by immunohistochemical experiments, using the specific antibody against tyrosine hydroxylase (TH). This dopaminergic neuroprotection is in line with our biochemical results showing that 17ß-estradiol treatment significantly decreased the high lipid peroxidation levels seen in the SN of weaver mouse, indicating high oxidative stress. Interestingly, co-administration of 17ß-estradiol with N-acetylcysteine (NAC, precursor molecule of glutathione (GSH)) further significantly increased the survival of dopaminergic neurons in the SN (by 85%), with a parallel further decrease of lipid peroxidation to normal levels. Our results show the in vivo neuroprotective effect of 17ß-estradiol, which is strongly enhanced by co administration of NAC, indicating a strong synergistic effect of the two drugs. Furthermore, the main mechanism underlying this neuroprotective action seems to be the reversal of the oxidative stress shown by the high peroxidation levels. These results could be of clinical relevance since both drugs are already used separately in the clinic, 17ß-estradiol for treatment of PD and NAC as a mucolytic agent and for the treatment of several disorders.

Cerebellar function, dyslexia and articulation speed.

The main aims of this study were a) to assess the cerebellar deficit hypothesis examining children's performance in cerebellar and cognitive tasks associated with the dyslexic syndrome and b) to investigate if there is a differentiation in articulation speed in children with dyslexia. A battery consisted of five cerebellar tests, five cognitive tests, and an articulation speed test was administered to three age- and sex-matched groups of dyslexics, children with attention deficit/hyperactivity disorder (ADHD) and normal readers aged 8-12 years. The dyslexics showed significant impairment in one cerebellar test compared with the control group and in two cognitive tests compared with both the control and the ADHD group. Additionally, the dyslexic children performed significantly worse than the control group during the articulation speed test; such a difference was not observed between the control and the ADHD group. The present study provides clues to support the cerebellar deficit hypothesis and the possible relationship between reading impairment and speed of articulation. Further research is considered essential to clarify the relationship between cerebellar function, dyslexia, and oral language speed.

Effect of cold exposure on thyroid hormone metabolism and nuclear binding in rat brain.

In this study we examined whether adult rat brain tissue (cerebral hemispheres) would under cold exposure respond with changes in the local metabolism and nuclear binding of thyroid hormones (T3, T4). Adult, control rats kept at 22 degrees C and cold exposed (4 degrees C, 20 h) rats were injected with trace of 125I-T4 or 125I-T3 returned to their respective environment and sacrificed four hours later. The radioactive hormonal forms were identified and quantified in the cytoplasmic and nuclear fractions. It was found that in cold exposed rats injected with 125I-T4, the total cytoplasmic radioactivity was higher than that of controls. This increase was not associated with 125I-T4 but it reflected an increase (88 %) in its deiodination product 125I-T3 (125I-T3 (T4)). Although total cytoplasmic 125I-T4 did not change, there was a decrease (28%) in its protein free cytoplasmic fraction. 125I-T3 (T4) and 125I-T4 bound to the nuclear fraction were found to decrease by 58 and 46% respectively. Cold exposed animals injected with 125I-T3 also showed an increase in cytoplasmic 125I-T3 (81%) and a decrease in 125I- (40%) whereas 125I-T3 bound to the nuclear fraction decreased by 64%. These results indicate that cold exposure of rats decreases brain local T3 metabolism and nuclear binding while it does not effect local T4 metabolism.

Effects of LiCl on triiodothyronine (T3) binding to nuclei from rat cerebral hemispheres.

The therapeutic effects of lithium in mania and depression are thought to be mediated by its effects on plasma thyroid hormone (T4, T3) levels. Inasmuch as T3 affects transcription by binding with its nuclear receptors, in this study we examined whether Li+ alters T3 nuclear binding. Although plasma T3 and T4 levels were not affected, 125I-T3 uptake was decreased, and both in vivo and in vitro studies showed a significant increase in nuclear T3 binding in brain and liver tissue. This increase was shown to reflect an increase in maximal binding density. On the basis of these findings, it is proposed that Li+ exerts its action by inducing "cellular hypothyroidism." Integrating existing information on thyroid hormones and affective diseases and the effects of hypothyroidism on neurotransmitters thought to be altered in mania and depression, this hypothesis is supported and contributes to understanding of the effects of LiCl and thyroid hormones in affective diseases.

Thyroxine deiodination, cytoplasmic distribution and nuclear binding of thyroxine and triiodothyronine in liver and brain of young and aged rats.

This study examines (a) the effects of aging on plasma thyroid hormone concentration and (b) in vivo binding and cytoplasmic distribution of thyroid hormones as well as the conversion of thyroxine (T4) to triiodothyronine (T3) in liver and cerebral hemispheric tissue. The results show that (a) in male Long-Evans rats aging decreases plasma T4 concentration but does not affect plasma T3 concentration and (b) the in vivo nuclear T3 binding does not change significantly. However, nuclear T3 binding derived from T4 is decreased as a consequence of reduced T4 to T3 conversion in both tissues. The nuclear T4 binding is also depressed, perhaps due to the decrease in the T4 of the protein free cytoplasmic compartment. Aging was also found to change protein free and protein bound cytoplasmic distribution of T4. That is, an increase was observed in protein bound cytoplasmic T4 and a decrease in the protein free cytoplasmic T4 of both tissues. These results indicate an overall alteration in thyroid hormone production and peripheral tissue binding and processing of thyroid hormones with a consequent suboptimal thyroid state with aging.

Characterization of nuclear triiodothyronine (T3) and tetraiodothyronine (T4) binding in developing brain tissue.

The main objective of this study was to characterize nuclear T3 and T4 binding in the developing rat brain. More specifically, we sought to determine (a) whether T3 and T4 bind to the same nuclear receptor, (b) whether there are multiple forms of nuclear T3 or T4 receptors, and (c) whether the above parameters are similar in nuclei of cerebral hemispheres and cerebellum of developing rat brain. From in vivo and in vitro binding experiments utilizing gel filtration techniques, we have shown that T3 binds to a main macromolecular fraction of molecular weight (M.W.) approx. 60 000 daltons; however, a minor binding component of M.W. greater than 100 000 daltons was also observed. Utilizing the same techniques it was shown that T4 does not bind with the main T3 binding macromolecule but only with the minor (M.W. greater than 100 000) binding component. Inasmuch as T4 competes with T3 for its binding, we have hypothesized that (a) the stability of the T4-receptor complex requires special stereochemical receptor-chromatin relationships that hold for in vivo or de novo conditions but not in the salt-extracted (0.4 M KCl) nuclear receptor preparation, or (b) T4 interacts with more than one receptor unit and forms unstable T4-receptor complexes corresponding to the high M.W. macromolecular fraction. The T3 and T4 binding characteristics described above were common to both brain regions at both developmental ages examined; however, these tissues were found to differ in quantitative aspects of T3 and T4 binding and with respect to the rate of the in vivo T4 to T3 conversion. We suggest that the nuclear T4 does not contribute to the end biological effects but, rather, it determines the number of free T3 binding sites. The end biological responses may thus be proportional to the binding of T3--derived from plasma and the local cellular conversion of T4 to T3--with its major nuclear binding protein and inversely proportional to the T4 nuclear concentration.