Factors and Mechanisms of Thyroid Hormone Activity in the Brain: Possible Role in Recovery and Protection.

Thyroid hormones (THs) are essential in normal brain development, and cognitive and emotional functions. THs act through a cascade of events including uptake by the target cells by specific cell membrane transporters, activation or inactivation by deiodinase enzymes, and interaction with nuclear thyroid hormone receptors. Several thyroid responsive genes have been described in the developing and in the adult brain and many studies have demonstrated a systemic or local reduction in TH availability in neurologic disease and after brain injury. In this review, the main factors and mechanisms associated with the THs in the normal and damaged brain will be evaluated in different regions and cellular contexts. Furthermore, the most common animal models used to study the role of THs in brain damage and cognitive impairment will be described and the use of THs as a potential recovery strategy from neuropathological conditions will be evaluated. Finally, particular attention will be given to the link observed between TH alterations and increased risk of Alzheimer's Disease (AD), the most prevalent neurodegenerative and dementing condition worldwide.

Effects of a catechins-enriched diet associated with moderate physical exercise in the prevention of hypertension in spontaneously hypertensive rats.

Hypertension represents the main risk factor for the onset of cardiovascular diseases. Pharmacological treatments to control hypertension have been associated with new treatments involving physical activity and/or the intake of natural components (nutraceuticals). We here report the effects produced by a combination of a natural component (catechins) and a moderate exercise program on the development of hypertension in spontaneous hypertensive rats compared with those of each individual treatment. Arterial blood pressure and heart rate were measured with a non-invasive method in 28 rats randomly assigned to four groups: rats subjected to moderate physical exercise; rats with a catechins-enriched diet; rats subjected to moderate physical exercise combined with a catechins-enriched diet; control, untreated-rats left to age. All treatments were applied for 6 weeks. The statistical analysis revealed that the three treatments significantly reduced the weekly increase in arterial blood pressure observed in control rats (SBP, P < 0.0001; DBP, P = 0.005). However, the reduction of arterial blood pressure induced by combined treatments was not higher than that induced by the single treatment, but more prolonged. All treatments showed strong antioxidative properties. Our data show that physical activity and a diet enriched with catechins individually have an important hypotensive effect, while the association did not produce a higher hypotensive effect than the single treatment, even if it was able to decrease blood pressure for a longer time. These findings have important implications for developing a protocol to apply in novel hypertension prevention procedures.

Deiodinases and the Three Types of Thyroid Hormone Deiodination Reactions.

Thyroid hormone (TH) signaling is strictly regulated by iodothyronine deiodinase activity, which both preserves the circulating levels of the biologically active triiodothyronine (T3) and regulates TH homeostasis at the local level, in a cell- and time-dependent manner. Three deiodinases have been identified-namely iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3-that differ in their catalytic properties and tissue distribution. The deiodinases represent a dynamic system that changes in the different stages of life according to their functions and roles in various cell types and tissues. Deiodinase activity at the tissue level permits cell-targeted fine regulation of TH homeostasis, mediating the activation (DIO1 and DIO2) and inactivation (DIO3) of THs. Deiodinase homeostasis is the driving force that leads T3-target cells towards customized TH signaling, which takes into account both the hormonal circulating levels and the tissue-specific response. This review analyzes the complex role of deiodinases in physiological and pathological contexts, exploring new challenges and opportunities deriving from a deeper knowledge of the dynamics underlying their roles and functions.

Thyroid hormone deiodinases response in brain of spontaneausly hypertensive rats after hypotensive effects induced by mandibular extension.

PURPOSE: The deiodinases activate or inactivate the thyroid hormones (TH) in virtually all tissues in both physiological and pathological conditions. The three deiodinases, DIO1, DIO2, and DIO3, have different catalytic functions and regulate TH tissue distribution. The aim of the present study was to evaluate the modulation of gene expression of the deiodinases and TH transporters and protein levels of DIO1 in parietal and frontal areas of cerebral cortex of spontaneously hypertensive rats (SHRs), after two successive mandibular extensions (ME). METHODS: ME was performed on anesthetized rats by a dilatator appropriately designed and real-time PCR and western blotting techniques were employed for gene expression and protein level study. RESULTS: Mean blood pressure (MBP) significantly decreased in 2ME-treated rats when compared to sham-operated rats (p < 0.001) and this decrease lasted for the entire observation period. In gene expression analysis, in 2ME-treated rats we did not observe any significant variation of DIO1 and DIO3 with respect to the sham-operated rats. Differently, DIO2 gene expression significantly increased in frontal area of 2ME-treated rats, with respect to sham-operated rats (p < 0.01). Furthermore, in parietal area, protein levels of DIO1 in 2ME-treated rats were significantly higher than in sham-operated rats (p < 0.01). Moreover MCT8 and OATP1C1 both resulted significantly higher (p < 0.05 and p < 0.001) in sham frontal cortex. CONCLUSION: In summary, our data on SHRs, while confirming the hypotensive effect of two MEs, show that the treatment also solicits the three deiodinases production in the cerebral cortex.

Effects of Mandibular Extension on Pial Arteriolar Diameter Changes in Glucocorticoid-Induced Hypertensive Rats.

Previously, in normotensive rats, it has been observed that a repetitive sub-maximal mouth opening (mandibular extension, ME) obtained by placing a home-made U-shaped dilator between the superior and inferior dental arches of the rat caused modulation of pial arteriolar tone. The present study was aimed to characterize pial microcirculation in two different cortical brain regions and to assess the hemodynamic effects of a single or double ME on pial arteriolar rhythmic diameter changes in rats rendered hypertensive by dexamethasone administrations. Cranial windows were prepared on parietal and frontal region. Pial arterioles were classified by Strahler method in five orders by in vivo fluorescence microscopy technique associated with a computerized system that permits off-line measurements of arteriolar diameter changes. Two 10 min ME at 10 min interval were applied; then the animals were monitored for further 240 min. Dexamethasone-treated rats exhibited a marked arterial rarefaction and asymmetry of bifurcation in the pial microvascular networks more evident in the frontal region. Starting from ME1, in both cortical areas, the arterioles dilated, and the vasodilation became significant compared to baseline after ME2 for the entire observation period. The spectral analysis carried out on order 2 arteriolar diameter change tracings, showed that double ME increased the spectral density of the frequency components related to endothelial, neuronal and myogenic activities in both the cortical regions studied. In conclusion, double ME has a generalized effect in the cortical areas by restoring the physiological vasomotion of the pial arterioles that was severely impaired by the experimentally hypertension.

Renin-Angiotensin System Responds to Prolonged Hypotensive Effect Induced by Mandibular Extension in Spontaneously Hypertensive Rats.

There is an ongoing interest in the renin-angiotensin system (RAS) contribution either to pathological mechanisms leading to hypertension (mainly regarding the ACE/AngII/AT1R axis), or, to RAS protective and pro-regenerative actions, primarily ascribed to the mediation of the AT2R and the MAS1 receptor. In the present study, we evaluated the modulation of gene expression and protein levels of "deleterious" (ACE/AngII/AT1R) and "protective" [ACE/AngII/AT2R and ACE2/Ang(1-7)/MAS1 arms] RAS components in parietal and frontal areas of cerebral cortex of spontaneously hypertensive rats (SHRs), after two periods of mandibular extensions (MEs). Blood pressure, BP and heart rate, HR were also measured. While no significant changes in BP and HR were present in the sham operated (SO) group, in rats after two MEs (2-ME rats), BP displayed a marked decrease (p < 0.001) at ME2, and remained then stably low for the subsequent observation period. In gene expression analysis, in SHRs undergoing two MEs, either in parietal or frontal cortex, we did not observe any significant variation of AT2R and ACE2 with respect to SO rats. In contrast, we observed a decrease in Mas1 gene expression in parietal area (p < 0.01) and an increase in frontal region (p < 0.01). AT1R and ACE gene expression was significantly higher in 2-ME rats than SO in parietal cortex (p < 0.05) but no difference was observed in the frontal area. Concerning protein levels, in parietal area, AT1R and AT2R did not change whereas MAS1 significantly decreased in 2-ME rats (p < 0.05). In frontal area, both AT1R and AT2R significantly decreased in 2-ME rats (p < 0.05), whereas MAS1 did not significantly change. Gene expression analysis in normotensive (NT) rats revealed the non-detectability of AT1R in both parietal and frontal zone. In parietal area, AT2R (p < 0.0001) and Mas1 (p < 0.01) were significantly decreased in 2-ME NT rats, when compared to SO, and ACE and ACE2 resulted not detectable whereas there was some expression of these genes after 2-ME procedure. In conclusion, our data in rat models indicated that a 2-ME procedure induced a hypotensive response and that a modulation of gene expression and protein levels of RAS components occurred in different cerebral cortex areas.

Evidence in hypertensive rats of hypotensive effect after mandibular extension.

Previous studies in anesthetized normotensive rats demonstrated that a single mouth opening for 10 min obtained by an ad hoc dilator (mandibular extension [ME]) produced a blood pressure reduction by about 20 mmHg lasting for about 2 h and that once-repeated ME prolonged this effect. We here describe these effects in hypertensive rats. Mean (intra) arterial blood pressure (MABP) and heart rate (HR) was followed for up to a maximum of 470 min after single or repeated 10 min-lasting ME in two groups of anesthetized, male, 6-9 months old hypertensive rats. In one group, hypertension was induced by dexamethasone (20 µg/kg/day, subcutaneously for 7 days; Dex-HT); the other group was spontaneously hypertensive rats (SHR). Studies were done, in Dex-HT rats, after only surgical procedures (no ME, sham-operated rats), single ME, early repeated (after 10 min) ME (ER-ME) and late repeated (after 160 min) ME (LR-ME) and, in SHR, after only surgical procedures and ER-ME. One-way ANOVA for repeated measures revealed no significant effect on MABP and HR in sham-operated groups. In Dex-HT rats, single ME was followed by a significant MABP decline by 25 mmHg, lasting for 100 min; ER-ME and LR-ME were followed by an even greater significant MABP decline by 40 mmHg, which outlasted the experimental observation period. In SHR, ER-ME gave similar results as in Dex-HT rats. HR significantly declined in all, except sham-operated groups. In conclusions, ME is followed by a prolonged MABP decline also in hypertensive rats. This effect is even more pronounced, in length and magnitude, after repeated ME.

Repeated Mandibular Extension in Rat: A Procedure to Modulate the Cerebral Arteriolar Tone.

Previous data have shown both in the rat and in the human that a single mandibular extension lasting 10 min induces a significant important and prolonged reduction in blood pressure and heart rate, affecting also rat pial microcirculation by the release of endothelial factors. In the present work, we assessed whether repeated mandibular extension could further prolong these effects. We performed two mandibular extensions, the second mandibular extension being applied 10 min after the first one. The second mandibular extension produced a reduction in blood pressure and heart rate for at least 240 min. As in the case of a single mandibular extension, pial arterioles dilated persisting up to 140 min after the second extension. Spectral analysis on 30 min recordings under baseline conditions and after repetitive mandibular extensions showed that the pial arterioles dilation was associated with rhythmic diameter changes sustained by an increase in the frequency components related to endothelial, neurogenic, and myogenic activity while a single mandibular extension caused, conversely, an increase only in the endothelial activity. In conclusion, repetitive mandibular extension prolonged the effects of a single mandibular extension on blood pressure, heart rate and vasodilation and induced a modulation of different frequency components responsible of the pial arteriolar tone, in particular increasing the endothelial activity.

Evidence in the human of a hypotensive and a bradycardic effect after mouth opening maintained for 10 min.

PURPOSE: We have recently shown that in humans submaximal mouth opening associated with partial masticatory movements for 10 min is followed by a small but significant and prolonged reduction of blood pressure and heart rate. We here report the effects of a fixed mouth opener. METHODS: In 22 seated normotensive volunteers the effect on blood pressure and heart rate was studied in randomized order after fixed mandibular extension and after a control procedure consisting in keeping a stick between the incisor teeth (both for 10 min). Automated recordings every 10 min were done for 40 min before and 120 min following the procedure. RESULTS: Two-way ANOVA for repeated measures on absolute values (actual recordings) and on changes from baseline revealed that, compared to controls, systolic, diastolic and mean blood pressure and heart rate were significantly lower after mandibular extension. Compared to controls, mandibular extension induced an average blood pressure drop of 2.88 mmHg (systolic), 2.55 mmHg (diastolic) and 2.42 mmHg (mean) over the entire observation period. The average decline over the central part of the observation period (30th to 80th min) was, respectively, of 3.62, 3.70 and 3.61 mmHg. The decrements of heart rate were of 2.11 and 2.66 beats per min. All these differences were statistically significant. The hypotensive and bradycardic responses persisted for 70-120 min. CONCLUSIONS: This study shows that, in normotensives, a single fixed submaximal mouth opening for 10 min is followed by prolonged albeit small reductions of blood pressure and heart rate.

Trigeminocardiac reflex by mandibular extension on rat pial microcirculation: role of nitric oxide.

In the present study we have extended our previous findings about the effects of 10 minutes of passive mandibular extension in anesthetized Wistar rats. By prolonging the observation time to 3 hours, we showed that 10 minutes mandibular extension caused a significant reduction of the mean arterial blood pressure and heart rate respect to baseline values, which persisted up to 160 minutes after mandibular extension. These effects were accompanied by a characteristic biphasic response of pial arterioles: during mandibular extension, pial arterioles constricted and after mandibular extension dilated for the whole observation period. Interestingly, the administration of the opioid receptor antagonist naloxone abolished the vasoconstriction observed during mandibular extension, while the administration of Nω-Nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, abolished the vasodilation observed after mandibular extension. Either drug did not affect the reduction of mean arterial blood pressure and heart rate induced by mandibular extension. By qRT-PCR, we also showed that neuronal nitric oxide synthase gene expression was significantly increased compared with baseline conditions during and after mandibular extension and endothelial nitric oxide synthase gene expression markedly increased at 2 hours after mandibular extension. Finally, western blotting detected a significant increase in neuronal and endothelial nitric oxide synthase protein expression. In conclusion mandibular extension caused complex effects on pial microcirculation involving opioid receptor activation and nitric oxide release by both neurons and endothelial vascular cells at different times.

Differential magnetic field effects on heart rate and nociception in anosmic pigeons.

Several studies have shown that exposure to altered magnetic fields affects nociception by suppressing stress-induced hypoalgesia, and that this effect is reduced or abolished if the treatment is performed in the absence of light. This raises the question as to whether other sources of sensory stimuli may also modulate these magnetic effects. We investigated the possible role of olfaction in the magnetically induced effects on sensitivity to nociceptive stimuli and heart rate (HR) in restraint-stressed homing pigeons exposed to an Earth-strength, irregularly varying (<1 Hz) magnetic field. The magnetic treatment decreased the nociceptive threshold in normally smelling birds and an opposite effect was observed in birds made anosmic by nostril plugging. Conversely, no differential effect of olfactory deprivation was observed on HR, which was reduced by the magnetic treatment both in smelling and anosmic pigeons. The findings highlight an important role of olfactory environmental information in the mediation of magnetic effects on nociception, although the data cannot be interpreted unambiguously because of the lack of an additional control group of olfactory-deprived, non-magnetically exposed pigeons. The differential effects on a pigeon's sensitivity to nociceptive stimulus and HR additionally indicate that the magnetic stimuli affect nociception and the cardiovascular system in different ways.

Prolonged hypotensive and bradycardic effects of passive mandibular extension: evidence in normal volunteers.

Various procedures involving stimulations of facial regions are known to induce so-called trigemino-cardiac reflexes that entail a decrease of heart rate and blood pressure. We here report the effects of a specific stimulation that consists in a submaximal passive mandibular extension obtained by means of a dilatator applied for 10 minutes between the upper and lower incisor teeth, associated with partial active masticatory movements. Blood pressure and heart rate were determined in 18 young normal volunteers by Omron M4, before (20 minutes), during (10 minutes) and after mandibular extension (80 minutes) and under control conditions (same overall duration without stimulation). While control values remained stable, mandibular extension was followed by a progressive decline of both blood pressure (up to about 12/11 mmHg) and heart rate (up to about 13 bpm), statistically confirmed by ANOVA both on absolute values and on changes from basal values. The decline of systolic blood pressure and heart rate significantly correlated with basal values. The present findings indicate that submaximal opening of the mouth, associated to partial masticatory movements, induces a prolonged reduction of blood pressure and heart rate in normotensive volunteers.

Investigations of a simulated geomagnetic field experienced by the International Space Station on attentional performance.

We have previously reported that the exposure to an abnormal magnetic field simulating the one encountered by the International Space Station (ISS) orbiting around the Earth may enhance autonomic response to emotional stimuli. Here we report the results of the second part of that study which tested whether this field also affects cognitive functions. Twenty-four volunteers participated in the study, 12 exposed to the natural geomagnetic field and 12 to the magnetic field encountered by ISS. The test protocol consisted of a set of eight tests chosen from a computerized test battery for the assessment of attentional performance. The duration of exposure was 90 min. No effect of exposure to ISS magnetic field was observed on attentional performance.

Pain perception and electromagnetic fields.

A substantial body of evidence has accumulated showing that exposure to electromagnetic fields (EMFs) affects pain sensitivity (nociception) and pain inhibition (analgesia). Consistent inhibitory effects of acute exposures to various EMFs on analgesia have been demonstrated in most studies. This renders examinations of changes in the expression of analgesia and nociception a particularly valuable means of addressing the biological effects of and mechanisms underlying the actions of EMFs. Here we provide an overview of the effects of various EMFs on nociceptive sensitivity and analgesia, with particular emphasis on opioid-mediated responses. We also describe the analgesic effects of particular specific EMFs, the effects of repeated exposures to EMFs and magnetic shielding, along with the dependence of EMF effects on lighting conditions. We further consider some of the underlying cellular and biophysical mechanisms along with the clinical implications of these effects of various EMFs.

Simulation of the geomagnetic field experienced by the International Space Station in its revolution around the Earth: effects on psychophysiological responses to affective picture viewing.

There is evidence suggesting that exposure to an abnormal magnetic environment may produce psychophysiological effects related to abnormalities in responses to stress. This may be of relevance for space medicine where astronauts are exposed to a magnetic field different from that exerted by the Earth. Aim of this study was to assess how the exposure of the head to a magnetic field simulating the one encountered by the International Space Station (ISS) during a single orbit (90 min) around the Earth affects the cardiovascular and psychophysiological parameters. Twenty-four human volunteers were studied double blindly in random order under sham and magnetic exposure. During exposure, the persons were shown a set of pictures of different emotional content while subjective self-rating, skin conductance (SC), blood pressure (BP), and heart rate (HR) were measured. In addition, BP, HR, and tooth pain threshold were assessed before and after exposure. While subjects were under magnetic exposure, skin conductance was strongly differentiated (F(2,36)=22.927; p=0.0001), being high during emotionally involving (positive and negative) pictures and low during neutral pictures. Conversely, when subjects were under sham exposure, no significant differences were observed. There was, however, a trend for higher heart rate during picture viewing under magnetic exposure as compared to sham exposure. No effects were found for the other variables. These results suggest that an abnormal magnetic field that simulates the one encountered by ISS orbiting around the Earth may enhance autonomic response to emotional stimuli.

Effects of magnetic field exposure on open field behaviour and nociceptive responses in mice.

Results of previous studies have shown that nociceptive sensitivity in male C57 mice is enhanced by exposure to a regular 37 Hz or an irregularly varying (<1 Hz) electromagnetic field. In order to test whether these fields affect more generally mouse behaviour, we placed Swiss CD-1 mice in a novel environment (open field test) and exposed them for 2 h to these two different magnetic field conditions. Hence, we analysed how duration and time course of various behavioural patterns (i.e. exploration, rear, edge chew, self-groom, sit, walk and sleep) and nociceptive sensitivity had been affected by such exposure. Nociceptive sensitivity was significantly greater in magnetically treated mice than in controls. The overall time spent in exploratory activities was significantly shorter in both magnetically treated groups (< 1 Hz, 33% and 37 Hz, 29% of total time), than in controls (42%). Conversely, the time spent in sleeping was markedly longer in the treated groups (both 27% of total time) than in controls (11%). These results suggest that exposure to altered magnetic fields induce a more rapid habituation to a novel environment.