Hypothyroid Rats Research Articles

Kisspeptin treatment reverses high prolactin levels and improves gonadal function in hypothyroid male rats

We evaluated whether the administration of kisspeptin-10 (Kp10) is capable of restoring gonadal function in hypothyroid male rats. Hypothyroidism was induced with 6-propyl-2-thiouracil (PTU) for three months. In the last month, half of the hypothyroid animals were treated with Kp10. Hypothyroidism reduced testicular and sex gland mass, decreased the proliferation of the seminiferous epithelium, and compromised sperm morphology, motility, and vigor. A decrease in plasma LH and testosterone levels and an increase in prolactin secretion were observed in the hypothyroid rats. Hypothyroidism reduced Kiss1 and Kiss1r protein and gene expression and Star and Cyp11a1 mRNA levels in the testis. Furthermore, it reduced Lhb, Prl, and Drd2 and increased Tshb and Gnrhr expression in the pituitary. In the hypothalamus, hypothyroidism increased Pdyn and Kiss1r while reducing Gnrh1. Kp10 treatment in hypothyroid rats restored testicular and seminal vesicle morphology, improved sperm morphology and motility, reversed high prolactin levels, and increased LH and testosterone levels. In addition, Kp10 increased testicular expression of Kiss1, Kiss1r, Fshr, and Nr5a1 and pituitary Kiss1 expression. Our findings describe the inhibitory effects of hypothyroidism on the male gonadal axis and sperm quality and demonstrate that Kp10 treatment reverses high prolactin levels and improves gonadal function and sperm quality in hypothyroid rats.

Thyroidectomy and PTU-Induced Hypothyroidism: Effect of L-Thyroxine on Suppression of Spatial and Non-Spatial Memory Related Signaling Molecules.

The calcium/calmodulin protein kinase II (CaMKII) signaling cascade is crucial for hippocampus-dependent learning and memory. Hypothyroidism impairs hippocampus- dependent learning and memory in adult rats, which can be prevented by simple replacement therapy with L-thyroxine (thyroxine, T4) treatment. In this study, we compared animal models of hypothyroidism induced by thyroidectomy and treatment with propylthiouracil (PTU) in terms of synaptic plasticity and the effect on underlying molecular mechanisms of spatial and non-spatial types of memory. Hypothyroidism was induced using thyroidectomy or treatment with propylthiouracil (PTU). L-thyroxin was used as replacement therapy. Synaptic plasticity was evaluated using in vivo electrophysiological recording. Training in the radial arm water maze (RAWM), where rats had to locate a hidden platform, generated spatial and non-spatial learning and memory. Western blotting measured signaling molecules in the hippocampal area CA1 area. Our findings show that thyroidectomy and PTU models are equally effective, as indicated by the identical plasma levels of thyroid stimulating hormone (TSH) and T4. The two models produced an identical degree of inhibition of synaptic plasticity as indicated by depression of long-term potentiation (LTP). For non-spatial memory, rats were trained to swim to a visible platform in an open swim field. Analysis of hippocampal area CA1 revealed that training, on both mazes, of control and thyroxine-treated hypothyroid rats, produced significant increases in the P-calcium calmodulin kinase II (P-CaMKII), protein kinase-C (PKCγ), calcineurin and calmodulin protein levels, but the training failed to induce such increases in untreated thyroidectomized rats. Thyroxine therapy prevented the deleterious effects of hypothyroidism at the molecular level.

Vitamin D alleviates hypothyroidism associated liver dysfunction: Histological and biochemical evidence

There is a complex correlation between thyroid hormones (THs) and liver function. Hypothyroidism as a failure of the thyroid gland to produce adequate thyroid hormones to fulfill the metabolic requirements of the body, may perturb liver structure and function. Emerging evidence suggests the protective effects of vitamin D against liver damage. Herein, this study aimed to investigate the role of vitamin D in hypothyroidism-associated liver injury. Forty male Wistar rats were classified into 4 groups: control, hypothyroid (Hypo) group received 0.05% PTU, Hypo- Vitamin D groups were given 100 and 500 IU/kg vitamin D orally via gavage for 6 weeks. Serum level of liver function including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were measured. Malondialdehyde (MDA) level, superoxide dismutase (SOD) enzyme activity, and total thiol content were measured as oxidative stress indicators in the liver tissue. Furthermore, to estimate liver tissue fibrosis, Masson's trichrome staining was done.Our findings showed that hypothyroidism-induced liver fibrosis was associated with increased levels of ALT, AST and ALP. Though, vitamin D administration could significantly reduce the ALT, AST and ALP in the serum and suppress the accumulation of collagen fibers. Moreover, the activity of SOD and total thiol content was notably reduced, while the MDA content was significantly increased in the PTU- induced hypothyroid rats compared to the control group. Nonetheless, treatment with vitamin D improved mentioned oxidative stress markers in the Hypo-vitamin D groups. In conclusion, vitamin D due to its potential antioxidant and anti-fibrotic properties could be effective in the decrease of hypothyroidism-associated liver injury.

A synergistic analgesic effect of morphine in combination with the CB1 receptor agonist, ACPA, in normal, hypothyroid, and hyperthyroid male rats.

Both cannabinoid and opioid receptors are involved in pain behavior. The administration of morphine and cannabis in rats has been shown to decrease thyroid weight and thyroid‑stimulating hormone (TSH) levels. We hypothesized that the third ventricle, due to its adjacency to the hypothalamus, is involved in the modulation of hypothalamic‑pituitary‑thyroid axis activity and descending pain pathways. The present study examined the effect of intra‑third ventricle administration of morphine and cannabis agents on the modulation of pain behavior in normal, hypothyroid (increased serum TSH), and hyperthyroid (decreased serum TSH) rats using the tail‑flick test. The results indicated that intra‑third ventricle injection of AM251 (CB1 receptor antagonist) caused hyperalgesia, while intra‑third ventricle administration of ACPA (CB1 receptor agonist) and morphine produced analgesia in normal, hypothyroid, and hyperthyroid rats. A non‑effective dose of morphine (0.5 μg/rat) did not attenuate hyperalgesia induced by an effective dose of AM251. Co‑injection of ACPA and morphine into the third ventricle induced anti‑nociceptive effect in normal, hypothyroid, and hyperthyroid rats. An isobolographic analysis demonstrated a synergistic effect between ACPA and morphine in the production of the anti‑nociceptive effect. Consequently, the third ventricle may modulate pain behavior induced by cannabinoid and opioid receptors via descending pain pathways in normal, hypothyroid, and hyperthyroid rats.

Yijung-tang improves thermogenesis and reduces inflammation associated with gut microbiota in hypothyroid rats

Currently, considerable attention is focused on exploring the potential relationship between herbal medicine (HM) and the gut microbiome in terms of thermoregulation, which is an important aspect of human health, in modern system biology. However, our knowledge of the mechanisms of HM in thermoregulation is inadequate. Here, we demonstrate that the canonical herbal formula, Yijung-tang (YJT), protects against hypothermia, hyperinflammation, and intestinal microbiota dysbiosis in PTU-induced hypothyroid rats. Notably, these properties were associated with alterations in the gut microbiota and signaling crosstalk between the thermoregulatory and inflammatory mediators in the small intestine and brown adipose tissue (BAT). In contrast to the conventional drug L-thyroxine for curing hypothyroidism, YJT has an efficacy for attenuating systematic inflammatory responses, related with depression in intestinal TLR4 and Nod2/Pglyrp1 signaling pathways. Our findings suggest that YJT could promote BAT thermogenesis and prevent systemic inflammation in PTU-induced hypothyroid rats, which was associated with its prebiotic effect on modulating of the gut microbiota and gene expression with relevance in the enteroendocrine function and innate immune systems. These findings may strengthen the rationale of the microbiota–gut–BAT axis for a paradigm shift to enable holobiont-centric medicine.

Sonographic Assessment of Submandibular Salivary Glands in Hypothyroid Rat’s Pups Before and After Ashwagandha Root Extract Treatment

Background: One of the most common chronic diseases globally is hypothyroidism. Thyroid hormones serve a significant role in maintaining the proper function and shape of the salivary gland. The aim of the study: Investigate the function of Ashwagandha roots extract in providing a protection role for salivary glands in hypothyroid rats following postnatal exposure to Propylthiouracil. Materials and Methods: Ten pregnant albino rats were obtained. Until the rat pups were detected, each pregnant rat was kept individually in clean rodent plastic. At postnatal day 3 (PND3), forty male rats were randomly assigned to one of two groups: group A, which served as a control group, and group B, which received orally (1mg/kg) Propylthiouracil (PTU) for three weeks. At PND22, group B was divided up into three subgroups: B1, the hypothyroid group that got no therapy; B2, the hypothyroid group that received an aqueous extract of Ashwagandha roots (200 mg/kg) for 21 days; and B3, the hypothyroid group that received Levothyroxine (4g/100g/day) for 21 days. At the end of the trial, the submandibular gland was assessed using sonographic instruments in all groups. Results: the sonographic assessment of hypothyroid group’s submandibular gland showed an increase in the overall size of the gland, a heterogeneous gland with a honeycomb appearance and hypoechoic regions in group remains without treatment, while the results in hypothyroid pups fed with Ashwagandha roots extract indicated a small improvement in gland size and echotexture when compared to pups who received levothyroxine, owing to its antioxidant properties.

DISTINCT CARDIAC CONNEXIN-43 EXPRESSION IN HEMODYNAMICALLY UPLOADED AND UNLOADED HEART MAY IMPACT VULNERABILITY TO MALIGNANT ARRHYTHMIAS

Objective: Experimental and clinical studies suggest that myocardial hypertrophy in response to hypertension and hyperthyroidism increases propensity to cardiac arrhythmias. While these are rare in conditions resulting in myocardial atrophy, such as hypothyroidism or type-1 diabetes mellitus (T1DM). One of the crucial factors impacting the susceptibility of the heart to life-threatening arrhythmias is gap junction channel protein connexin-43 (Cx43), which ensure cardiac cell-to-cell coupling for electrical signal propagation that induce contraction. We aimed to explore abundance of Cx43 protein and its cardiomyocyte topology in hemodynamically uploaded hypertrophied versus unloaded hypotrophic cardiac phenotype. Design and method: Analysis were performed in left ventricular tissue of adult male rats of following groups: 1. spontaneously hypertensive rat (SHR); 2. normotensive Wistar Kyoto rats (WKY) treated for 8-weeks with L-thyroxine (0.15 μg/kg, i.v.) to induce hyperthyroid status; 3. WKY rats treated with methimazol (0.05% solution, p.o.) to induce hypothyroid status; 4. WKY rats treated with strepotozotocin (50mg/kg, i.p.) to induce T1DM. Animals were compared with non-treated normotensive control rats. Results: Comparing to healthy non-treated rats there was a decrease of total myocardial Cx43 protein and its variant phosphorylated at serine368 in SHR and hyperthyroid rats. Besides, enhanced abnormal localisation of Cx43 was demonstrated on lateral sides of hypertrophied cardiomyocytes. In contrast, total Cx43 protein and its serine368 variant were increased in atrophied left ventricle of hypothyroid and T1DM rats. It was associated with less pronounced alterations in Cx43 topology. In parallel, the abundance of PKC epsilon, which phosphorylates Cx43 at serine368 that stabilize Cx43 function and distribution was reduced in hypertrophied heart while enhanced in atrophied once. Conclusions: Findings suggest that differences in the abundance of cardiac Cx43, its variant phosphorylated at serine368 and Cx43 topology may explain, in part, distinct propensity of uploaded and unloaded heart to malignant arrhythmias. It suggests that hemodynamically overloaded heart might benefit from interventions promoting unloading. This research was supported by VEGA grants 2/0002/20, 2/0006/23, Slovak Research and Development Agency under the Contract no. 21-0410

Distinct Cardiac Connexin-43 Expression in Hypertrophied and Atrophied Myocardium May Impact the Vulnerability of the Heart to Malignant Arrhythmias. A Pilot Study.

Our and other studies suggest that myocardial hypertrophy in response to hypertension and hyperthyroidism increases propensity of the heart to malignant arrhythmias, while these are rare in conditions of hypothyroidism or type-1 diabetes mellitus associated with myocardial atrophy. One of the crucial factors impacting the susceptibility of the heart to life-threatening arrhythmias is gap junction channel protein connexin-43 (Cx43), which ensure cell-to-cell coupling for electrical signal propagation. Therefore, we aimed to explore Cx43 protein abundance and its topology in hypertrophic and hypotrophic cardiac phenotype. Analysis were performed in left ventricular tissue of adult male spontaneously hypertensive rat (SHR), Wistar Kyoto rats treated for 8-weeks with L-thyroxine, methimazol or strepotozotocin to induce hyperthyroid, hypothyroid and type-1 diabetic status as well as non-treated animals. Results showed that comparing to healthy rats there was a decrease of total myocardial Cx43 and its variant phosphorylated at serine368 in SHR and hyperthyroid rats. Besides, enhanced localization of Cx43 was demonstrated on lateral sides of hypertrophied cardiomyocytes. In contrast, total Cx43 protein and its serine368 variant were increased in atrophied left ventricle of hypothyroid and type-1 diabetic rats. It was associated with less pronounced alterations in Cx43 topology. In parallel, the abundance of PKCepsilon, which phosphorylates Cx43 at serine368 that stabilize Cx43 function and distribution was reduced in hypertrophied heart while enhanced in atrophied once. Findings suggest that differences in the abundance of cardiac Cx43, its variant phosphorylated at serine368 and Cx43 topology may explain, in part, distinct propensity of hypertrophied and atrophied heart to malignant arrhythmias.

Nano-selenium relieved hepatic and renal oxidative damage in hypothyroid rats.

Hypothyroidism can induce oxidative stress. Nano-selenium (Nano Sel) has antioxidant effects. The current research explored Nano Sel effects on hepatic and renal oxidative damage induced by hypothyroidism in rats. Animals were grouped into (1) Control; (2) Propylthiouracil (PTU) group which received water mixed with 0.05% of PTU; (3) PTU-Nano Sel 50; (4) PTU-Nano Sel 100; and (5) PTU-Nano Sel 150. Besides PTU, the PTU-Nano Sel groups were treated with 50, 100, or 150 μg/kg of Nano Sel intraperitoneally. Treatments were done for 6 weeks. The serum level of T4, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), albumin, total protein, creatinine, and blood urea nitrogen (BUN) was evaluated. Malondialdehyde (MDA) and total thiol concentration and the activity of catalase (CAT) and superoxide dismutase (SOD) in hepatic and renal tissues also were checked. Hypothyroidism induced by PTU significantly increased AST, ALT, ALP, creatinine, BUN, and MDA concentration and noticeably reduced albumin, total protein, total thiol level, and SOD and CAT activity. Administration of Nano Sel ameliorated the adverse effects of hypothyroidism on liver and kidney function. Nano Sel applied protective effects against hepatic and renal damage resulting from hypothyroidism via ameliorating the oxidative stress status. More cellular and molecular experiments need to be done to understand the exact mechanisms.

ACOX-driven peroxisomal heterogeneity and functional compartmentalization in brown adipocytes of hypothyroid rats.

We previously demonstrated that hypothyroidism increases peroxisomal biogenesis in rat brown adipose tissue (BAT). We also showed heterogeneity in peroxisomal origin and their unique structural association with mitochondria and/or lipid bodies to carry out β-oxidation, contributing thus to BAT thermogenesis. Distinctive heterogeneity creates structural compartmentalization within peroxisomal population, raising the question of whether it is followed by their functional compartmentalization regarding localization/colocalization of two main acyl-CoA oxidase (ACOX) isoforms, ACOX1 and ACOX3. ACOX is the first and rate-limiting enzyme of peroxisomal β-oxidation, and, to date, their protein expression patterns in BAT have not been fully defined. Therefore, we used methimazole-induced hypothyroidism to study ACOX1 and ACOX3 protein expression and their tissue immunolocalization. Additionally, we analysed their specific peroxisomal localization and colocalization in parallel with peroxisomal structural compartmentalization in brown adipocytes. Hypothyroidism caused a linear increase in ACOX1 expression, while a temporary decrease in ACOX3 levels is only recovered to the control level at day 21. Peroxisomal ACOX1 and ACOX3 localization and colocalization patterns entirely mirrored heterogeneous peroxisomal biogenesis pathways and structural compartmentalization, e.g. associations with mitochondria and/or lipid bodies. Hence, different ACOX isoforms localization/colocalization creates distinct functional heterogeneity of peroxisomes and drives their functional compartmentalization in rat brown adipocytes.

Combined levothyroxine and testosterone treatment for restoring erectile dysfunction in propylthiouracil-induced hypothyroid rats.

Sexual dysfunction may indicate severe endocrine diseases. Recent research has suggested a link between hypothyroidism, low testosterone (T) levels, and erectile dysfunction (ED); however, the exact cause is unknown. We sought to investigate possible beneficial effects of levothyroxine and T alone or in combination on ED in propylthiouracil (PTU)-induced hypothyroid rats. Adult Wistar rats (n = 35) were divided into 5 groups: control, PTU-induced hypothyroidism, PTU + levothyroxine, PTU + Sustanon (a mixture of 4 types of T: propionate, phenylpropionate, isocaproate, and decanoate) and PTU + levothyroxine + Sustanon. PTU was given in drinking water for 6 weeks. Four weeks after PTU administration, levothyroxine (20μg microgram kg/day, oral) and Sustanon (10mg/kg/week, intramuscular) were given for 2weeks. Serum levels of total T, triiodothyronine (T3), and thyroxine (T4) were determined. In vivo erectile response and in vitro relaxant responses were measured. Localization of neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS), and phosphodiesterase type 5 (PDE5) were determined using immunohistochemical analysis. The relative area of smooth muscle to collagen was measured using Masson trichrome staining. Outcome variables included in vivo erectile function, in vitro relaxant and contractile responses of corpus cavernosum (CC) strips; protein localization of eNOS, nNOS, and PDE5; and smooth muscle content in penile tissue. The rat model of hypothyroidism showed a significant decline in serum levels of total T, T3, and T4. Levothyroxine increased T3 and T4 levels, whereas Sustanon normalized only total T levels. Combined treatment enhanced all hormone levels. Rats with hypothyroidism displayed the lowest erectile response (P < 0.001 vs controls). Combined treatment returned reduced responses, while partial amelioration was observed after levothyroxine and Sustanon treatment alone. Acetylcholine (P < 0.01 vs controls), electrical field stimulation (P < 0.001 vs controls), and sildenafil-induced relaxant responses (P < 0.05 vs controls) were decreased in the CC strips from hypothyroid rats. The combined treatment increased the reduction in relaxation responses. Levothyroxine and Sustanon restored decreases in eNOS and nNOS expression in the hypothyroid group. There was no significant difference in PDE5 expression among groups. Monotreatment partially enhanced reduced smooth muscle mass, while combined therapy completely recovered. The combination of thyroid hormones and T is likely to be a therapeutic approach for treatment of hypothyroidism-induced ED in men. Beneficial effects of levothyroxine and Sustanon treatment were shown in vitro and in vivo in PTU-induced hypothyroid rats. The main limitation of the study was the lack of measurement of androgen-sensitive organ weights and luteinizing hormone, follicle-stimulating hormone, and prolactin levels. These findings demonstrate that neurogenic and endothelium-dependent relaxation responses are reduced by hypothyroidism, which is detrimental to T levels and erectile responses. Levothyroxine and Sustanon combination medication was able to counteract this effect.

Phytochemical profiling of polyphenols and thyroid stimulatory activity of Ficus religiosa leaf extract in 6-propyl-thiouracil-induced hypothyroid rats

Ethnopharmacological relevanceThe plant, Ficus religiosa (L.) from the family Moraceae, has been extensively used in Ayurveda and Unani. Traditionally this plant is known for the treatment of constipation, liver diseases and neurological disorders that are related to hypothyroidism. Aim of the studyThis study was primarily designed to evaluate the effect of Ficus religiosa leaf (FL) extract in ameliorating hypothyroidism in rats and to identify the major bioactive compounds in the test extract that might be responsible for the thyroid-altering activity. In addition, the probable mechanism underlying the thyroid regulation of the main FL constituents were analyzed by molecular docking. Materials and methodsAdult female Wistar rats were used. LC-ESI-MS/MS was performed to identify the compounds present in the extract. HPLC analysis of FL extract was also performed. A pilot study was made using 3 doses of FL extract. Out of 50, 100, and 200 mg/kg, 100 mg/kg appeared to be the most effective one as it could increase thyroid hormones and decreased TSH levels. In the final experiment, propyl-thiouracil (PTU)-induced hypothyroid rats were orally treated with FL extract (100 mg/kg) or L-thyroxine (100 μg/kg, i.p.) daily for 28 consecutive days. On 29th day, all rats were sacrificed and the serum levels of triiodothyronine (T3), thyroxine (T4), thyrotropin (TSH), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and hepatic 5′ deiodinase-1(5′D1) were estimated by ELISA. Liver marker enzymes (alanine aminotransferase, ALT and aspartate aminotransferase, AST); total cholesterol (TC) and triglycerides (TG); hepatic lipid peroxidation (LPO) and the activities of antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) content were estimated in liver tissues. ResultsLC-MS-MS analyses of the leaf extract identified 11 compounds including the three major compounds, betulinic acid (BA), chlorogenic acid (CGA), and quinic acid (QA). While the PTU treatment decreased the levels of thyroid hormones and 5′D1 activity, it increased the TSH, ALT, AST, TNF-α, IL-6, TC, and TG levels. Furthermore, hepatic LPO significantly increased with a decrease in reduced GSH, SOD, CAT, and GPx. However, FL treatment in PTU-induced animals nearly reversed these adverse effects and improved liver function by decreasing ALT, AST, hepatic LPO and increasing the levels of antioxidants. FL not only improved the liver histology, but also suppressed the inflammatory cytokines, TNF-α and IL-6 in PTU-induced animals. A molecular docking study towards the understanding of the thyroid stimulatory mechanism of action revealed that BA, CGA, and QA might have augmented thyroid hormones by interacting with the thyroid hormone receptor (TRβ1) and TSH receptor (TSHR). ConclusionFor the first time, we report the pro-thyroidal potential of Ficus religiosa leaf extract. We postulate that its main bioactive compounds, BA, CGA, and QA involved in this action may serve as novel thyroid agonists in ameliorating hypothyroidism.

Inflammatory Immune Process and Depression-like Behavior in Hypothyroid Rats: A [18F] DPA-714 Micro Positron Emission Tomography Study.

Hypothyroidism is closely related to mental disorders, mainly depression, through an as-yet-unknown mechanism. The cerebral inflammatory immune process has been implied to play a pivotal role in the onset of affective symptoms in several conditions. In order to gain insight into the mechanism underlying the depressive behaviors in hypothyroid rats, brain microglial activation was evaluated using micro positron emission tomography imaging with a translocator protein (TSPO) radioligand. Hypothyroidism was induced in adult male Wistar rats by administration of 0.05% propylthiouracil in drinking water for five weeks. Open field, forced swimming and tail suspension tests were employed to evaluate the depressive behavior in hypothyroid rats, and the relationship between the behavioral changes and brain microglial activation was evaluated using [18F] DPA-714 micro positron emission tomography imaging. The open field test revealed significantly reduced first-minute activity and rearing behavior in the hypothyroid group, as well as significantly increased immobility in the forced swimming test and the tail suspension test. Hypothyroidism induced significantly increased microglial activation in the hippocampus. The radioligand uptake in the hippocampus correlated negatively with first-minute activity in the open field test (p < 0.05), and the radioligand uptake in the hippocampus correlated positively with changes in the immobility time in the forced swimming test and the tail suspension test (p < 0.05). Immunohistochemistry also confirmed the activation of microglia and inflammatory bodies in hypothyroid rats. The results indicate that hypothyroidism can induce depressive behavior in adult Wistar rats, microglial activation in the hippocampus plays an important role in the depressive behavior in hypothyroid rats and the inflammatory immune mechanism may underlie the behavioral abnormalities in thyroid dysfunction. Furthermore, the findings in the present study suggest there might be a common mechanism underlying depressive behavior in adult-onset hypothyroidism and depression.

Attenuation of Hypothyroidism-Induced Cognitive Impairment by Modulating Serotonin Mediation

Thyroid hormones play an important role in the modeling of neural networks in the brain. Besides its metabolic effects, thyroid dysfunction, and hypothyroidism in particular, is frequently associated with cognitive decline and depressive-like behavior. The current study aimed to examine the changes in behavior, cognition, and memory in rats with propylthiouracil-induced overt hypothyroidism. The behavior and cognition were assessed using the open field test, T-maze, and novel object recognition test. We found significant differences in the behavioral patterns of the hypothyroid animals showing a reduction in locomotor activity, frequency of rearing, and impaired memory function compared to the euthyroid controls. As serotonin is an essential biomarker regulating cognition and mood, we tried to modulate the serotonin mediation in hypothyroid animals through tryptophan administration. Treatment with 5-hydroxy-tryptophan (5-OH-TRP) intraperitoneally for 10 days or directly into the hippocampus as a single injection led to attenuation of the hypothyroidism-induced cognitive and memory decline. A staggering amount of research is suggesting that the common denominators in the pathophysiology of depression and the behavior changes in hypothyroidism are the hippocampal complex and the distorted serotonin metabolism. In our study, it was observed a significant alleviation of cognitive impairment and an improvement of memory performance in hypothyroid rats after 5-OH-TRP administration. Current results are promising and may serve as groundwork for further investigation of functional and structural changes in the hippocampus during a hypothyroid state, and in particular, the effects of serotonin mediation in hypothyroid-associated depressive-like behavior.

Thyroid hormone disorder and the heart: The role of cardiolipin in calcium handling.

What is the central question of this study? Do alterations in thyroid status affect haemodynamic parameters and echocardiographic measurements in the rat postnatal heart, and calcium handling, contractility, relaxation and cardiolipin content in isolated rat cardiomyocytes? What is the main finding and its importance? An imbalance in phospholipids of the mitochondrial membrane such as cardiolipin is related to defects in mitochondrial function. T3 -dependent cardiolipin signals contribute to the maintenance of mitochondrial homeostasis and involve Ca2+ handling, this pathway being more important in hypothyroidism. The objective of this study was to evaluate whether alterations in thyroid status affect (1) haemodynamic parameters and echocardiographic measurements in the rat postnatal heart, and (2) calcium handling, contractility, relaxation and cardiolipin content in isolated rat cardiomyocytes. Sprague-Dawley rats aged 2months treated with T3 (hyperthyroid, 20μg/100g body weight) or 0.02% methimazole (hypothyroid, w/v) for 28 days. Heart function was evaluated by echocardiography. Measurements of mean arterial pressure (MAP), heart rate, Ca2+ transients, cardiomyocyte shortening, number of spontaneous contractions per minute and cardiolipin (CL) content were performed. Thyroid disorders were associated with changes in pacemaker activity without modifications of MAP. Thyroid disorder induced changes in left ventricular diameter which were correlated with modifications of cardiac contractility (altered cell shortening and sarcoplasmic reticulum Ca2+ content). Endocrine disorders altered cardiomyocyte relaxation (reduction in the time to 50% re-lengthening and the time to 50% Ca2+ decay). Thyroid disorder increased the number of spontaneous contractions per minute (an index of pro-arrhythmogenic behaviour). CL content was increased only in hypothyroid rats. Changes in CL content, CL composition and CL-protein interaction in mitochondria from hypothyroid animals are responsible for alterations of contractile and relaxation cardiac function. This mechanism may be not be involved in T3 -treated rats. Maintenance of euthyroidism is of crucial importance to preserve cardiac performance. An imbalance in relation to phospholipids of the mitochondrial membrane such as CL is related to defects in mitochondrial function. T3 -dependent CL signals contribute to the maintenance of mitochondrial homeostasis and involve Ca2+ handling, this pathway being more important in hypothyroidism.

Vitamin E Prevented Hepatic and Renal Tissue Damage in Hypothyroid Rats.

Considering antioxidant effects of vitamin E (Vit E), in the present study, the effect of Vit E on liver and kidney functions and oxidative stress parameters in tissues of these organs of hypothyroid (Hypo) rats were reported. The animals were included in three groups:(1) control, (2) hypo, and (3) hypo-hypo-Vit E. Hypothyroidism was induced in rats by giving 0.05% propylthiouracil (PTU) in drinking water. Besides PTU, the rats in group 3 were daily injected with Vit E (20 mg/kg) for 42 days. The animals were deeply anesthetized and sacrificed, and the serum of the rats was immediately removed to measure thyroxin level and subsequent analysis. The liver and kidney tissues were also immediately removed for biochemical oxidative stress criteria. PTU administration reduced serum thyroxin level and also thiol content, superoxide dismutase (SOD), and catalase (CAT) activities in the liver and kidney tissues while increasing malondialdehyde (MDA). Hypothyroidism also increased alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine while decreasing albumin. Vit E increased thiol, SOD, and CAT in the liver and kidney tissues while diminished MDA. Vit E also decreased ALT, BUN, and creatinine while increased albumin. The results of this study showed that Vit E prevented liver and renal tissue damage in hypothyroid rats.

Cardiac toxicity in experimentally induced hypothyroid rats and alleviation by Withania Somnifera and Shilajit

Cardiac toxicity in experimentally induced hypothyroid rats and alleviation by Withania Somnifera and Shilajit

The influence of Olmesartan on the Renin-angiotensin-aldosterone System of Rats with Thyroid Dysfunction

Background : The thyroid gland and its hormones participate and have a critical part in the development and function of different parts of the body like the kidney, which is the most important site of renin synthesis and release which is followed by angiotensin and aldosterone formation. As needs are; any abnormality in this gland’s function can harm the Renin-Angiotensin -Aldosterone System. We aimed to discover the effects of using an Angiotensin Receptor Blocker (Olmesartan) on the Renin-Angiotensin-Aldosterone System (RAAS) in rats with abnormal thyroid functions. Methods : Thirty rats were used and three groups were formed. 6 rats (First group) were the control. 12 rats (Second group) was the hypothyroid group (6 rats control, 6 rats given Olmesartan). 12 rats (the Third group) was the hyperthyroid group (6 rats control, 6 rats given Olmesartan). L-Thyroxine and Propylthiouracil (PTU) were given orally daily for induction of hyperthyroidism and hypothyroidism respectively. Blood pressure measurement was done on days 1 and 40th day of the study. The rats were sacrificed on day 40th of the study. Results : In hyperthyroid rats, T4 was raised and the use of Olmesartan on these rats caused a lowering of this parameter. Renin levels increased in hyperthyroid rats treated with Olmesartan. Angiotensin I increased in hyperthyroid rats. Systolic BP increased in hyperthyroid rats and the use of Olmesartan on these rats caused a lowering of this parameter. Diastolic BP and Mean BP both increased in the hyperthyroid rats. T3 and T4 levels dropped and TSH increased in hypothyroid and hypothyroid treated with Olmesartan rats. The level of Renin decreased in hypothyroid rats and increased in Olmesartan-treated rats. Angiotensin I decreased in hypothyroid and Olmesartan-treated hypothyroid rats. Blood Pressure components decreased in both hypothyroid and hypothyroid treated with Olmesartan rats. Conclusions : Olmesartan was able to decrease T4 level along with Systolic BP in hyperthyroid rats. It also decreased Angiotensin I and Blood Pressure components in hypothyroid rats.

Thymoquinone protects the testes of hypothyroid rats by suppressing pro-inflammatory cytokines and oxidative stress and promoting SIRT1 testicular expression.

Background: Hypothyroidism has been linked to many testicular structural and dysfunctional changes in males. Thymoquinone (TQ) has shown a potent testicular protective effect through its antioxidant, anti-inflammatory, antiapoptotic, fertility-enhancing, and endocrine modulatory activities. Objectives: This study aimed to investigate the efficacy of TQ in preserving the testicular structure of a model of experimentally induced hypothyroidism in rats and identify the mechanism behind this effect. Materials and methods: Propylthiouracil (PTU) was used to induce hypothyroidism in adult male Wistar rats, who were then treated with TQ (50mg/kg/body weight) for 4weeks and compared to the untreated rats. Thyroid hormonal profile, oxidants/antioxidants profile, and serum testosterone levels were assessed. Gene expression and immune expression of SIRT1 and pro-inflammatory cytokines TNF-α and NF-κB were also assessed in the testicular tissue. Results: TQ administration successfully improved PTU-induced disturbance in the thyroid hormonal profile (T3, T4, and TSH), serum testosterone level, and pancreatic antioxidants compared to the untreated hypothyroid group. TQ significantly downregulated (p = 0.001, p ˂ 0.001) TNF-α and NF-κB transcription, while it significantly upregulated (p = 0.01) SIRT1 transcription in the testes of hypothyroid rats. TQ markedly relieved the histopathological testicular changes induced by PTU and significantly increased (p = 0.002, p = 0.01) the sectional area of seminiferous tubules and germinal epithelial height, respectively. TUNEL-positive apoptotic germinal cells were significantly decreased (p ˂ 0.001), while PCNA-positive proliferating germinal cells and androgen receptor expression were significantly increased (p ˂ 0.001) in the testes of TQ-treated hypothyroid rats. Conclusion: Thymoquinone could limit the hypothyroidism-induced structural changes in the testis, mostly through the upregulation of SIRT1 expression, which seems to mediate its promising antioxidant, anti-inflammatory and antiapoptotic effects that were evident in this study. Therefore, TQ is recommended as an adjuvant safe supplement in managing hypothyroidism, especially in males.

Anti-apoptotic and neurogenic properties in the hippocampus as possible mechanisms for learning and memory improving impacts of vitamin D in hypothyroid rats during the growth period

The current study was designed to investigate the protective effects of Vitamin D (VD) on hippocampal neurogenesis, apoptosis, and subsequent hippocampal-dependent learning and memory performance in hypothyroid juvenile rats. Twenty eight male Wistar rats were randomly divided into four groups as; control, Hypothyroid (Hypo), Hypo-VD100 and Hypo-VD500. Hypothyroidism was induced by giving 0.05 % propylthiouracil (PTU), and VD (100 or 500 IU/kg) treatment was performed daily by gavage. At the end of treatment, Morris water maze (MWM) was carried out and evaluated hippocampal neurogenesis, apoptosis, and dark neurons (DNs). Our results revealed that the escape latency and the traveled distance to find the platform in the Hypo group were significantly longer but the time spent and distance traveled in the target area in probe trial was lower than the control group. Hypothyroidism was accompanied by a marked decrease in hippocampal neurogenesis, and a significant increase in the number of apoptotic neurons and DNs compared to the control group. VD decreased escape latency and the traveled distance to find the platform but increased the time spent and distance traveled in the target area in probe trial than the Hypo group. VD also increased neurogenesis, reduced apoptosis and DNs production compared to the Hypo group. In conclusion, these results support a role for VD in the restoring hippocampal neurogenesis impairment, reducing neuronal apoptosis, and DNs in hypothyroid rats as well as raise the possibility that VD may contribute as a therapeutic approach to improve the learning and memory deficits associated with hypothyroidism.