C-Phycocyanin prevents acute myocardial infarction-induced oxidative stress, inflammation and cardiac damage.

CONTEXT: C-Phycocyanin is a protein with anti-scavenger, antioxidant and anti-inflammatory actions against agents that cause cellular damage. The cardioprotective action of C-phycocyanin against acute myocardial infarction (AMI) has not been studied in animal models. OBJECTIVE: To investigate C-phycocyanin's effect on oxidative stress, inflammation and cardiac damage in a model of isoproterenol-induced AMI. MATERIALS AND METHODS: Wistar rats were divided into four groups: (1) sham + vehicle (0.9% saline solution by oral gavage, OG); (2) sham + C-phycocyanin (50 mg/kg/d, OG); (3) AMI + vehicle, and (4) AMI + C-phycocyanin. AMI was induced by administering isoproterenol (20, 10, 5 and 3 mg/kg each dose per day), and serum cardiac enzymes were quantified. After five days, the animals were euthanized; the heart was dissected to determine oxidative stress, redox environment, inflammation and cardiac damage markers. RESULTS: We observed that C-phycocyanin reduced AMI-increased cardiac enzymes (CK by about 53%, CKMB by about 60%, AST by about 16% and ALT by about 21%), lipid peroxidation (57%), reactive oxygen species (50%), nitrites (46%), oxidized glutathione (41%), IL1ß (3%), INFγ (5%), TNFα 3%), Bcl2 (37%), Bax (43%), COX2 (21%) and caspase 9 (61%). Finally, C-phycocyanin reduced AMI-induced aberrant histological changes related to myonecrosis, interstitial oedema and inflammatory infiltration in the heart muscle. CONCLUSIONS: C-Phycocyanin prevents AMI-induced oxidative stress, inflammation and heart damage. This study is the first report that employed C-phycocyanin in an animal model of AMI and supports the potential use of C-phycocyanin in the management of AMI.

C-phycoerythrin from Phormidium persicinum Prevents Acute Kidney Injury by Attenuating Oxidative and Endoplasmic Reticulum Stress.

C-phycoerythrin (C-PE) is a phycobiliprotein that prevents oxidative stress and cell damage. The aim of this study was to evaluate whether C-PE also counteracts endoplasmic reticulum (ER) stress as a mechanism contributing to its nephroprotective activity. After C-PE was purified from Phormidium persicinum by using size exclusion chromatography, it was characterized by spectrometry and fluorometry. A mouse model of HgCl2-induced acute kidney injury (AKI) was used to assess the effect of C-PE treatment (at 25, 50, or 100 mg/kg of body weight) on oxidative stress, the redox environment, and renal damage. ER stress was examined with the same model and C-PE treatment at 100 mg/kg. C-PE diminished oxidative stress and cell damage in a dose-dependent manner by impeding the decrease in expression of nephrin and podocin normally caused by mercury intoxication. It reduced ER stress by preventing the activation of the inositol-requiring enzyme-1α (IRE1α) pathway and avoiding caspase-mediated cell death, while leaving the expression of protein kinase RNA-like ER kinase (PERK) and activating transcription factor 6α (ATF6α) pathways unmodified. Hence, C-PE exhibited a nephroprotective effect on HgCl2-induced AKI by reducing oxidative stress and ER stress.

Thyroxine Treatment During the Perinatal Stage Prevents the Alterations in the ObRb-STAT3 Leptin Signaling Pathway Caused by Congenital Hypothyroidism.

Thyroid hormone deficiency during crucial stages of development causes congenital hypothyroidism. This syndrome alters hypothalamic pathways involved in long-term bodyweight regulation as ObRb-STAT3 leptin signaling pathway, which is associated with metabolic syndrome. This study aimed to determine if thyroxine treatment during pregnancy and lactation in hypothyroid mothers avoids, in the congenital hypothyroid offspring, the alterations in metabolic programming related to metabolic syndrome and the ObRb-STAT3 leptin signaling pathway in hypothalamus. Twenty-four virgin female Wistar rats were divided into euthyroid, hypothyroid, and hypothyroid with thyroxine treatment (20 µg/kg/day T4 since pregnancy until lactation). The bodyweight and energy intake, insulin resistance, glucose tolerance, metabolic and hormonal parameters were determined in offspring at 28 weeks after birth. Then, the rats were euthanized to obtain adipose tissue reserves and hypothalamus to measure the expression of ObRb, STAT3, pSTAT3, and SOCS3. Congenital hypothyroidism presented metabolic syndrome such as insulin resistance, glucose tolerance, dyslipidemias, an increase in cardiovascular risk (Castelli I males:166.67%, females: 173.56%; Castelli II males: 375.51%, females: 546.67%), and hypothalamic leptin resistance (SOCS3, Males: 10.96%, females: 25.85%). Meanwhile, the thyroxine treatment in the mothers during pregnancy and lactation prevents the metabolic disturbance. In conclusion, thyroxine treatment during the critical perinatal stage for metabolic programming prevents congenital hypothyroidism-caused metabolic syndrome and hypothalamic leptin resistance.

Endoplasmic reticulum stress participates in the pathophysiology of mercury-caused acute kidney injury.

Acute exposure to mercury chloride (HgCl2) causes acute kidney injury (AKI). Some metals interfere with protein folding, leading to endoplasmic reticulum stress (ERS), and the activation of cell death mechanisms, but in the case of mercury, there is no knowledge about whether the ERS mediates tubular damage. This study aimed to determinate if HgCl2 causes an AKI course with temporary activation of ERS and if this mechanism is involved in kidney cell death. Male mice were intoxicated with 5 mg/kg HgCl2 and sacrificed after 24, 48, 72, and 96 h of mercury administration. The kidneys of euthanized mice were used to assess the renal function, oxidative stress, redox environment, antioxidant enzymatic system, cell death, and reticulum stress markers (PERK, ATF-6, and IRE1α pathways). The results indicate temporary-dependent renal dysfunction, oxidative stress, and an increase of glutathione-dependent enzymes involved in the bioaccumulation process of mercury, as well as the enhancement of caspase 3 activity along with IRE1a, GADD-153, and caspase 12 expressions. Mercury activates the PERK/eIF2α branch during the first 48 h. Meanwhile, the activation of PERK/ATF-4 branch allowed for ATF-4, ATF-6, and IRE1α pathways to enhance GADD-153. It led to the activation of caspases 12 and 3, which mediated the deaths of the tubular and glomerular cells. This study revealed temporary-dependent ERS present during AKI caused by HgCl2, as well as how it plays a pivotal role in kidney cell damage.

The antihypertensive action of C-phycocyanin is related to the prevention of angiotensin II-caused vascular dysfunction in chronic kidney disease.

C-phycocyanin (CPC) is a photosynthetic protein found in Arthrospira maxima with a nephroprotective and antihypertensive activity that can prevent the development of hemodynamic alterations caused by chronic kidney disease (CKD). However, the complete nutraceutical activities are still unknown. This study aims to determine if the antihypertensive effect of CPC is associated with preventing the impairment of hemodynamic variables through delaying vascular dysfunction. Twenty-four normotensive male Wistar rats were divided into four groups: (1) sham + 4 mL/kg/d vehicle (100 mM of phosphate buffer, PBS) administered by oral gavage (og), (2) sham + 100 mg/kg/d og of CPC, (3) CKD induced by 5/6 nephrectomy (CKD) + vehicle, (4) CKD + CPC. One week after surgery, the CPC treatment began and was administrated daily for four weeks. At the end treatment, animals were euthanized, and their thoracic aorta was used to determine the vascular function and expression of AT1, AT2, and Mas receptors. CKD-induced systemic arterial hypertension (SAH) and vascular dysfunction by reducing the vasorelaxant response of angiotensin 1-7 and increasing the contractile response to angiotensin II. Also, CKD increased the expression of the AT1 and AT2 receptors and reduced the Mas receptor expression. Remarkably, the treatment with CPC prevented SAH, renal function impairment, and vascular dysfunction in the angiotensin system. In conclusion, the antihypertensive activity of CPC is associated with avoiding changes in the expression of AT1, AT2, and Mas receptors, preventing vascular dysfunction development and SAH in rats with CKD.

The joint effect of congenital hypothyroidism and hypercaloric diet consumption as triggers of type 2 diabetes mellitus.

Introduction: Congenital hypothyroidism affects metabolic and thyroid programming, having a deleterious effect on bodyweight regulation promoting metabolic diseases. This work aimed to demonstrate the development of type 2 diabetes mellitus (T2D) in animals with congenital hypothyroidism, only by the consumption of a mild hypercaloric diet in the extrauterine stage. Methods: Two groups of female Wistar rats (n = 9): euthyroid and hypothyroid were used. Hypothyroidism was induced by a thyroidectomy with parathyroid reimplantation. Male offsprings post-weaning were divided into four groups (n = 10): euthyroid, hypothyroid, euthyroid + hypercaloric diet, and hypothyroid + hypercaloric diet. The hypercaloric diet consisted of ground commercial feed plus 20% lard and was administered until postnatal week 40. Bodyweight and energy intake were monitored weekly. Also, metabolic and hormonal markers related to cardiovascular risk, insulin resistance, and glucose tolerance were analyzed at week 40. Then, animals were sacrificed to perform the morphometric analysis of the pancreas and adipose tissue. Results: T2D was developed in animals fed a hypercaloric diet denoted by the presence of central obesity, hyperphagia, hyperglycemia, dyslipidemia, glucose tolerance, insulin resistance and hypertension, as well as changes in the cytoarchitecture of the pancreas and adipose tissue related to T2D. The results show that congenital hypothyroid animals had an increase in metabolic markers and an elevated cardiovascular risk. Conclusions: Congenital hypothyroid animals develop T2D, having the highest metabolic disturbances and a worsened clinical prognosis than euthyroid animals.

The Nutraceutical Antihypertensive Action of C-Phycocyanin in Chronic Kidney Disease Is Related to the Prevention of Endothelial Dysfunction.

C-phycocyanin (CPC) is an antihypertensive that is not still wholly pharmacologically described. The aim of this study was to evaluate whether CPC counteracts endothelial dysfunction as an antihypertensive mechanism in rats with 5/6 nephrectomy (NFx) as a chronic kidney disease (CKD) model. Twenty-four male Wistar rats were divided into four groups: sham control, sham-treated with CPC (100 mg/Kg/d), NFx, and NFx treated with CPC. Blood pressure was measured each week, and renal function evaluated at the end of the treatment. Afterward, animals were euthanized, and their thoracic aortas were analyzed for endothelium functional test, oxidative stress, and NO production. 5/6 Nephrectomy caused hypertension increasing lipid peroxidation and ROS production, overexpression of inducible nitric oxide synthase (iNOS), reduction in the first-line antioxidant enzymes activities, and reduced-glutathione (GSH) with a down-expression of eNOS. The vasomotor response reduced endothelium-dependent vasodilation in aorta segments exposed to acetylcholine and sodium nitroprusside. However, the treatment with CPC prevented hypertension by reducing oxidative stress, NO system disturbance, and endothelial dysfunction. The CPC treatment did not prevent CKD-caused disturbance in the antioxidant enzymes activities. Therefore, CPC exhibited an antihypertensive activity while avoiding endothelial dysfunction.

An increase of oxidative stress markers and the alteration of the antioxidant enzymatic system are associated with spleen damage caused by methimazole-induced hypothyroidism.

Methimazole is the most widely used antithyroid drug in Europe and North America, but it causes several undesirable side effects, such as hematological dysfunctions and immunosuppression. Our aim in this work was to compare, over a time course, markers of oxidative stress, the redox environment, the antioxidant enzymatic system, and the glutathione cycle in the spleen of rats with methimazole- or thyroidectomy-caused hypothyroidism. We used 70-male Wistar rats divided into four groups: 1) euthyroid; 2) sham thyroidectomy; 3) thyroidectomy-caused hypothyroidism, with parathyroid reimplant; and 4) methimazole-caused hypothyroidism. Five rats of the euthyroid- and methimazole-caused hypothyroidism groups were killed at the end of weeks 1, 2, 3, and 4 after treatment, and 5 rats of the sham thyroidectomy and thyroidectomy-caused hypothyroidism groups were killed at the end of weeks 2, 4, and 8 after the surgical procedure. Each spleen was excised and stored at -70°C until oxidative stress, REDOX environment, and the antioxidant enzymatic-system markers were tested. The histological study showed that only methimazole-induced hypothyroidism caused cell damage. This damage was associated with an increase of oxidative-stress markers that were not compensated for by the antioxidant system. The increase of the glutathione-cycle enzymes was insufficient to prevent oxidative-stress markers. Methimazole causes oxidative stress and cell damage in the spleen, whereas hypothyroidism per se does not cause cell damage in this organ. Therefore, it is necessary to develop new antithyroid drugs without causing oxidative stress and cellular damage.

Gallic Acid Prevents the Oxidative and Endoplasmic Reticulum Stresses in the Hippocampus of Adult-Onset Hypothyroid Rats.

Thyroid hormone is essential for hippocampal redox environment and neuronal viability in adulthood, where its deficiency causes hypothyroidism related to oxidative and endoplasmic reticulum stresses in the hippocampus, resulting in neuronal death. One option of treatment is antioxidants; however, they must be transported across the blood-brain barrier. Gallic acid is a polyphenol that meets these criteria. Thus, this study aimed to prove that the neuroprotective mechanism of GA is associated with the prevention of oxidative and endoplasmic reticulum stresses in the hippocampus of adult-onset hypothyroid rats. Male Wistar rats were divided into euthyroid (n = 20) and hypothyroid groups (n = 20). Thyroidectomy with parathyroid gland reimplementation caused hypothyroidism. Each group was subdivided into two: vehicle and 50 mg/kg/d of gallic acid. 3 weeks after thyroidectomy, six animals of each group were euthanized, and the hippocampus was dissected to evaluate oxidative and endoplasmic reticulum stress markers. The rest of the animals were euthanized after 4 weeks of treatment for histological analysis of the hippocampus. The results showed that hypothyroidism increased lipid peroxidation, reactive oxygen species, and nitrites; it also increased endoplasmic reticulum stress by activating the inositol-requiring enzyme-1α (IRE1α) pathway, the protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activated transcription factor 6α (ATF6α) pathways associated with a proapoptotic state that culminates in hippocampal neuronal damage. Meanwhile, the hypothyroid rat treated with gallic acid reduced oxidative stress and increased endoplasmic reticulum-associated degradation (ERAD) through IRE1α and ATF6. Also, the gallic acid treatment prevented the Bax/BCl2 ratio from increasing and the overexpression of p53 and caspase 12. This treatment in hypothyroid animals was associated with the neuronal protection observed in the hippocampus. In conclusion, gallic acid prevents hypothyroidism-induced hippocampal damage associated with oxidative and endoplasmic reticulum stresses.

Phycocyanobilin is the molecule responsible for the nephroprotective action of phycocyanin in acute kidney injury caused by mercury.

C-Phycocyanin (CPC) exerts therapeutic, antioxidant, anti-inflammatory and immunomodulatory actions. It prevents oxidative stress and acute kidney damage caused by HgCl2. However, the exact mechanism of the pharmacological action of C-phycocyanin is as yet unclear. Some proposals express that CPC metabolism releases the active compound phycocyanobilin (PCB) that is able to induce CPC's therapeutical effects as an antioxidant, anti-inflammatory and nephroprotective. This study is aimed to demonstrate that PCB is the molecule responsible for C-phycocyanin's nephroprotective action in the acute kidney injury model caused by HgCl2. PCB was purified from C-phycocyanin and characterized by spectroscopy and mass spectrometry methods. Thirty-six male mice were administrated with 0.75, 1.5, or 3 mg per kg per d of PCB 30 min before the 5 mg kg-1 HgCl2 administration. PCB was administered during the following five days, after which the mice were euthanized. Kidneys were dissected to determine oxidative stress and redox environment markers, first-line antioxidant enzymes, effector caspase activities, and kidney damage markers.The quality of purified PCB was evaluated by spectroscopy and mass spectrometry. All PCB doses prevented alterations in oxidative stress markers, antioxidant enzymes, and caspase 9 activities. However, only the dose of 3 mg per kg per d PCB avoided the redox environment disturbance produced by mercury. All doses of PCB partially prevented the down-expression of nephrin and podocin with a consequent reduction in the damage score in a dose-effect manner. In conclusion, it was proven that phycocyanobilin is the molecule responsible for C-phycocyanin's nephroprotective action on acute kidney injury caused by mercury.

Arthrospira maxima (Spirulina) prevents endoplasmic reticulum stress in the kidney through its C-phycocyanin.

Arthrospira maxima (Spirulina) is a cyanobacterium which is considered a nutraceutical because it has antioxidant, anti-inflammatory, and cytoprotective properties in different renal disease models (Rodriguez-Sánchez et al., 2012; Aziz et al., 2018; Memije-Lazaro et al., 2018). The therapeutic effects are due to the presence of metabolites with biological effects similar to those of essential fatty acids ω-3 and ω-6, vitamins A, C and E, and accessory pigments such as phycobiliproteins. One of the most abundant phycobiliproteins in A. maxima is C-phycocyanin (Mysliwa-Kurdziel and Solymosi, 2017). This molecule is responsible for nephroprotective action in a model of acute kidney injury (AKI) because it reduces oxidative stress and caspase activation (Rodriguez-Sánchez et al., 2012; Rojas-Franco et al., 2018). However, both A. maxima and its C-phycocyanin are related to the reduction of the redox environment. Thus, they probably help to maintain the adequate function of the intracellular organelles like the endoplasmic reticulum. However, this therapeutic action has not been evaluated previously.

Methimazole-induced hypothyroidism causes alteration of the REDOX environment, oxidative stress, and hepatic damage; events not caused by hypothyroidism itself.

UNLABELLED: Our objective was to compare, over a time-course, markers of oxidative stress, the REDOX environment, and the antioxidant enzymatic system in the liver of rats with methimazole- or thyroidectomy-caused hypothyroidism. METHODS: We used 60 male Wistar rats divided into four groups: 1) the euthyroid, which received only tap water, 2) false thyroidectomy, which received the surgery and postoperative treatment, 3) thyroidectomy-caused hypothyroidism, which had the thyroid gland removed and a parathyroid reimplant, and 4) methimazole-caused hypothyroidism in rats that received 60 mg/kg/d of the antithyroid drug in drinking water. Five rats of the euthyroid and methimazole-caused hypothyroidism groups were killed at the end of the first, second, third, and fourth week after treatment, and five rats of false thyroidectomy and thyroidectomy-caused hypothyroidism groups were killed at the end of the second and eighth week after the surgical procedure. Each liver was removed and stored at -70 degrees C until oxidative stress, REDOX environment, and antioxidant enzymatic system markers were tested. We also made a histological study at the end of the treatment. RESULTS: The histological study revealed that only the methimazole-caused hypothyroidism caused cell damage. This damage is associated with an increase of oxidative stress markers that were not compensated for by the antioxidant system. The catalase activity is reduced and this allows H2O2-caused damage. In conclusion methimazole causes cell damage in the liver, whereas hypothyroidism per se does not cause hepatic-cell damage.

Lidocaine affects the redox environment and the antioxidant enzymatic system causing oxidative stress in the hippocampus and amygdala of adult rats.

AIMS: Our objective was to investigate if oxidative stress is involved in the neural damage caused by lidocaine. MAIN METHODS: Male Wistar rats were used. The control group received 0.9% saline ip and the treated group received a single 60 mg/kg lidocaine dose ip. On days 1, 2, 5, and 10 after dosing, ten rats were sacrificed and their brains were quickly removed. The amygdala and hippocampus were dissected. Five samples were used to determine lipid peroxidation, reactive oxygen species (ROS), reduced glutathione (GSH), and oxidized glutathione (GSSG). Another five were used to measure antioxidant activities of glutathione peroxidase (GPX), catalase, Cu-Zn SOD (superoxide dismutase), Mn SOD, and total SOD. KEY FINDINGS: Ten days after injection of lidocaine, lipid peroxidation increases in the hippocampus because the ROS are enhanced from day 5, whereas in the amygdala lipid peroxidation and the ROS were enhanced only on the first day postinjection. Lidocaine causes an increased concentration of GSH and GSSG in the hippocampus from the first day. In the amygdala the GSH and GSSG content were increased at day 10. In the hippocampus the catalase activity was enhanced, whereas the total SOD and Cu-Zn SOD activities were decreased. In the amygdala the lidocaine enhances the activities of catalase and GPX, but no SOD isoenzymes were modified. SIGNIFICANCE: In this research we demonstrated that lidocaine affects the redox environment and promotes increases of the oxidative markers both in the hippocampus and amygdala but in a different pattern.

Hypothyroidism Causes Endoplasmic Reticulum Stress in Adult Rat Hippocampus: A Mechanism Associated with Hippocampal Damage.

Thyroid hormones (TH) are essential for hippocampal neuronal viability in adulthood, and their deficiency causes hypothyroidism, which is related to oxidative stress events and neuronal damage. Also, it has been hypothesized that hypothyroidism causes a glucose deprivation in the neuron. This study is aimed at evaluating the temporal participation of the endoplasmic reticulum stress (ERE) in hippocampal neurons of adult hypothyroid rats and its association with the oxidative stress events. Adult Wistar male rats were divided into euthyroid and hypothyroid groups. Thyroidectomy with parathyroid gland reimplementation caused hypothyroidism at three weeks postsurgery. Oxidative stress, redox environment, and antioxidant enzyme markers, as well as the expression of the ERE through the pathways of PERK, ATF6, and IRE1, were evaluated at the 3rd and 4th weeks postsurgery. We found a rise in ROS and nitrite production; also, catalase increased and glutathione peroxidase diminished their activities. These events promote an enhancement of the lipoperoxidation, as well as of γ-GT, myeloperoxidase, and caspase 3 activities. With respect to ERE, there were ATF6, IRE1, and GADD153 overexpressions with a reduction in mitochondrial activity and GSH2/GSSG ratio. We conclude that the endoplasmic reticulum stress might play a pivotal role in the activation of hypothyroidism-induced hippocampal cell death.

Hippocampus and amygdala neurotoxicity produced by systemic lidocaine in adult rats.

There is evidence that using lidocaine-treated cellular culture produces cell damage. However, there are no studies in vivo demonstrating the potential injurious effect of lidocaine on the central nervous system. Therefore, the aim of our study was to investigate if lidocaine is involved in neuronal damage in the CA3 hippocampus and amygdala regions when using a single subconvulsive or a convulsive lidocaine dose. Two-month-old male Wistar rats (57) were used. The animals were randomly assigned to one of three groups. Group I received 0.9% saline ip (n=9), group II received a single lidocaine dose of 60 mg/kg (n=18), and group III received 90 mg/kg ip (n=12). At day 2, 7, and 10 after the dosing, three to six rats per group were sacrificed. The brains of the rats were removed and were embedded in paraffin. Coronal cuts of 7 microm were made. Each brain section was stained with cresyl-eosin. We evaluated the number of normal and abnormal neurons in the hippocampal CA3 (pyramidal) and basolateral amygdala (large and medium neurons) regions in a 10,000 microm2 section. To explore an association between lidocaine-induced seizure and neuronal damage, diazepam was used (10 mg/kg ig) as an anticonvulsant two hours before a 90 mg/kg dose of lidocaine. Lidocaine causes a morphological neuronal alteration in the CA3 hippocampal region and the basolateral amygdala and possibly an inhibition-excitation imbalance. Diazepam prevents lidocaine-induced seizures, but not neuronal damage in brain structures. Interaction of lidocaine with the membrane components produces disrupted Ca+2 homeostasis and causes neuronal damage. Moreover, it is possible that lidocaine or its metabolites could actively participate in the neuronal damage observed.

A Canola Oil-Supplemented Diet Prevents Type I Diabetes-Caused Lipotoxicity and Renal Dysfunction in a Rat Model.

We investigated the effect of a canola oil-supplemented diet on the metabolic state and diabetic renal function of a type I diabetes experimental model. Male Sprague-Dawley rats were randomly divided into four groups: (1) normoglycemic+chow diet, (2) normoglycemic+a canola oil-supplemented chow diet, (3) diabetic+chow diet, and (4) diabetic+a canola oil-supplemented chow diet. For 15 weeks, animals were fed a diet of Purina rat chow alone or supplemented with 30% canola oil. Energetic intake, water intake, body weight, and adipose tissue fat pad were measured; renal function, electrolyte balance, glomerular filtration rate, and the plasmatic concentration of free fatty acids, cholesterol, triglycerides, and glucose were evaluated. The mesenteric, retroperitoneal, and epididymal fat pads were dissected and weighed. The kidneys were used for lipid peroxidation (LP) and reactive oxygen species (ROS) quantifications. Diabetic rats fed with a canola oil-supplemented diet had higher body weights, were less hyperphagic, and their mesenteric, retroperitoneal, and epididymal fat pads weighed more than diabetic rats on an unsupplemented diet. The canola oil-supplemented diet decreased plasmatic concentrations of free fatty acids, triglycerides, and cholesterol; showed improved osmolarity, water clearances, and creatinine depuration; and had decreased LP and ROS. A canola oil-supplemented diet decreases hyperphagia and prevents lipotoxicity and renal dysfunction in a type I diabetes mellitus model.

Hypothyroidism minimizes the effects of acute hepatic failure caused by endoplasmic reticulum stress and redox environment alterations in rats.

The aim of this study was to investigate if a protective effect from hypothyroidism in acute liver failure resulted from reduced endoplasmic reticulum stress and changes to the redox environment. Twenty male Sprague-Dawley rats were divided in four groups: (1) euthyroid (sham surgery), (2) hypothyroid, (3) euthyroid (sham surgery)+thioacetamide and (4) hypothyroid+thioacetamide. Hypothyroidism was confirmed two weeks after thyroidectomy, and thioacetamide (TAA) (400mg/kg, ip) was administrated to the appropriate groups for three days with supportive therapy. Grades of encephalopathy in all animals were determined using behavioral tests. Animals were decapitated and their blood was obtained to assess liver function. The liver was dissected: the left lobe was used for histology and the right lobe was frozen for biochemical assays. Body weight, rectal temperature and T4 concentration were lower in hypothyroid groups. When measurements of oxidative stress markers, redox environment, γ-glutamylcysteine synthetase and glutathione-S-transferase were determined, we observed that hypothyroid animals with TAA compensated better with oxidative damage than euthyroid animals treated with TAA. Furthermore, we measured reduced expressions of GADD34, caspase-12 and GRP78 and subsequently less hypothyroidism-induced cellular damage in hypothyroid animals. We conclude that hypothyroidism protects against hepatic damage caused by TAA because it reduces endoplasmic reticulum stress and changes to the redox environment.

Methimazole-induced hypothyroidism causes cellular damage in the spleen, heart, liver, lung and kidney.

It is known that a hypothyroidism-induced hypometabolic state protects against oxidative damage caused by toxins. However, some workers demonstrated that antithyroid drug-induced hypothyroidism can cause cellular damage. Our objective was to determine if methimazole (an antithyroid drug) or hypothyroidism causes cellular damage in the liver, kidney, lung, spleen and heart. Twenty-five male Wistar rats were divided into 5 groups: euthyroid, false thyroidectomy, thyroidectomy-induced hypothyroidism, methimazole-induced hypothyroidism (60 mg/kg), and treatment with methimazole (60 mg/kg) and a T4 injection (20 µg/kg/d sc). At the end of the treatments (4 weeks for the pharmacological groups and 8 weeks for the surgical groups), the animals were anesthetized with sodium pentobarbital and they were transcardially perfused with 10% formaldehyde. The spleen, heart, liver, lung and kidney were removed and were processed for embedding in paraffin wax. Coronal sections were stained with hematoxylin-eosin. At the end of treatment, animals with both the methimazole- and thyroidectomy-induced hypothyroidism had a significant reduction of serum concentration of thyroid hormones. Only methimazole-induced hypothyroidism causes cellular damage in the kidney, lung, liver, heart, kidney and spleen. In addition, animals treated with methimazole and T4 showed cellular damage in the lung, spleen and renal medulla with lesser damage in the liver, renal cortex and heart. The thyroidectomy only altered the lung structure. The alterations were prevented by T4 completely in the heart and partially in the kidney cortex. These results indicate that tissue damage found in hypothyroidism is caused by methimazole.

Hypothyroidism during neonatal and perinatal period induced by thyroidectomy of the mother causes depressive-like behavior in prepubertal rats.

The objective of this study was to see if neonatal and perinatal hypothyroidism caused anxiety and depressive-like behaviors. Twenty female Wistar rats were randomly divided into two groups: 1) thyroidectomy caused hypothyroidism, in which the thyroid gland had been removed and the parathyroid reimplanted; and 2) false thyroidectomy. The thyroidectomy was made on rats anesthetized with ketamine-xylazine. The rats were mated and one day after giving birth, eight pups were assigned to each group randomly and they were distributed into two groups: a hypothyroid group containing male pups of a hypothyroid mother with a hypothyroid wet nurse; and a euthyroid group of male pups of a euthyroid mother with a euthyroid wet nurse. We analyzed the behavioral test at a prepubertal age. The neonatal and perinatal hypothyroidism caused by the mother's thyroidectomy caused a decrease in body weight and length. We found that the neonatal and perinatal hypothyroidism enhanced the total exploratory activity without affecting social contact and the time spent in the open and closed arms in an elevated plus-maze. The hypothyroidism caused immobility without altering the lower climbing duration in the swimming test. This study shows a novel model to cause neonatal and perinatal hypothyroidism without using pharmacological drugs. We demonstrated that hypothyroid animals had a reduction in body weight and length, a retardation of neurodevelopment, and they had depressive-like behavior.

Neonatal bilateral lidocaine administration into the ventral hippocampus caused postpubertal behavioral changes: An animal model of neurodevelopmental psychopathological disorders.

Our aim was to investigate if neonatal bilateral administration of lidocaine into the ventral hippocampus would cause behavioral changes related to schizophrenia. A neonatal ventral-hippocampal lesion (nVH lesion) was made with lidocaine in Wistar male pups. Two groups were formed, the first received lidocaine (4 mug/0.3 muL) and the second an equal volume of vehicle. At day 35 and 56, both groups were tested for social contact, immobility caused by clamping the neck and dorsal immobility, locomotor activity in an open field, and tail flick (TF) latency after a painful heat stimulus. All animals were then killed. Coronal cuts (7 mum) of the brain were obtained and each brain section was stained with cresyl violet-eosin. The animals which received the nVH lesion with lidocaine had decreased social interaction at both ages. The rats with lesions, only at day 58 postnatal, increased their distance traveled and ambulatory time, with a decrease in their nonambulatory and reset time. The rats with lesions had a longer duration of immobility caused by clamping the neck and a longer dorsal immobility at both days 34 and 57 compared to control rats. The lidocaine-treated group spent less time to deflect the tail compared to the control group at postpubertal age. The neonatal bilateral administration of lidocaine into the ventral hippocampus caused some alterations, such as chromatin condensation, nucleolus loss, and cell shrinkage, but glial proliferation was not seen. Neonatal bilateral lidocaine administration into the ventral hippocampus caused postpubertal behavioral changes.