Moderate exercise prevents the cell atrophy caused by hypothyroidism in rats.

Adult­onset hypothyroidism is associated with an increase in cell atrophy of the hippocampal pyramidal neurons. Physical exercise implies diverse actions on the neural tissue that promote neuron proliferation and survival. The beneficial effects of exercise seem to be inversely linked to its intensity, so that strenuous exercise has reduced protective effects. In this study we evaluated the capacity of a moderate forced­exercise routine to counteract the neurodegenerative effects of a hypothyroid condition induced during adulthood. Simultaneously with a chronic anti­thyroid chemical treatment, a group of rats was forced to walk in a motorized wheel for 30 min daily five times a week. In four weeks of treatment the rats developed a plain hypothyroid condition that in non­exercised rats was accompanied by a marked increase in the number of atrophic cells in all CA regions of the hippocampus. The forced­exercise treatment did not counter the development of hypothyroidism and its signs, but it did prevent almost completely the associated neuronal damage in all CA regions. The forced exercise also improved the cognitive function in a spatial­learning test. These results indicate that moderate exercise has the potential to prevent the structural and functional deficits associated with a hypothyroid condition.

Cerebrolysin enhances the expression of the synaptogenic protein LRRTM4 in the hippocampus and improves learning and memory in senescent rats.

Aging reduces the efficiency of the organs and systems, including the cognitive functions. Brain aging is related to a decrease in the vascularity, neurogenesis, and synaptic plasticity. Cerebrolysin, a peptide and amino acid preparation, has been shown to improve the cognitive performance in animal models of Alzheimer's disease. Similarly, the leucine-rich repeat transmembrane 4 protein exhibits a strong synaptogenic activity in the hippocampal synapses. The aim of this study was to evaluate the effect of the cerebrolysin treatment on the learning and memory abilities, sensorimotor functions, and the leucine-rich repeat transmembrane 4 protein expression in the brain of 15-month-old rats. Cerebrolysin (1076 mg/kg) or vehicle was administered to Wistar rats intraperitoneally for 4 weeks. After the treatments, learning and memory were tested using the Barnes maze test, and the acoustic startle response, and its pre-pulse inhibition and habituation were measured. Finally, the leucine-rich repeat transmembrane 4 expression was measured in the brainstem, striatum, and hippocampus using a Western-blot assay. The 15-month-old vehicle-treated rats showed impairments in the habituation of the acoustic startle response and in learning and memory when compared to 3-month-old rats. These impairments were attenuated by the subchronic cerebrolysin treatment. The leucine-rich repeat transmembrane 4 protein expression was lower in the old vehicle-treated rats than in the young rats; the cerebrolysin treatment attenuated that decrease in the old rats. The leucine-rich repeat transmembrane 4 protein was not expressed in striatum or brainstem. These results suggest that the subchronic cerebrolysin treatment enhances the learning and memory abilities in aging by increasing the expression of the leucine-rich repeat transmembrane 4 protein in the hippocampus.

The homeostatic feeding response to fasting is under chronostatic control.

Eating behavior is controlled by the energy needs of the organism. The need to provide a constant supply of energy to tissues is a homeostatic drive that adjusts feeding behavior to the energetic condition of the organism. On the other hand, food intake also shows a circadian variation synchronized to the light-dark cycle and food availability. Thus, feeding is subjected to both homeostatic and circadian regulation mechanisms that determine the amount and timing of spontaneous food intake in normal conditions. In the present study we contrasted the influence of the homeostatic versus the chronostatic mechanisms on food intake in normal conditions and in response to fasting. A group of rats was subjected to food deprivation under two different temporal schemes. A constant-length 24-h food deprivation started at different times of day resulted in an increased compensatory intake. This compensatory response showed a circadian variation that resembled the rhythm of intake in non-deprived animals. When subjected to fasting periods of increasing length (24-66 h), the amount of compensatory feeding varied according to the time of day in which food was made available, being significantly less when the fast ended in the middle of the light phase or beginning of the dark phase. These oscillatory changes did not have a correlation with variations in the level of glucose or ß-hydroxybutyrate in the blood. The results suggest that the mechanism of homeostatic compensation is modulated chronostatically, presumably as part of the alternation of catabolic and anabolic states matching the daily cycles of activity.

Neuroprotective effect of Arthrospira (Spirulina) platensis against kainic acid-neuronal death.

Context Arthrospira (Spirulina) platensis (SP) is a cyanobacterium which has attracted attention because of its nutritional value and pharmacological properties. It was previously reported that SP reduces oxidative stress in the hippocampus and protects against damaging neurobehavioural effects of systemic kainic acid (KA). It is widely known that the systemic administration of KA induces neuronal damage, specifically in the CA3 hippocampal region. Objective The present study determines if the SP sub-chronic treatment has neuroprotective properties against KA. Materials and methods Male SW mice were treated with SP during 24 d, at doses of 0, 200, and 800 mg/kg, once daily, and with KA (35 mg/kg, ip) as a single dose on day 14. After the treatment, a histological analysis was performed and the number of atrophic neuronal cells in CA3 hippocampal region was quantified. Results Pretreatment with SP does not protect against seizures induced by KA. However, mortality in the SP 200 and the SP 800 groups was of 20%, while for the KA group, it was of 60%. A single KA ip administration produced a considerable neuronal damage, whereas both doses of SP sub-chronic treatment reduced the number of atrophic neurons in CA3 hippocampal region with respect to the KA group. Discussion The SP neurobehaviour improvement after KA systemic administration correlates with the capacity of SP to reduce KA-neuronal death in CA3 hippocampal cells. This neuroprotection may be related to the antioxidant properties of SP. Conclusion SP reduces KA-neuronal death in CA3 hippocampal cells.

The NMDA receptor antagonist MK-801 abolishes the increase in both p53 and Bax/Bcl2 index induced by adult-onset hypothyroidism in rat.

Hypothyroidism affects neuron population dynamics in the hippocampus of the adult rat, with neuronal damage as the main feature of its effect. This effect is prevented by the blockade of NMDA receptors, which suggests that glutamatergic activity mediates cell death in this condition. Glutamate can also stimulate cell proliferation and survival of newborn neurons, indicating that it can affect different stages of the cell cycle. In this work we measured the expression of specific proteins that control cell proliferation (cycline-D1), cell arrest (p21), damage (p53) or apoptosis (Bax and Bcl2) in the hippocampus of hypothyroid rats treated with the NMDA receptor (NMDAR) blocker MK-801 during the induction of hypothyroidism. The results show that hypothyroidism increases the expression of markers of DNA damage, cell arrest, and apoptosis, but does not affect the marker of cell proliferation. NMDAR blockade prevents the increase on markers of DNA damage and apoptosis, but does not influence cell arrest or cell proliferation. This suggests that hypothyroidism promotes cell death mainly by an excitotoxic effect of glutamate.

The long-term regulation of food intake and body weight depends on the availability of thyroid hormones in the brain.

OBJECTIVES: We evaluated the contribution of the thyroid hormones to the long-term maintenance of feeding behavior and body weight, while distinguishing their direct central effects from those resulting from the metabolic rate in the peripheral tissues. METHODS: We assessed the effect of hypothyroidism on the long-term (6 months) regulation of food intake, body weight, and energy expenditure in rats. We then generated the recovery of a euthyroid condition in the brain while maintaining a low T3 availability for the peripheral organs, i.e. a combined condition of central euthyroidism with peripheral hypothyroidism, with the aid of a pharmacological combination. RESULTS: Hypothyroidism caused a decrease in the daily food intake, body weight, and body temperature. The food intake and body temperature stabilized at a lower value, whereas body weight kept decreasing at a constant rate. The administration of exogenous T4 increased food intake and body-weight gain, but had no effect on body temperature. CONCLUSIONS: The thyroid hormones are necessary for the long-term regulation of energy intake, storage, and expenditure by different mechanisms. The feeding behavior seems to be partially dependent on a direct action of the thyroid hormones on the brain and this effect is independent of the energy expenditure in the peripheral organs. The body weight is closely dependent on the thyroid status and its maintenance seems to involve thyroid action on mechanisms other than feeding and metabolic rate.

Participation of NMDA-glutamatergic receptors in hippocampal neuronal damage caused by adult-onset hypothyroidism.

We analyzed the participation of N-methyl-d-aspartate (NMDA) receptors in the neuronal damage caused by adult-onset hypothyroidism. Wistar rats were randomly assigned into four groups. The euthyroid group received tap water. The hypothyroid group received methimazole (60 mg/kg) in their drinking water to induce hypothyroidism. Two more groups of rats received the antithyroid treatment and were injected daily with the NMDA antagonist ketamine (15 mg/kg, sc) or MK-801 (0.5mg/kg, ip). Treatments were administered during 4 weeks. At the end of the respective treatments rats were deeply anaesthetized and perfused intracardially with 0.9% NaCl followed by 4% paraformaldehyde. The brains were removed from the skull, and coronal brain sections (7microm thick) were obtained. Neurons were counted in the CA1, CA2, CA3, and CA4 hippocampal regions differentiating between normal and atrophic cells by an experimenter blind to the treatment. The percentage of neuronal damage found in the MMI group was significantly greater in the hippocampal regions compared to the euthyroid group. In contrast, both NMDA antagonists were able to prevent the neuronal damage secondary to hypothyroidism in all hippocampal regions. Our results suggest that the neuronal damage caused in the hippocampus of adult-onset hypothyroid rats requires activation of NMDA channels.

The maintenance of hippocampal pyramidal neuron populations is dependent on the modulation of specific cell cycle regulators by thyroid hormones.

The onset of adult hypothyroidism causes neuronal damage in the CA3 hippocampal region, which is attenuated by T(4) administration. We analyzed the expression of molecular proliferation markers (Cyclin D1 and PCNA), cellular damage-arrest (p53 and p21), and apoptosis (Bax/Bcl-2 index) in the hippocampus of hypothyroid (methimazole; 60 mg/kg) or thyroid replaced (T(4), 20 microg/kg; MMI+T(4) or T(3), 20 microg/kg; MMI+T(3)) adult male rats. Histological analysis showed that hypothyroid animals exhibit significant neuronal damage in all regions of the hippocampus accompanied by the triggering of the apoptotic pathway (increases in p53, p21 and the Bax/Bcl-2 index) and no changes in proliferation (Cyclin D1 and PCNA). MMI+T(4) replaced animals were completely protected with no changes in molecular markers. In contrast, MMI+T(3) replaced animals showed partial protection in which, although pro-apoptotic effects remained (increase in the Bax/Bcl-2), proliferative mechanisms were triggered (increase in p53, Cyclin D1 and PCNA expression). Our results indicate that thyroid hormones participate in the maintenance of the hippocampal neuronal population even in adulthood, suggesting that THs have different physiological roles as neuronal survival factors: T(4) prevents the activation of apoptotic pathways, whereas T(3) activates cell differentiation and proliferation mechanisms.

Kainic acid does not affect CA3 hippocampal region pyramidal cells in hypothyroid rats.

Thyroid hormones exert a crucial role on trophic events of the central nervous system during development, adulthood, and ageing. The deficiency of thyroid hormones could also produce a deficiency in neurotransmission in the hippocampal region. Kainic acid (KA) has become an important tool for studying functions related to excitatory amino acid transmission in mammals. Its neurotoxic effects on the pyramidal neurons of the CA3 hippocampal region are well known. We have examined the neurotoxicity of KA on these cells in hypothyroid rats. The hypothyroid state was induced by administration of methimazole. After 4 weeks of treatment, KA was administered once intraperitoneally at doses of 0, 1, 2.5, and 5mg/kg to the hypothyroid group, and 0 and 5mg/kg to the euthyroid group. In the euthyroid group, KA reduced the neuronal density in the CA3 hippocampal region, and in the hypothyroid rats with no administration of KA, the neuronal density of the CA3 hippocampal region is reduced also. Administering KA in hypothyroid rats did not reduce the number of CA3 pyramidal cells.