Hypothyroidism in the Adult Rat Causes Incremental Changes in Brain-Derived Neurotrophic Factor, Neuronal and Astrocyte Apoptosis, Gliosis, and Deterioration of Postsynaptic Density

Cortés, Claudia; Eugenín, Eliseo A.; Aliaga, Esteban; Carreño, Leandro J.; Bueno, Susan M.; González, Pablo A; Gayol, Silvina; Naranjo, David; Noches, Verónica; Marassi, Michelle P.; Rosenthal, Doris; Jadue, Cindy; Ibarra, Paula; Keitel, Cecilia; Wohllk, Nelson; Court, Felipe A.; Kalergis, Alexis M.; Riedel, Claudia A.

doi:10.1089/thy.2010.0400

Cited by 41 publications

(31 citation statements)

References 40 publications

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“…The morphological changes of the myelin sheath demonstrated delamination and an incompact structure, with reduced thickness and irregular outline. These morphological alterations caused by hypothyroidism have been described in other tissues, such as the hippocampus and cuneate nucleus ( 26 – 28 ). The morphological integrity of the neurons and the efficacy of synaptic transmission of the PFC are of primary importance for the role played by this region in various forms of learning and memory.…”

Section: Discussionmentioning

confidence: 74%

Concurrent administration of thyroxine and donepezil induces plastic changes in the prefrontal cortex of adult hypothyroid rats

Wang

Zha

et al. 2017

Molecular Medicine Reports

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The aim of the present study was to observe the effects of the concurrent administration of thyroxine (T4) and an acetylcholinesterase (AChE) inhibitor, donepezil (DON), on the hypothyroidism-induced ultrastructural changes of the prefrontal cortex (PFC) in adult rats. The acetylcholine (ACh) content and AChE activity was assessed, as well as the expressions of synaptotagmin-1 (syt-1) and SNAP-25 were analyzed in the rats. Adding 0.05% propylthiouracil to rats' drinking water induced a hypothyroid rat model. The animals were treated with T4 and DON administered separately or in combination from the fifth week. Transmission electron microscope analysis revealed that hypothyroidism induced marked ultrastructural changes, including the neurons, the synapses and the myelin sheath in the PFC. T4 or DON treatment improved the morphologic features of the PFC, and the performance of the T4 combined DON group was the closest to the control group. Moreover, hypothyroidism significantly decreased the content of ACh (29.8%) and activity of AChE (27.8%), which were restored to control values by T4 administration. In addition, DON treatment restored ACh content to normal. At the protein level, hypothyroidism increased the levels of syt-1 and SNAP-25 in the PFC, both of which were not restored to control values following T4 administration, while concurrent administration of T4 and DON was able to induce this effect. These results suggested that adult-onset hypothyroidism induce morphological, biochemical and molecular alterations in the PFC, combined administration of T4 and DON induce plastic changes in the PFC, different from that of the standard T4 therapy, and that the DON treatment may facilitate the recovery of synaptic protein impairments induced by hypothyroidism.

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Section: Discussionmentioning

confidence: 74%

Concurrent administration of thyroxine and donepezil induces plastic changes in the prefrontal cortex of adult hypothyroid rats

Wang

Zha

et al. 2017

Molecular Medicine Reports

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“…So, the structural organization of pyramidal cell in CA1 region and its characteristic palisade arrangement was absent with a significantly reduced volume of the CA1 pyramidal cell layers [29] . Other author explained that by cell death andl or disturbance of neurogenesis due to THs lack [30][31] .…”

Section: Discussionmentioning

confidence: 99%

Donepezil Improves Histological and Biochemical Changes in the Hippocampus of Adult Hypothyroid Male Rats

Mohamed

Ahmed

2018

Egyptian Journal of Histology

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Introduction: Hormonal imbalances are involved in many related pathologies, such as neurodegenerative and psychiatric disorders. Adult hypothyroidism is a prevalent condition in humans with an incidence of 8% in the adult population and could impair learning and memory processes. Even though tetra-iodothyronine (T4) treatment can overcome the hypothyroidism in the majority of cases, it cannot fully recover the patient's learning capacity and memory. Donepezil (DON) was a cholinesterase inhibitor, that can effectively improve the cognitive and memory impairments. Aim of work: This work analyzed the histological and biochemical changes in the hippocampal Cornu Ammonis (CA1) region occurring in experimental hypothyroidism and assessed the possible role of Donepezil in such condition. Materials and Methods: Forty eight healthy adult male rats were randomly divided into four groups; Group I (control group), rats of group II were subjected to thyroidectomy, Group III (thyroid-supplemented) and Group IV (combined DON+thyroxin). The hippocampus (CA1 region) sections were prepared and stained with hematoxylin and eosin and Cresyl fast violet. Immunohistochemical staining for glial fibrillary acid protein (GFAP), P53 and calretinin and electron microscopic examination were also done. The results were statistically analyzed. Results: Hippocampus of hypothyroid adult rats displayed increased apoptosis in neurons and astrocytes with reactive gliosis as compared with controls. Moreover, the oxidative stress markers increased. Thyroid replacement induced some improvement, however DON could improve some of alterations to be similar to normal. Conclusion: Our data concluded that adult hypothyroidism affects the hippocampus by a mechanism that alters the composition of GFAP, reduced neuronal and astrocyte survival, and alters the content of oxidative redox. Thyroxin replacement improved the structural alterations within limits. However combined thyroxin with DON could improve almost all of the biochemical and histological alterations.

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“…Perinatal hypothyroidism alters the expression of Gap-43, Sema3A, and Camk4-Creb pathways (Morte et al, 2010 ; Navarro et al, 2014 ) and the Erk1/2-Creb pathway is altered in the hippocampus of pups born to late hypothyroid dams (Lu et al, 2005 ; Berbel et al, 2010 ). BDNF expression is abnormal in the hippocampus of adult hypothyroid rats (Cortés et al, 2012 ), and it is involved in regulating the translational expression of VGluT1 in cultured hippocampal neurons (Chakraborty et al, 2012 ; Melo et al, 2013 ), in the regulation of FMRP synaptic function (Nishimura et al, 2007 ; Castrén and Castrén, 2014 ). In addition, the sonic hedgehog (Shh) signaling pathway, which is involved in the formation of microcircuits in the cerebral cortex (Harwell et al, 2012 ), is altered in embryonic and adult hypothyroid rats.…”

Section: Discussionmentioning

confidence: 99%

Gestational and early postnatal hypothyroidism alters VGluT1 and VGAT bouton distribution in the neocortex and hippocampus, and behavior in rats

et al. 2015

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Thyroid hormones are fundamental for the expression of genes involved in the development of the CNS and their deficiency is associated with a wide spectrum of neurological diseases including mental retardation, attention deficit-hyperactivity disorder and autism spectrum disorders. We examined in rat whether developmental and early postnatal hypothyroidism affects the distribution of vesicular glutamate transporter-1 (VGluT1; glutamatergic) and vesicular inhibitory amino acid transporter (VGAT; GABAergic) immunoreactive (ir) boutons in the hippocampus and somatosensory cortex, and the behavior of the pups. Hypothyroidism was induced by adding 0.02% methimazole (MMI) and 1% KClO4 to the drinking water starting at embryonic day 10 (E10; developmental hypothyroidism) and E21 (early postnatal hypothyroidism) until day of sacrifice at postnatal day 50. Behavior was studied using the acoustic prepulse inhibition (somatosensory attention) and the elevated plus-maze (anxiety-like assessment) tests. The distribution, density and size of VGluT1-ir and VGAT-ir boutons in the hippocampus and somatosensory cortex was abnormal in MMI pups and these changes correlate with behavioral changes, as prepulse inhibition of the startle response amplitude was reduced, and the percentage of time spent in open arms increased. In conclusion, both developmental and early postnatal hypothyroidism significantly decreases the ratio of GABAergic to glutamatergic boutons in dentate gyrus leading to an abnormal flow of information to the hippocampus and infragranular layers of the somatosensory cortex, and alter behavior in rats. Our data show cytoarchitectonic alterations in the basic excitatory hippocampal loop, and in local inhibitory circuits of the somatosensory cortex and hippocampus that might contribute to the delayed neurocognitive outcome observed in thyroid hormone deficient children born in iodine deficient areas, or suffering from congenital hypothyroidism.

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Hypothyroidism in the Adult Rat Causes Incremental Changes in Brain-Derived Neurotrophic Factor, Neuronal and Astrocyte Apoptosis, Gliosis, and Deterioration of Postsynaptic Density

Abstract: Our data suggest that adult hypothyroidism affects the hippocampus by a mechanism that alters the composition of PSD, reduces neuronal and astrocyte survival, and alters the content of the signaling neurotrophic factors, such as BDNF.

Cited by 41 publications

References 40 publications

Concurrent administration of thyroxine and donepezil induces plastic changes in the prefrontal cortex of adult hypothyroid rats

Concurrent administration of thyroxine and donepezil induces plastic changes in the prefrontal cortex of adult hypothyroid rats

Donepezil Improves Histological and Biochemical Changes in the Hippocampus of Adult Hypothyroid Male Rats

Gestational and early postnatal hypothyroidism alters VGluT1 and VGAT bouton distribution in the neocortex and hippocampus, and behavior in rats

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