propylthiouracil and Cognition-Disorders

Hypothyroidism has a variety of adverse effects on cognitive function. The treatment of levothyroxine alone cannot restore cognitive defects of hypothyroid patients. Antioxidant vitamin E supplementation could be useful in disturbances which are associated with oxidative stress and could effectively slow the progression of Alzheimer disease. Thus, the purpose of this study was to evaluate oxidative stress status of the serum and hippocampus in hypothyroidism and to examine the effects of levothyroxine replacement therapy with vitamin E supplementation on cognitive deficit. Sprague-Dawley rats were randomly divided into five groups: control group, PTU group, PTU + Vit E group, PTU + L-T4 group, and PTU + L-T4 + Vit E group. Serum and hippocampus malondialdehyde (MDA) levels were determined using the thiobarbituric-acid reactive substances method. Serum and hippocampus superoxide dismutase (SOD) levels were determined by measuring its ability to inhibit the photoreduction of nitroblue tetrazolium. Learning and memory was assessed by Morris water maze test. In the present study, we found that the rats of PTU + Vit E group spent less time to find the platform on days 2, 3, 4, and 5 than the PTU group. Moreover, the rats of PTU + L-T4 + Vit E group spent less time to find the platform on days 4 and 5 than the PTU + L-T4 group. The time spent in the target quadrants was measured in the probe test and no difference was observed in all groups. Oxidative damage has been observed in the serum and hippocampus of hypothyroidism rat. SOD levels of serum and hippocampus tissue were significantly increased and MDA levels were significantly decreased in the PTU + Vit E and PTU + L-T4 + Vit E groups than the PTU and PTU + L-T4 groups. Therefore, these findings indicate that levothyroxine replacement therapy with vitamin E supplementation may ameliorate cognitive deficit in PTU-induced hypothyroidism through the decrease of oxidative stress status.

Topics: Animals; Cognition Disorders; Dietary Supplements; Disease Models, Animal; Hippocampus; Hormone Replacement Therapy; Hypothyroidism; Male; Malondialdehyde; Maze Learning; Oxidative Stress; Propylthiouracil; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Thyroxine; Vitamin E

This study addressed the influence of propylthiouracil (PTU)-induced hypothyroidism on postnatal and adult neurogenesis. PTU was administered from birth to postnatal day 10 (P10) or P21, leading to decreased neural stem cell/progenitor proliferation in the dentate gyrus, as well as significantly fewer granule cells and reduced hippocampal volume. Upon P22 PTU withdrawal, plasma thyroid hormone levels were normal by P90, there was no difference in the number of dentate gyrus or subventricular proliferating cells, but brain weight was smaller. In addition, dentate gyrus density of surviving BrdU-labeled cells increased, with no changes to the olfactory bulb. Quantitative PCR revealed decreased FGF-2, NGF, Wnt3a, and VEGF-A hippocampal expression during PTU treatment, with recovery in adulthood. Pro-apoptotic Bax was up-regulated, and anti-apoptotic Bcl-2 was down-regulated, during PTU treatment, both of which were normalized in the adult brain. In contrast, apoptosis-inducing factor (AIF) was down-regulated in the adult. These results suggest that mechanisms in the adult brain attempt to compensate for decreased neurogenesis due to postnatal hypothyroidism.

Topics: Aging; Animals; Animals, Newborn; Antithyroid Agents; Apoptosis Regulatory Proteins; Atrophy; Brain; Cell Count; Cognition Disorders; Dentate Gyrus; Disease Models, Animal; Down-Regulation; Hypothyroidism; Neurogenesis; Neurons; Organ Size; Propylthiouracil; Rats; Rats, Wistar; Thyroid Hormones

Thyroid hormones are essential for neonatal brain development. It is well established that insufficiency of thyroid hormone during critical periods of development can impair cognitive functions. The mechanisms that underlie learning deficits in hypothyroid animals, however, are not well understood. As impairments in synaptic function are likely to contribute to cognitive deficits, the current study tested whether thyroid hormone insufficiency during development would alter quantitative characteristics of synaptic function in the hippocampus. Developing rats were exposed in utero and postnatally to 0, 3, or 10 ppm propylthiouracil (PTU), a thyroid hormone synthesis inhibitor, administered in the drinking water of dams from gestation d 6 until postnatal day (PN) 30. Excitatory postsynaptic potentials and population spikes were recorded from the stratum radiatum and the pyramidal cell layer, respectively, in area CA1 of hippocampal slices from offspring between PN21 and PN30. Baseline synaptic transmission was evaluated by comparing input-output relationships between groups. Paired-pulse facilitation, paired-pulse depression, long-term potentiation, and long-term depression were recorded to examine short- and long-term synaptic plasticity. PTU reduced thyroid hormones, reduced body weight gain, and delayed eye-opening in a dose-dependent manner. Excitatory synaptic transmission was increased by developmental exposure to PTU. Thyroid hormone insufficiency was also dose-dependently associated with a reduction paired-pulse facilitation and long-term potentiation of the excitatory postsynaptic potential and elimination of paired-pulse depression of the population spike. The results indicate that thyroid hormone insufficiency compromises the functional integrity of synaptic communication in area CA1 of developing rat hippocampus and suggest that these changes may contribute to learning deficits associated with developmental hypothyroidism.

Topics: Action Potentials; Animals; Animals, Newborn; Antithyroid Agents; Cognition Disorders; Dendrites; Excitatory Postsynaptic Potentials; Female; Hippocampus; Hypothyroidism; Long-Term Potentiation; Long-Term Synaptic Depression; Neuronal Plasticity; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Long-Evans; Synaptic Transmission

Stiff limb syndrome is a recently described variant of stiff man syndrome and is characterized by limb stiffness and spasms. Unlike stiff man syndrome, stiff limb syndrome is rarely associated with anti GAD antibodies, poorly improves after symptomatic treatment, and has a relapsing and remitting course. Both stiff man and stiff limb syndromes are frequently associated with auto-immune diseases. We report a case of a 70-year old man who presented with a stiff limb syndrome associated with symptoms highly suggestive of Hashimoto's encephalopathy. The signs of encephalopathy dramatically resolved after corticosteroid treatment, and remissions was complete after 12 months. The stiff limb syndrome had a remitting course despite symptomatic treatment including diazepam, baclofen and vigabatrin and immunomodulating treatments including corticoid and intravenous immunoglobulins.

Topics: Aged; Antibody Specificity; Anticonvulsants; Antithyroid Agents; Autoantibodies; Autoimmune Diseases; Baclofen; Brain Diseases, Metabolic; Cognition Disorders; Combined Modality Therapy; Diazepam; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Male; Muscle Relaxants, Central; Prednisone; Propylthiouracil; Remission Induction; Stiff-Person Syndrome; Thyroiditis, Autoimmune; Vigabatrin