الفهرس 
Thyroid hormonesOnly 14 pages are availabe for public view
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Abstract
THs are involved in the regulation of numerous body functions, including lipid and carbohydrate metabolism, oxygen consumption and numerous physiological processes such as development, reproduction and growth. Hyperthyroidism cause many health problems e.g. cardiovascular and hepatocellular complications. For a long time, the brain was believed to be unresponsive to THs. However, THs receptors were detected in human and rat brain. Besides the crucial role of thyroid hormones in brain development and physiology, recent investigations have highlighted the involvement of these hormones in affecting the characteristics of various neurotransmitter systems and neurotransmission. By binding to nuclear receptors and modulating gene expression, thyroid hormones influence neuronal migration, differentiation, myelination, synaptogenesis and neurogenesis in developing adult brains. The mechanism underlying brain dysfunction that results from thyroid disorders is still vague. Oxidative stress, lipid peroxidation and cellular apoptosis are the major culprits. Several antioxidant or anti-apoptotic agents have been used to ameliorate hyperthyroidism-induced brain dysfunction.
N-Acetylcysteine (NAC) crosses the blood brain barrier (BBB), replenishes brain GSH and augments neurogenesis of neuronal stem cells and maintains neuronal persistence. NAC is now emerging as a treatment of neurological disorders. Safranal is a volatile compound and is one of the main active constituents of saffron. The potent significance of safranal as an antioxidant agent in biological systems has been attributed to its proficiency to stabilize bio-membranes, scavenge ROS, and decline the peroxidation of unsaturated membrane lipids due to its hydroxyl radical- scavenging activity. To the best of our knowledge, the role of NAC or safranal in ameliorating the brain dysfunction induced by hyperthyroidism has been seldom studied before. Consequently, we planned the present study to determine whether these compounds could attenuate hyperthyroidism-induced abnormalities in brain function, and investigate the potential biochemical and molecular mechanisms underlying their effects.
Administration of L-T4 induced hyperthyroidism, as confirmed by the observed increase in fT3 and fT4 levels and a decrease in TSH level. Co-administration of NAC or safranal with L-T4 produced a signficant decrease in fT3 and fT4 levels and increase in TSH level as compared to L-T4 treated group.
Administration of NAC or safranal ameliorated the L-T4-induced decrease in body weight. Injection of L-T4 induced non-signficant decreases in the weights of brain regions (cerebral cortex, thalamus & hypothalamus and hippocampus) as compared to the control group. These changes were ameliorated by NAC or safranal co-administration.
Administration of L-T4 was associated with significant elevations in dopamine (DA) and serotonine (5-HT) content in selected brain regions. Administration of either NAC or safranal with L-T4 resulted in a marked decline in both neurotransmitters content. Also, administration of L-T4 signficantly increased the 5-HIAA content in cerebral cortex and hippocampus compared to control rats. The elevation in the 5-HIAA content caused by L-T4 was ameliorated by simultaneous administration of either NAC or safranal with L-T4 in both cerebral cortex and hippocampus. Combined treatment with NAC or safranal and L-T4 significantly suppressed the elevations in monoamine oxidase (MAO) activity induced by L-T4 in all the brain regions studied. L-T4 treatment had no significant effect on norepinephrine (NE) content in cerebral cortex and thalamus & hypothalamus. However, a significant decrease in NE content was recorded in the hippocampus in hyperthyroid animals. Combined treatment with NAC or safranal and L-T4 induced non-significant difference in NE content of the discrete brain regions examined.
Induction of hyperthyroidism resulted in a significant increase in the level of MDA and NO but significant decrease in CAT and SOD activities, as well as GSH level compared to the control group. Co-administration of NAC or safranal completely prevented these alterations. Similarly, supplementation of NAC or safranal to normal rats induced a significant decline in MDA and NO levels and significant elevations in CAT and SOD activities and GSH level as compared to the control rats.
Immunohistochemical findings revealed that administration of L-T4 produced a significant increase in the Caspase-9 and Caspase-3 levels compared to control group and a significant decrease in antiapoptotic marker Bcl-2. Co-administration of NAC or safranal significantly reduced the L-T4-induced Caspases toward the normal levels and caused a significant increase in Bcl-2 when compared to hyperthyroid group. Comet assay demonstrated a considerable DNA damage in brain of hyperthyroid rats. Administration of L-T4 caused a significant increase in tail length, tail DNA % and tail moment. Co-administration of NAC or safranal with L-T4 resulted in a significant decrease in the level of DNA damage induced by L-T4.
Forebrain sections of the control, NAC, and safranal treated rats showed healthy architecture. The forebrain tissue of the L-T4-treated rats showed histopathological changes characterized by focal gliosis in the cerebral cortex and associated with degeneration in the pyramidal neural cells of the hippocampus. The striatum of the cerebrum showed congestion in the blood vessels as well as focal homogenous eosinophilic plagues formation. Forebrains from rats treated with NAC or safranal combined with L-T4 revealed less prominent histopathological changes when compared with those from the L-T4.