Experimentally-induced maternal hypothyroidism alters crucial enzyme activities in the frontal cortex and hippocampus of the offspring rat

Abstract

Thyroid hormone insufficiency during neurodevelopment can result into significant structural and functional changes within the developing central nervous system (CNS), and is associated with the establishment of serious cognitive impairment and neuropsychiatric symptomatology. The aim of the present study was to shed more light on the effects of gestational and/or lactational maternal exposure to propylthiouracil (PTU)-induced hypothyroidism as a multilevel experimental approach to the study of hypothyroidism-induced changes on crucial brain enzyme activities of 21-day-old Wistar rat offspring in a brain region-specific manner. This experimental approach has been recently developed and characterized by the authors based on neurochemical analyses performed on newborn and 21-day-old rat offspring whole brain homogenates; as a continuum to this effort, the current study focused on two CNS regions of major significance for cognitive development: the frontal cortex and the hippocampus. Maternal exposure to PTU in the drinking water during gestation and/or lactation resulted into changes in the activities of acetylcholinesterase and two important adenosinetriphosphatases (Na(+),K(+)- and Mg(2+)-ATPase), that seemed to take place in a CNS-region-specific manner and that were dependent upon the PTU-exposure timeframe followed. As these findings are analyzed and compared to the available literature, they: (i) highlight the variability involved in the changes of the aforementioned enzymatic parameters in the studied CNS regions (attributed to both the different neuroanatomical composition and the thyroid-hormone-dependent neurodevelopmental growth/differentiation patterns of the latter), (ii) reveal important information with regards to the neurochemical mechanisms that could be involved in the way clinical hypothyroidism could affect optimal neurodevelopment and, ultimately, cognitive function, as well as (iii) underline the need for the adoption of more consistent approaches towards the experimental simulation of congenital and early-age-occurring hypothyroidism.

Effect of adult onset hypothyroidism on behavioral parameters and acetylcholinesterase isoforms activity in specific brain regions of male mice

“…Our findings are in fully agreement with the available literature, indicating reduced total AChE activity in adult hypothyroid brain [8,65,66]. Furthermore, our results highlighted that TH deficiency did not affect the brain region-specific pattern distribution of AChE SS fraction activity; that is, cerebral cortex, cerebellum and hippocampus exhibited similar AChE SS fraction activity in euthyroid mice, a pattern which is preserved in the hypothyroid animals.…”

“…In addition, midbrain and striatum demonstrated double AChE SS activity compared with that of cerebral cortex, cerebellum and hippocampus in euthyroid mice and this pattern remained similar in the hypothyroid animals. The highest statistically significant impairment was observed in the cerebral cortex (32%), a brain region that has been related with several effects of hypothyroidism on adult brain [8,65]. Interestingly, it has been established that G1 isoform accumulation (SS fraction) protects neurons from damage associated with prolonged conflict behavior [67].…”

“…Although most studies focus on the defects of perinatal hypothyroidism on CNS [8][9][10], it has been shown that adult onset hypothyroidism also exerts adverse effects on neurotransmission and behavior [11][12][13]. Of particular interest is that, adult onset hypothyroidism is closely related to neuropsychiatric and cognitive disorders [14].…”

“…In addition, increasing experimental evidence support an extensive interrelationship between TH and brain cholinergic system [29][30][31]. However, a comprehensive study of the effects of adult on set hypothyroidism on both G1 and G4 AChE isoforms has never been performed so far and most studies focus on the investigation of developmental hypothyroidism on cholinergic system function with emphasis on total or G1 AChE isoform activity [8,[32][33][34] To this end, recently, it has been reported that TH have a direct effect on total AChE activity and consequently on the metabolism of acetylcholine at least in the hippocampus of adult rodents [35].…”

Protective effects of GM-CSF in experimental neonatal hypothyroidism

“…Thyroid hormones (THs) could regulate the development and critical biochemical functions in developing brain [1][2][3]. MMI (anti-thyroid drug) could inhibit THs synthesis because it could interfere with the conversion of iodide (Iˉ) to iodine (I°) and consequently, the iodination of tyrosyl groups [4].…”