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

Wang,Fen; Wu,Zhangbi; Zha,Xiaoxue; Cai,Yaojun; Wu,Bo; Jia,Xuemei; Zhu,Defa

doi:10.3892/mmr.2017.6977

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

Authors:
- Fen Wang
- Zhangbi Wu
- Xiaoxue Zha
- Yaojun Cai
- Bo Wu
- Xuemei Jia
- Defa Zhu
View Affiliations

Affiliations: Department of Endocrinology, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China, Comprehensive Laboratory, College of Basic Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
Published online on: July 14, 2017 https://doi.org/10.3892/mmr.2017.6977
Pages: 3233-3241
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

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.

View Figures

View References

1	Dugbartey AT: Neurocognitive aspects of hypothyroidism. Arch Intern Med. 158:1413–1418. 1998. View Article : Google Scholar : PubMed/NCBI
2	Zhu DF, Wang ZX, Zhang DR, Pan ZL, He S, Hu XP, Chen XC and Zhou JN: fMRI revealed neural substrate for reversible working memory dysfunction in subclinical hypothyroidism. Brain. 129:2923–2930. 2006. View Article : Google Scholar : PubMed/NCBI
3	Jessell TM and Kandel ER: Synaptic transmission: A bidirectional and self-modifiable form of cell-cell communication. Cell. 72:(Suppl). S1–S30. 1993. View Article : Google Scholar
4	Zhou Q, Lai Y, Bacaj T, Zhao M, Lyubimov AY, Uervirojnangkoorn M, Zeldin OB, Brewster AS, Sauter NK, Cohen AE, et al: Architecture of the synaptotagmin-SNARE machinery for neuronal exocytosis. Nature. 525:62–67. 2015. View Article : Google Scholar : PubMed/NCBI
5	Mehta PP, Battenberg E and Wilson MC: SNAP-25 and synaptotagmin involvement in the final Ca⁽²⁺⁾-dependent triggering of neurotransmitter exocytosis. Proc Natl Acad Sci USA. 93:10471–10476. 1996. View Article : Google Scholar : PubMed/NCBI
6	de Wit H, Walter AM, Milosevic I, Gulyás-Kovács A, Riedel D, Sørensen JB and Verhage M: Synaptotagmin-1 docks secretory vesicles to syntaxin-1/SNAP-25 acceptor complexes. Cell. 138:935–946. 2009. View Article : Google Scholar : PubMed/NCBI
7	Sudhof TC: The synaptic vesicle cycle. Annu Rev Neurosci. 27:509–547. 2004. View Article : Google Scholar : PubMed/NCBI
8	Chapman ER: How does synaptotagmin trigger neurotransmitter release? Annu Rev Biochem. 77:615–641. 2008. View Article : Google Scholar : PubMed/NCBI
9	Salvati S, Attorri L, Campeggi LM, Olivieri A, Sorcini M, Fortuna S and Pintor A: Effect of propylthiouracil-induced hypothyroidism on cerebral cortex of young and aged rats: Lipid composition of synaptosomes, muscarinic receptor sites, and acetylcholinesterase activity. Neurochem Res. 19:1181–1186. 1994. View Article : Google Scholar : PubMed/NCBI
10	Carageorgiou H, Pantos C, Zarros A, Mourouzis I, Varonos D, Cokkinos D and Tsakiris S: Changes in antioxidant status, protein concentration, acetylcholinesterase, (Na⁺, K⁺)-, and Mg2⁺- ATPase activities in the brain of hyper- and hypothyroid adult rats. Metab Brain Dis. 20:129–139. 2005. View Article : Google Scholar : PubMed/NCBI
11	Carageorgiou H, Pantos C, Zarros A, Stolakis V, Mourouzis I, Cokkinos D and Tsakiris S: Changes in acetylcholinesterase, Na⁺, K⁺-ATPase, and Mg²⁺-ATPase activities in the frontal cortex and the hippocampus of hyper- and hypothyroid adult rats. Metabolism. 56:1104–1110. 2007. View Article : Google Scholar : PubMed/NCBI
12	Yang HY, Sun CP, Jia XM, Gui L, Zhu DF and Ma WQ: Effect of thyroxine on SNARE complex and synaptotagmin-1 expression in the prefrontal cortex of rats with adult-onset hypothyroidism. J Endocrinol Invest. 35:312–316. 2012.PubMed/NCBI
13	Liu CL, Xu YX, Zhan Y, Hu HL, Jia XM, Chen GH and Zhu DF: Effect of thyroxine on synaptotagmin 1 and SNAP-25 expression in dorsal hippocampus of adult-onset hypothyroid rats. J Endocrinol Invest. 34:280–286. 2011. View Article : Google Scholar : PubMed/NCBI
14	Wang F, Zeng X, Zhu Y, Ning D, Liu J, Liu C, Jia X and Zhu D: Effects of thyroxine and donepezil on hippocampal acetylcholine content, acetylcholinesterase activity, synaptotagmin-1 and SNAP-25 expression in hypothyroid adult rats. Mol Med Rep. 11:775–782. 2015.PubMed/NCBI
15	No authors listed: Drugs for hypothyroidism. Med Lett Drugs Ther. 57:147–150. 2015.PubMed/NCBI
16	Wekking EM, Appelhof BC, Fliers E, Schene AH, Huyser J, Tijssen JG and Wiersinga WM: Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism. Eur J Endocrinol. 153:747–753. 2005. View Article : Google Scholar : PubMed/NCBI
17	Samuels MH, Schuff KG, Carlson NE, Carello P and Janowsky JS: Health status, psychological symptoms, mood, and cognition in L-thyroxine-treated hypothyroid subjects. Thyroid. 17:249–258. 2007. View Article : Google Scholar : PubMed/NCBI
18	Saravanan P, Chau WF, Roberts N, Vedhara K, Greenwood R and Dayan CM: Psychological well-being in patients on ‘adequate’ doses of l-thyroxine: Results of a large, controlled community-based questionnaire study. Clin Endocrinol (Oxf). 57:577–585. 2002. View Article : Google Scholar : PubMed/NCBI
19	Wang N, Cai Y, Wang F, Zeng X, Jia X, Tao F and Zhu D: Effects of thyroxin and donepezil on hippocampal acetylcholine content and syntaxin-1 and munc-18 expression in adult rats with hypothyroidism. Exp Ther Med. 7:529–536. 2014.PubMed/NCBI
20	Madeira MD, Sousa N, Lima-Andrade MT, Calheiros F, Cadete-Leite A and Paula-Barbosa MM: Selective vulnerability of the hippocampal pyramidal neurons to hypothyroidism in male and female rats. J Comp Neurol. 322:501–518. 1992. View Article : Google Scholar : PubMed/NCBI
21	Madeira MD, Cadete-Leite A, Andrade JP and Paula-Barbosa MM: Effects of hypothyroidism upon the granular layer of the dentate gyrus in male and female adult rats: A morphometric study. J Comp Neurol. 314:171–186. 1991. View Article : Google Scholar : PubMed/NCBI
22	Pepeu G and Giovannini MG: Cholinesterase inhibitors and beyond. Curr Alzheimer Res. 6:86–96. 2009. View Article : Google Scholar : PubMed/NCBI
23	Yoshiyama Y, Kojima A, Ishikawa C and Arai K: Anti-inflammatory action of donepezil ameliorates tau pathology, synaptic loss and neurodegeneration in a tauopathy mouse model. J Alzheimers Dis. 22:295–306. 2010. View Article : Google Scholar : PubMed/NCBI
24	Riepe MW: Cholinergic treatment: What are the early neuropathological targets? Eur J Neurol. 12:(Suppl 3). S3–S9. 2005. View Article : Google Scholar
25	Gerges NZ, Stringer JL and Alkadhi KA: Combination of hypothyroidism and stress abolishes early LTP in the CA1 but not dentate gyrus of hippocampus of adult rats. Brain Res. 922:250–260. 2001. View Article : Google Scholar : PubMed/NCBI
26	Cortes C, Eugenin E, Aliaga E, Carreño LJ, Bueno SM, Gonzalez PA, Gayol S, Naranjo D, Noches V, Marassi MP, et al: Hypothyroidism in the adult rat causes incremental changes in brain-derived neurotrophic factor, neuronal and astrocyte apoptosis, gliosis, and deterioration of postsynaptic density. Thyroid. 22:951–963. 2012. View Article : Google Scholar : PubMed/NCBI
27	Madeira MD and Paula-Barbosa MM: Reorganization of mossy fiber synapses in male and female hypothyroid rats: A stereological study. J Comp Neurol. 337:334–352. 1993. View Article : Google Scholar : PubMed/NCBI
28	David S and Nathaniel EJ: Neuronal changes induced by neonatal hypothyroidism: An ultrastructural study. Am J Anat. 167:381–394. 1983. View Article : Google Scholar : PubMed/NCBI
29	Gold PE: Acetylcholine modulation of neural systems involved in learning and memory. Neurobiol Learn Mem. 80:194–210. 2003. View Article : Google Scholar : PubMed/NCBI
30	Bartus RT, Dean RL III, Beer B and Lippa AS: The cholinergic hypothesis of geriatric memory dysfunction. Science. 217:408–414. 1982. View Article : Google Scholar : PubMed/NCBI
31	Molinengo L, Cassone MC and Oggero L: Action of hypo- and hyperthyroidism on the postmortal decay of acetylcholine in the rat spinal cord. Neuroendocrinology. 42:28–31. 1986. View Article : Google Scholar : PubMed/NCBI
32	Virgili M, Saverino O, Vaccari M, Barnabei O and Contestabile A: Temporal, regional and cellular selectivity of neonatal alteration of the thyroid state on neurochemical maturation in the rat. Exp Brain Res. 83:555–561. 1991. View Article : Google Scholar : PubMed/NCBI
33	Carageorgiou H, Pantos C, Zarros A, Stolakis V, Mourouzis I, Cokkinos D and Tsakiris S: Effects of hyper- and hypothyroidism on acetylcholinesterase, (Na(⁺), K (⁺))- and Mg (²⁺)-ATPase activities of adult rat hypothalamus and cerebellum. Metab Brain Dis. 22:31–38. 2007. View Article : Google Scholar : PubMed/NCBI
34	Kundu S, Pramanik M, Roy S, De J, Biswas A and Ray AK: Maintenance of brain thyroid hormone level during peripheral hypothyroid condition in adult rat. Life Sci. 79:1450–1455. 2006. View Article : Google Scholar : PubMed/NCBI
35	Semba K: Phylogenetic and ontogenetic aspects of the basal forebrain cholinergic neurons and their innervation of the cerebral cortex. Prog Brain Res. 145:3–43. 2004.PubMed/NCBI
36	Owasoyo JO, Egbunike GN and Iramain CA: The influence of thyroid gland and thyroxine on the acetylcholinesterase activity of rat brain and adenohypophysis. Endokrinologie. 77:242–246. 1981.PubMed/NCBI
37	Cao L, Jiang W, Wang F, Yang QG, Wang C, Chen YP and Chen GH: The reduced serum free triiodothyronine and increased dorsal hippocampal SNAP-25 and Munc18-1 had existed in middle-aged CD-1 mice with mild spatial cognitive impairment. Brain Res. 1540:9–20. 2013. View Article : Google Scholar : PubMed/NCBI
38	Quintanar JL and Salinas E: Effect of hypothyroidism on synaptosomal-associated protein of 25 kDa and syntaxin-1 expression in adenohypophyses of rat. J Endocrinol Invest. 25:754–758. 2002. View Article : Google Scholar : PubMed/NCBI
39	Vara H, Martínez B, Santos A and Colino A: Thyroid hormone regulates neurotransmitter release in neonatal rat hippocampus. Neuroscience. 110:19–28. 2002. View Article : Google Scholar : PubMed/NCBI
40	Ruiz-Marcos A, Sánchez-Toscano F, del Escobar Rey F and de Morreale Escobar G: Reversible morphological alterations of cortical neurons in juvenile and adult hypothyroidism in the rat. Brain Res. 185:91–102. 1980. View Article : Google Scholar : PubMed/NCBI
41	Ruiz-Marcos A, Salas J, Sanchez-Toscano F, del Escobar Rey F and de Morreale Escobar G: Effect of neonatal and adult-onset hypothyroidism on pyramidal cells of the rat auditory cortex. Brain Res. 285:205–213. 1983. View Article : Google Scholar : PubMed/NCBI
42	Ruiz-Marcos A, Sanchez-Toscano F, del Escobar Rey F and de Morreale Escobar G: Severe hypothyroidism and the maturation of the rat cerebral cortex. Brain Res. 162:315–329. 1979. View Article : Google Scholar : PubMed/NCBI
43	Ipina SL, Ruiz-Marcos A, del Escobar Rey F and de Morreale Escobar G: Pyramidal cortical cell morphology studied by multivariate analysis: Effects of neonatal thyroidectomy, ageing and thyroxine-substitution therapy. Brain Res. 465:219–229. 1987. View Article : Google Scholar : PubMed/NCBI
44	Honegger P and Lenoir D: Triodothyronine enhancement of neuronal differentiation in aggregating fetal rat brain cells cultured in a chemically defined medium. Brain Res. 199:425–434. 1980. View Article : Google Scholar : PubMed/NCBI
45	Akuzawa K and Wakabayashi K: A serum-free culture of the neurons in the septal, preoptic and hypothalamic region. Endocrinol Jpn. 32:163–173. 1985. View Article : Google Scholar : PubMed/NCBI
46	Alzoubi KH, Gerges NZ and Alkadhi KA: Levothyroxin restores hypothyroidism-induced impairment of LTP of hippocampal CA1: Electrophysiological and molecular studies. Exp Neurol. 195:330–341. 2005. View Article : Google Scholar : PubMed/NCBI
47	Saiyed M and Riker WK: Cholinergic and anticholinergic drug effects on survival during hypoxia: Significant gender differences. J Pharmacol Exp Ther. 264:1146–1153. 1993.PubMed/NCBI
48	Dimitrova DS and Getova-Spassova DP: Effects of galantamine and donepezil on active and passive avoidance tests in rats with induced hypoxia. J Pharmacol Sci. 101:199–204. 2006. View Article : Google Scholar : PubMed/NCBI
49	Alcantara-Gonzalez F, Juarez I, Solis O, Martinez-Tellez I, Camacho-Abrego I, Masliah E, Mena R and Flores G: Enhanced dendritic spine number of neurons of the prefrontal cortex, hippocampus and nucleus accumbens in old rats after chronic donepezil administration. Synapse. 64:786–793. 2010.PubMed/NCBI
50	Akasofu S, Kimura M, Kosasa T, Sawada K and Ogura H: Study of neuroprotection of donepezil, a therapy for Alzheimer's disease. Chem Biol Interact. 175:222–226. 2008. View Article : Google Scholar : PubMed/NCBI
51	Akaike A, Takada-Takatori Y, Kume T and Izumi Y: Mechanisms of neuroprotective effects of nicotine and acetylcholinesterase inhibitors: Role of alpha4 and alpha7 receptors in neuroprotection. J Mol Neurosci. 40:211–216. 2010. View Article : Google Scholar : PubMed/NCBI
52	Shen H, Kihara T, Hongo H, Wu X, Kem WR, Shimohama S, Akaike A, Niidome T and Sugimoto H: Neuroprotection by donepezil against glutamate excitotoxicity involves stimulation of alpha7 nicotinic receptors and internalization of NMDA receptors. Br J Pharmacol. 161:127–139. 2010. View Article : Google Scholar : PubMed/NCBI
53	Takada-Takatori Y, Kume T, Izumi Y, Ohgi Y, Niidome T, Fujii T, Sugimoto H and Akaike A: Roles of nicotinic receptors in acetylcholinesterase inhibitor-induced neuroprotection and nicotinic receptor up-regulation. Biol Pharm Bull. 32:318–324. 2009. View Article : Google Scholar : PubMed/NCBI
54	Meunier J, Ieni J and Maurice T: The anti-amnesic and neuroprotective effects of donepezil against amyloid beta25-35 peptide-induced toxicity in mice involve an interaction with the sigma1 receptor. Br J Pharmacol. 149:998–1012. 2006. View Article : Google Scholar : PubMed/NCBI