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Effects of thyroxine and donepezil on hippocampal acetylcholine content, acetylcholinesterase activity, synaptotagmin-1 and SNAP-25 expression in hypothyroid adult rats.

Wang F, Zeng X, Zhu Y, Ning D, Liu J, Liu C, Jia X, Zhu D - Mol Med Rep (2014)

Bottom Line: Protein levels of syt-1 and SNAP-25 were determined by immunohistochemistry.The results demonstrated that syt-1 was expressed at significantly lower levels in hypothyroid rats, while SNAP-25 levels were notably higher compared with the controls.Two-week treatment with T4 alone failed to normalize the expression levels of these two proteins, while co-administration of T4 and DON was able to induce this effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Endocrinology, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China.

ABSTRACT
A growing number of studies have revealed that neurocognitive impairment, induced by adult-onset hypothyroidism, may not be fully restored by traditional hormone substitution therapies, including thyroxine (T4). The present study has investigated the effect of T4 and donepezil (DON; an acetylcholinesterase (AChE) inhibitor) treatment on the hypothyroidism-induced alterations of acetylcholine (ACh) content and AChE activity. Furthermore, we examined synaptotagmin-1 (syt-1) and SNAP-25 expression in the hippocampus of adult rats. Adding 0.05% propylthiouracil to their drinking water for five weeks induced hypothyroidism in the rat models. From the fourth week, the rats were treated with T4, DON or a combination of both. Concentration of ACh and the activity of AChE was determined colorimetrically. The results demonstrated that hypothyroidism induced a significant decrease of Ach content and AChE activity (by 17 and 34%, respectively), which were restored to control values by T4 administration. DON treatment also restored Ach to the normal level. Protein levels of syt-1 and SNAP-25 were determined by immunohistochemistry. The results demonstrated that syt-1 was expressed at significantly lower levels in hypothyroid rats, while SNAP-25 levels were notably higher compared with the controls. Two-week treatment with T4 alone failed to normalize the expression levels of these two proteins, while co-administration of T4 and DON was able to induce this effect. These data suggested that the thyroid hormone, T4, may have a direct effect on the metabolism of hippocampal ACh in adult rats, and that the DON treatment may facilitate the recovery of synaptic protein impairments induced by hypothyroidism.

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Photomicrographs of coronal sections showing syt-1 immunoreactivity in CA1, CA3 and DG subregions of hippocampus of rats from Hypo, T4, DON, T4+DON and C groups (n=10–12). Distinct punctate spots of reaction product were observed in every layer of CA1, CA3 and DG subregions; note that slight decrease in overall staining intensity of CA1-SO, CA1-SR, CA3-SL, CA3-SR and DG-ML in the Hypo, DON and T4 groups was observed; the overall staining intensity was equal in CA1-SLM, CA3-SO and DG-PL of five groups; magnification: ×400, scale bar = 50 μm. Hypo, hypothyroid group; DON, hypothyroid rats treated with 0.005% (w/v) DON; T4, hypothyroid rats treated with 6 μg T4/100 g body weight; T4+DON, hypothyroid rats treated with 6 μg T4/100 g body weight beside adding 0.005% (w/v) donepezil to the drinking water; C, Control group. Syt-1, synaptotagmin-1; T4, thyroxine; DON, donepezil; DG, dentate gyrus; SO, stratum oriens; SR, stratum radiatum; SLM, stratum lacunosum-moleculare; SL, stratum lucidum; ML, molecular layer; PL, polymorphic layer; w/v, weight/volume.
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f3-mmr-11-02-0775: Photomicrographs of coronal sections showing syt-1 immunoreactivity in CA1, CA3 and DG subregions of hippocampus of rats from Hypo, T4, DON, T4+DON and C groups (n=10–12). Distinct punctate spots of reaction product were observed in every layer of CA1, CA3 and DG subregions; note that slight decrease in overall staining intensity of CA1-SO, CA1-SR, CA3-SL, CA3-SR and DG-ML in the Hypo, DON and T4 groups was observed; the overall staining intensity was equal in CA1-SLM, CA3-SO and DG-PL of five groups; magnification: ×400, scale bar = 50 μm. Hypo, hypothyroid group; DON, hypothyroid rats treated with 0.005% (w/v) DON; T4, hypothyroid rats treated with 6 μg T4/100 g body weight; T4+DON, hypothyroid rats treated with 6 μg T4/100 g body weight beside adding 0.005% (w/v) donepezil to the drinking water; C, Control group. Syt-1, synaptotagmin-1; T4, thyroxine; DON, donepezil; DG, dentate gyrus; SO, stratum oriens; SR, stratum radiatum; SLM, stratum lacunosum-moleculare; SL, stratum lucidum; ML, molecular layer; PL, polymorphic layer; w/v, weight/volume.

Mentions: Representative photomicrographs of the immuno-labeled syt-1 and SNAP-25 in subfields (CA1, CA3 and DG) of the hippocampus from different groups are demonstrated in Fig. 3 and Fig. 4, respectively. The immunoreactivity distributions of the proteins were similar among these groups. Punctate spots of reaction product were distributed in every layer of the CA1, CA3 and DG subregions of the hippocampus.


Effects of thyroxine and donepezil on hippocampal acetylcholine content, acetylcholinesterase activity, synaptotagmin-1 and SNAP-25 expression in hypothyroid adult rats.

Wang F, Zeng X, Zhu Y, Ning D, Liu J, Liu C, Jia X, Zhu D - Mol Med Rep (2014)

Photomicrographs of coronal sections showing syt-1 immunoreactivity in CA1, CA3 and DG subregions of hippocampus of rats from Hypo, T4, DON, T4+DON and C groups (n=10–12). Distinct punctate spots of reaction product were observed in every layer of CA1, CA3 and DG subregions; note that slight decrease in overall staining intensity of CA1-SO, CA1-SR, CA3-SL, CA3-SR and DG-ML in the Hypo, DON and T4 groups was observed; the overall staining intensity was equal in CA1-SLM, CA3-SO and DG-PL of five groups; magnification: ×400, scale bar = 50 μm. Hypo, hypothyroid group; DON, hypothyroid rats treated with 0.005% (w/v) DON; T4, hypothyroid rats treated with 6 μg T4/100 g body weight; T4+DON, hypothyroid rats treated with 6 μg T4/100 g body weight beside adding 0.005% (w/v) donepezil to the drinking water; C, Control group. Syt-1, synaptotagmin-1; T4, thyroxine; DON, donepezil; DG, dentate gyrus; SO, stratum oriens; SR, stratum radiatum; SLM, stratum lacunosum-moleculare; SL, stratum lucidum; ML, molecular layer; PL, polymorphic layer; w/v, weight/volume.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4262484&req=5

f3-mmr-11-02-0775: Photomicrographs of coronal sections showing syt-1 immunoreactivity in CA1, CA3 and DG subregions of hippocampus of rats from Hypo, T4, DON, T4+DON and C groups (n=10–12). Distinct punctate spots of reaction product were observed in every layer of CA1, CA3 and DG subregions; note that slight decrease in overall staining intensity of CA1-SO, CA1-SR, CA3-SL, CA3-SR and DG-ML in the Hypo, DON and T4 groups was observed; the overall staining intensity was equal in CA1-SLM, CA3-SO and DG-PL of five groups; magnification: ×400, scale bar = 50 μm. Hypo, hypothyroid group; DON, hypothyroid rats treated with 0.005% (w/v) DON; T4, hypothyroid rats treated with 6 μg T4/100 g body weight; T4+DON, hypothyroid rats treated with 6 μg T4/100 g body weight beside adding 0.005% (w/v) donepezil to the drinking water; C, Control group. Syt-1, synaptotagmin-1; T4, thyroxine; DON, donepezil; DG, dentate gyrus; SO, stratum oriens; SR, stratum radiatum; SLM, stratum lacunosum-moleculare; SL, stratum lucidum; ML, molecular layer; PL, polymorphic layer; w/v, weight/volume.
Mentions: Representative photomicrographs of the immuno-labeled syt-1 and SNAP-25 in subfields (CA1, CA3 and DG) of the hippocampus from different groups are demonstrated in Fig. 3 and Fig. 4, respectively. The immunoreactivity distributions of the proteins were similar among these groups. Punctate spots of reaction product were distributed in every layer of the CA1, CA3 and DG subregions of the hippocampus.

Bottom Line: Protein levels of syt-1 and SNAP-25 were determined by immunohistochemistry.The results demonstrated that syt-1 was expressed at significantly lower levels in hypothyroid rats, while SNAP-25 levels were notably higher compared with the controls.Two-week treatment with T4 alone failed to normalize the expression levels of these two proteins, while co-administration of T4 and DON was able to induce this effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Endocrinology, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China.

ABSTRACT
A growing number of studies have revealed that neurocognitive impairment, induced by adult-onset hypothyroidism, may not be fully restored by traditional hormone substitution therapies, including thyroxine (T4). The present study has investigated the effect of T4 and donepezil (DON; an acetylcholinesterase (AChE) inhibitor) treatment on the hypothyroidism-induced alterations of acetylcholine (ACh) content and AChE activity. Furthermore, we examined synaptotagmin-1 (syt-1) and SNAP-25 expression in the hippocampus of adult rats. Adding 0.05% propylthiouracil to their drinking water for five weeks induced hypothyroidism in the rat models. From the fourth week, the rats were treated with T4, DON or a combination of both. Concentration of ACh and the activity of AChE was determined colorimetrically. The results demonstrated that hypothyroidism induced a significant decrease of Ach content and AChE activity (by 17 and 34%, respectively), which were restored to control values by T4 administration. DON treatment also restored Ach to the normal level. Protein levels of syt-1 and SNAP-25 were determined by immunohistochemistry. The results demonstrated that syt-1 was expressed at significantly lower levels in hypothyroid rats, while SNAP-25 levels were notably higher compared with the controls. Two-week treatment with T4 alone failed to normalize the expression levels of these two proteins, while co-administration of T4 and DON was able to induce this effect. These data suggested that the thyroid hormone, T4, may have a direct effect on the metabolism of hippocampal ACh in adult rats, and that the DON treatment may facilitate the recovery of synaptic protein impairments induced by hypothyroidism.

Show MeSH
Related in: MedlinePlus