Artemisinin ameliorates the thyroid function and the complications in adult male hypothyroid rats via upregulating L1 cell adhesion molecule

doi:10.21203/rs.3.rs-4165982/v1

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Artemisinin ameliorates the thyroid function and the complications in adult male hypothyroid rats via upregulating L1 cell adhesion molecule

https://doi.org/10.21203/rs.3.rs-4165982/v1

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published 19 Aug, 2024

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Hypothyroidism, a common worldwide syndrome caused by in sufficient thyroid hormone secretion, affects a good deal of people at different ages. Artemisinin (ART), a well-known effective agent in the treatment of malaria, also owns anti-oxidative stress functions in various diseases. L1 cell adhesion molecule also exerts multiple protective roles in diseased systems. Hence, the aim of this study is to evaluate the role of ART in the in adult male hypothyroid rats and the underlying mechanisms. In the current study, we revealed that, ART can amelioratethe thyroid function, mitigate the depression and anxiety symptoms, attenuate the cognition impairments, improve the liver, kidney and heart functions, and inhibit the oxidative stress, whereas, theses conducive effects exerted by ART cannot be observed when L1 was silenced by L1 siRNA.These combined results indicated that ART can upregulate L1 cell adhesion molecule to ameliorate the thyroid function and the complications in adult male hypothyroid rats, laying the foundation for ART to be a novel strategy for the treatment of hypothyroidism.

hypothyroidism

Artemisinin (ART)

oxidative stress

With an increase in metabolic diseases in recent years, thyroiddysfunctions, especially hypothyroidism, represent the mostcommon endocrine disorders and areassociated with an increased risk of comorbidity, which impacts ability to work and quality of life worldwide[1].Hypothyroidism is a prevalent medical condition characterized by a reduction in the body's metabolic activity due to a decrease in the synthesis and secretion of thyroid hormones or their efficacy [2]. Due to the important roles of thyroid hormones in theproper functions of the heart, kidneys, liver,and brain, these organs are adversely affected by hypothyroidism[3, 4].Thyroid hormones havea vital impact on the development and normal work ofthe brain throughout life[5]. Adultonsethypothyroidism is associated with depression, anxiety[6], and memory deficits [7, 8]both in humans and in animal models [9, 10].Thyroid hormones are crucial for oxidative metabolism and energy expenditure[11].The conventionaltreatment of hypothyroidism generates adverse drugevents, high treatment costs, and compliance issues, thus, the potential anti-oxidative stress strategies associated with the eart, kidneys, liver,and brain dysfunctionsmay behelpful for the treatment of hypothyroidism.

Attempts to apply beneficial molecules that may treathypothyroidism have led to experimentson animal models and have, to some extent, ameliorated the complications. Among several molecules,the promising candidate isartemisinin (ART), a compound first discovered in the 1970 s and comprising sesquiterpene lactones from sweet wormwood plants (Artemisia annua)[12, 13] andthe derivatives have been reported to save millions of people suffering from malaria worldwide over the decades[12].Also, ARTcan attenuate thebrain inflammation and memory impairments [14].ART could protectagainstoxidative stress in neurons [15, 16].ART caneasily pass through the blood–brain barrier without any obvious side effects [17].

Yet, since multiple underlying mechanisms relating tohypothyroidism, we then searched for other possible targetsassociated withART that could ameliorate hypothyroidism and its complications. This target is L1 cell adhesion molecule, encoded by L1CAM genecontaining 28 exons[18], isa transmembrane glycoproteinprimarily discovered in the nervous system. L1 mediates cell–cell adhesion, neuronal cell survival and migration, and synaptogenesis [19].L1 can exert key roles in learning,memory, and regeneration following insult[20–23].L1 can affect protein kinase D1 phosphorylation in mouse cerebellar granule neurons[24] and cerebral cortex in Alzheimer's disease[25]. Also, berberine enhance L1 expression to promote the recoveryof rats after brachial plexus root avulsion[26].

Given the essential roles of ART and L1 in normal and diseased conditions, we then were very interested in the potential functional relationshil between ART and L1 in hypothyroidism, hence, we here hypothesized that ART may exert a protective role in hypothyroidism by activatingL1. Herein, in the current study, we reported that ART was capable of ameliorating the thyroid function and the complications in brain, liver, kidney and heart in adult male hypothyroid rats through upregulating L1.

2.1 Animals

The 8-week male Sprague–Dawley rats (200–220 g) purchased from Hunan MedicalLaboratory Animal Center (China) were maintained in an environment(temperature:22–23°C, the relative humidity: 45–50%), and the light cycle is 12/12 h. All procedures carried out onrats were approved by the Laboratory Animal Ethics Committee of The First Affiliated Hospital of University of South China (Approval No. LL20210708002).

2.2 Groups and treatments

The PTU rat modelwas constructed referred to theprevious pulication[27]. Rats were randomly divided intothe CTRL group (n = 10), and the PTU group (n = 20), the PTU + ART group, and the PTU + ART + L1 siRNA group.The rats in the CTRL group drank water normally, whilethe rats in the other 3 groups drank tap water containing0.05% PTU[28]. After 28 days,the rats in the CTRL group and thePTU group were intraperitoneallyinjected saline once a day, while the ratsin the PTU + ART group and the PTU + ART + L1 siRNA group were intraperitoneally injected5 mg/kg ARTwith or without L1 siRNA (sense: 5′-GCA UUAGUG GCC AUC CUU UTT-3′, antisense: 3′-TTC GUA AUC ACC GGUAGG AAA-5′)[29] once a day for continuous 2 weeks.

2.3 Behavior tests

2.3.1 Tail suspension test

The tail suspension test was commonlycarried out on rats as described [30, 31]. In brief, the individualrat washanged with a hook by approximately 1 cm from the tip of thetail using adhesive tape (distance from the floor was 50 cm). The duration of immobility time was determined for 6 min. Immobility was calculatedwhen the rat remains motionless or makes only little, non-escape-associated movements.

2.3.2 Forced swimming test

The forced swimming test wascommonlycarried out on rats as described[32]. The individual rat was placed to swim in a plastic cylinder with a height of 40cm and a diameter of 20 cm filled and with 15 cm ofwater at 25 ± 1℃. Two sessions were included in thisexperiment. In a first session, each rat was forced to swim for 15 min inthe water-filled plastic cylinder for adapting. After 24 h, the rats werefollowed by the 5-min test session. The escape responses,including climbing timeand swimming time, werecalculated.

2.3.3 Elevated plus maze test

The wlevated plus maze testwascommonlycarried out on rats as described[33, 34]. 2 opposite closed arms (50 cm × 10 cm × 40 cm) and 2 opposite open arms (50cm × 10 cm) were connected by a centralsquare (10 × 10 cm) make up the apparatus placed 50 cm above the floor. Theindividualrat was placed in the central zone facing one of the open armsduring 5-min experimental period. The % of open-arm entries(open/total entries × 100) and the % of time spent in the open arms (open/total timespent × 100) were determined. The more increased of open arm activity, themore serious anxiety behavior [35].

2.3.4Morris water maze test

The Morris water maze testwascommonlycarried out on rats as described[36]. The maze was with a diameterof 1.6 m and a height of 50 cm.The pool water with a 30-cmdepth at 22–23°C was black dyed with food coloring. Two sessions were included in this experiment. In the first positioningnavigation experiment, the rats received training for 4 d with 4 times each day. The second specific training,before entering the water, put the rat onthe underwater platform to adapt for 30 s,the swimming distance of the rat from the four quadrantsand different entry points to the platform was recorded within1 min.

On the 5th day, the space search experiment was conducted, after removing the platform, and the rats were placedinto the water from the entry point in the opposite quadrantof the platform, facing the wall of the pool, and theswimming trajectory of the rats within 1 min wasrecorded.

2.3.5 Novel object recognitiontest

The open-fieldbox that was used in this experiment was 50 cm × 40 cm ×30 cm. To avoid being pushed or bitten by rats, the recognizedobjects were cylinders and tubes with a certain weightas well as hardness. The whole experiment was divided intothree periods: the adaptation period, training period, andtesting period. The discrimination index was calculated to reflectthe cognitive function of the rat, which was defined by thefollowing equation: discrimination index = [(time spent onfamiliar object-time spent on novel object)/(time spent onfamiliar object + time spent on novel object)] × 100.

2.3.6 Y-Maze test

The Y-maze testwascommonlycarried out on rats as described. The experimental apparatusconsisted of three identical labeled arms (A, B, and C) atequal angles. The alternation performancewas calculated to evaluate the spatial differentiationmemory of rats.

2.4Body weight gain and food consumption

The body weight gain was calculated for each groupby subtracting the initial weight (at the beginning of theexperiment) from the final weight (at the end of experiment). And the food consumption per day was calculated.

2.5 Core temperature

We used a non-invasive, continuous, longitudinal monitoring ofcore temperature in the physiological context[37, 38]. In brief, ThermochroniButton, DS1922L-F5# (with a precision of 0.0625°C) wasprogrammed to start recording Tb 1 week after implantation at30- or 60-minute intervals and then coated with a thin layer ofparaffin wax for waterproofing (3:1 ratio). The iButton wasimplanted surgically into the peritoneal cavity under generalanesthesia (by inhaling 3–5% isoflurane).

2.6Serum glucose determination

Glucose level was determined directly after blood samplingusing a kit purchased from Spectrum-diagnostic Company(Egypt) according to the method of Trinder [39].

2.7Serum biochemical parameter assays

Blood samples were collected from theinfraorbital vein and then centrifuged at 1500 × g for 30min toobtain serum.We used enzyme-linked immunosorbent assay kits (ELISA) toestimate the levels in the serum,thyroid stimulating hormone (TSH), total triiodothyronine (T3), and total thyroxine (T4),ghrelin, glucagon-like peptide-1 (GLP-1), alanine aminotransferase (ALT), aspartateaminotransferase (AST), alkaline phosphatase (ALP), urea, creatinine, lactate dehydrogenase (LDH), creatine Kinase MB (CK-MB).

2.8 Serum oxidative stress measurements

The levels of NO, malondialdehyde(MDA), 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE), 8-oxo-deoxyguanosine (8-OHDG), reactive oxygen species (ROS), catalase (CAT),glutathione(GSH), and superoxide dismutase (SOD) were determinedusing commercial kitsaccording to the manufacturer’s protocols.

2.9 Statistical analysis

Data are expressed as the mean ± standard deviation (SD). Statisticalanalyses were performed using GraphPad Prism 6 software with one-way analysis of variance (ANOVA) followed by a post-hoc Bonferronitest.

3.1 ART ameliorates the thyroid function via upregulating L1 in adult male hypothyroid rats

To determine the effect of ART on the thyroid function after hypothyroidism in rats, body weight, food intake per day, core body temperature, glucose level, serum thyroid stimulating hormone (TSH), tri-iodothyronine (T3), and L-thyroxine (T4)levels, ghrelin and glucagon-like peptide-1 (GLP-1)secretion were calculated.

In comparison to the CTRL group, the body weight gain was increased in response to the PTU treatment, but it was decreased by ART treatment, however, following the L1 inhibition by L1 siRNA, ART cannot alter body weight (Fig. 1A); the similar pattern for food intake per day (Fig. 1B) and core body temperature (Fig. 1C), and a reverse pattern for glucose level (Fig. 1D) were also observed.

In comparison to the CTRL group, the TSH level was increased in response to the PTU treatment, but it was decreased by ART treatment, however, following the L1 inhibition by L1 siRNA, ART cannot alter TSH level (Fig. 1E); the reverse pattern for T3 level (Fig. 1F), and a similar pattern for T4 level (Fig. 1G) were also observed.

In comparison to the CTRL group, the ghrelinsecretion was decreased in response to the PTU treatment, but it was increased by ART treatment, however, following the L1 inhibition by L1 siRNA, ART cannot alter ghrelinsecretion (Fig. 1H); the reverse pattern for GLP-1secretion (Fig. 1I) was also observed.

3.2ARTmitigates the depression and anxiety symptoms via upregulating L1 in adult male hypothyroid rats

To determine the effect of ART on the depression and anxiety dysfuntions after hypothyroidism in rats, tail suspension test, forced swimming test, and elevated plus maze test were performed.

In tail suspension test, in comparison to the CTRL group, the immobility time was increased in response to the PTU treatment, but it was decreased by ART treatment, however, following the L1 inhibition by L1 siRNA, ART cannot alter the immobility time (Fig. 2A).

In forced swimming test, in comparison to the CTRL group, the climbing time was decreased in response to the PTU treatment, but it was increased by ART treatment, however, following the L1 inhibition by L1 siRNA, ART cannot alter the climbing time (Fig. 2B); a similar pattern for swimming time (Fig. 2C) was also observed.

In elevated plus maze test,in comparison to the CTRL group, the percentage of open-arm entries was decreased in response to the PTU treatment, but it was increased by ART treatment, however, following the L1 inhibition by L1 siRNA, ART cannot alter the percentage of open-arm entries (Fig. 2D), a similar pattern for time spent in the open arms (Fig. 2E) was also observed.

3.3 ARTattenuates the cognition impairments via upregulating L1 in adult male hypothyroid rats

To determine the effect of ART on the cognition dysfuntion after hypothyroidism in rats, Morris water maze test,Novel object recognition (NOR) test, andY-Maze test were performed.

In Morris water maze test, in comparison to the CTRL group, the escape latency was increased in response to the PTU treatment, but it was decreased by ART treatment, however, following the L1 inhibition by L1 siRNA, ART cannot alter the escape latency(Fig. 3A);asimilar pattern for distance traveled (Fig. 3B), and a reverse pattern for swim speed (Fig. 3C) were also observed.

In NOR test, no significant difference observed in thetotal time in both training (Fig. 3D) and test period (Fig. 3E) among each experimentalgroups; in comparison to the CTRL group, the recognition index was decreased in response to the PTU treatment, but it was increased by ART treatment, however, following the L1 inhibition by L1 siRNA, ART cannot alter the recognition index(Fig. 3F).

InY-Maze test, no significant difference observed in the number of total arm entries among each experimentalgroups (Fig. 3G); in comparison to the CTRL group, the alternation performance was decreased in response to the PTU treatment, but it was increased by ART treatment, however, following the L1 inhibition by L1 siRNA, ART cannot alter the alternation performance (Fig. 3H).

3.4 ART improves the liver, kidney and heart functions via upregulating L1 in adult male hypothyroid rats

To determine the effect of ART on the liver, kidney and heart functions after hypothyroidism in rats, the serum alanine aminotransferase (ALT), aspartateaminotransferase (AST), alkaline phosphatase (ALP), urea, creatinine,lactate dehydrogenase (LDH), ceatine kinase MB (CK-MB) activities were determined.

For liver function, in comparison to the CTRL group, the AST level was increased in response to the PTU treatment, but it was decreased by ART treatment, however, following the L1 inhibition by L1 siRNA, ART cannot alter AST level (Fig. 4A); the similar patterns for ALT level (Fig. 4B) and ALP level (Fig. 4C) were also observed.

For kidney function, in comparison to the CTRL group, the urea level was increased in response to the PTU treatment, but it was decreased by ART treatment, however, following the L1 inhibition by L1 siRNA, ART cannot alter urea level (Fig. 4A); asimilar patterns for creatinine level (Fig. 4B) was also observed.

For heart function,in comparison to the CTRL group, the LDH level was increased in response to the PTU treatment, but it was decreased by ART treatment, however, following the L1 inhibition by L1 siRNA, ART cannot alter LDH level (Fig. 4A); a similar patterns for CK-MB level (Fig. 4B) was also observed.

3.5 ART inhibits the oxidative stress via upregulating L1 in adult male hypothyroid rats

To determine the effect of ART on the oxidative stress after hypothyroidism in rats, ELISA was performed to calculate the levels of NO, MDA, 3-NT, 4-HNE, 8-OHGD, CAT, GSH, ROS, and SOD in serum.

In comparison to the CTRL group, the NO level was up-regulated in response to the PTU treatment, but it was down-regulated by ART treatment, however, following the L1 inhibition by L1 siRNA, ART cannot alter the NO level (Fig. 5A). The similar patterns for MDA, 3-NT, 4-HNE, 8-OHGD (Fig. 5B-E), and reverse patterns for CAT, GSH, ROS, SOD (Fig. 5F-I) were also observed.

Previous study has demonstrated that ARTcan upregulate L1 to reduce the neurological deficitsin mice after intracerebral hemorrhage[40]. In the current study, we revealed that ART can ameliorate the thyroid function and the complications, including the depression, anxiety and cognition impairments, and the associated kidney, liver and heart dysfunctions in adult male hypothyroid rats.

Hypothyroidism is characterizedby a high level of TSH,insufficient production of T3, T4 in serum[41].Thyroid hormones can regulate basalenergy consuption either indirectly by changingother regulatory hormones or directly by affecting carbohydrate,protein, and lipid metabolism [42]. Therefore, thyroid hormones deficiency hasbeen found to reduce glucose availability, alter the correctabsorption of glucose [43].PTU can affect the ghrelin(anorexigenic hormone)levels in serum, it promoted the GLP-1 (an anorexigenic hormone)secretion, leading tothe decreased food intake[44]. In the current study, we revealed that ART can ameliorate the thyroid function via upregulating L1.

Thyroid hormones exert a key role in the development of brain and make contributions to keep health state in brainin adulthood [45]. Also, thyroidhormones were reported to be associated with cognition [46]. It has been shown that the attention,memory and spatial ability in patients suffering from hypothyroidism are decreased significantly, while thedepression and anxietydysfunctions were increased [47]. In the current study, we revealed that ART can mitigate the depression and anxiety symptoms, and cognition impairement via upregulating L1.

The confused lipid metabolism caused by hypothyroidismis associated withthe nonalcoholicfatty liver [48]. Anobvious positive relationship betweenaspartate AST and TSH activities has been observed in patients suffering from liver cirrhosis[49].IAlso, hypothyroidism may lead tothekidney functionimpairment[50].Anobviously positiverelationship exists between up-regulated LDH and CK-MBin ischemic myocardial injury [51].In the current study, we revealed that ART can improve the liver, kidney and heart functions via upregulating L1.

Oxidative stress was reported to exert an essential role in the development and pathology of thyroid diseases [52]. Compared with healthy controls, higher oxidative stress was observed in hypothyroid patients [53].Previous study has reported that thymoquinone can protect against the testes of hypothyroid rats by suppressing oxidative stress[54].In the current study, we revealed that ART can inhibit the oxidative stress via upregulating L1.

Taken together, the combined data indicated that ART treatment can not only ameliorate hypothyroidism but alsoprevent the implications induced by hypothyroidismsuch as depression, anxiety and cognition impairments, and the associated kidney, liver and heart dysfunctions via increasing L1 to inhibit the oxidative stress, suggesting that ART may be a novel strategy for the treatment of hypothyroidism.

Competing interests / COI statement

The authors declare that they have no conflicts ofinterest.

Funding

This study was supported by the Health Research Project of Hunan Provincial Health Commission (grant number. 202214024303).

Authors' contributions

Conceptualization, LL; methodology, investigation, and writing, LL, HX, ZH and LL; review and editing, LL, LL, supervision, LL. All authors have read and approved the publish of the manuscript.

Acknowledgements

Not applicable.

Ethics approval and consent to participate

All procedures carried out onrats were approved by the Laboratory Animal Ethics Committee of The First Affiliated Hospital of University of South China (Approval No. LL20210708002).

Consent for publication

Not applicable.

Availability of data and materials

The datasets generated and/or analyzed during the current study can be available from the corresponding author on reasonable request

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No competing interests reported.

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Journal Publication

published 19 Aug, 2024

Read the published version in Thyroid Research →

Editorial decision: Revision requested
31 Mar, 2024
Submission checks completed at journal
27 Mar, 2024
Editor assigned by journal
27 Mar, 2024
First submitted to journal
25 Mar, 2024

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Artemisinin ameliorates the thyroid function and the complications in adult male hypothyroid rats via upregulating L1 cell adhesion molecule

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Journal Publication

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Abstract

Figures

1. Introduction

2. Materials and methods

2.1 Animals

2.2 Groups and treatments

2.3 Behavior tests

2.3.1 Tail suspension test

2.3.2 Forced swimming test

2.3.3 Elevated plus maze test

2.3.4Morris water maze test

2.3.5 Novel object recognitiontest

2.3.6 Y-Maze test

2.4Body weight gain and food consumption

2.5 Core temperature

2.6Serum glucose determination

2.7Serum biochemical parameter assays

2.8 Serum oxidative stress measurements

2.9 Statistical analysis

3. Results

3.1 ART ameliorates the thyroid function via upregulating L1 in adult male hypothyroid rats

3.2ARTmitigates the depression and anxiety symptoms via upregulating L1 in adult male hypothyroid rats

3.3 ARTattenuates the cognition impairments via upregulating L1 in adult male hypothyroid rats

3.5 ART inhibits the oxidative stress via upregulating L1 in adult male hypothyroid rats

4. Discussion

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1