Lithium Carbonate Alleviate Neuronal Apoptosis to Improve Depression Symptoms in Mice by the JNK/c-Jun Signaling Pathway

doi:10.21203/rs.3.rs-3740670/v1

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Research Article

Lithium Carbonate Alleviate Neuronal Apoptosis to Improve Depression Symptoms in Mice by the JNK/c-Jun Signaling Pathway

https://doi.org/10.21203/rs.3.rs-3740670/v1

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Objective

Lithium is a monovalent cation that was introduced in 1949 by John Cade for the treatment of bipolar disorder，especially for mania.As for mood stabilizer, it should be effective in treatment of depression.To explore lithium alleviate the apoptosis of nerve cells through JNK/ C-Jun signaling pathway and improve the depressive symptoms in depressed mice.

Methods

30 male mice were randomly divided into blank control(control) , model group(stress) and drug intervention group(stress+lithium). A model of depression was established by Chronic unpredictable mild stress (CUMS). Mice in stress+lithium group were given lithium from 4th weekend. The behavior of mice were evaluated and Western blot was used to detect expression levels of related proteins.

Results

Compared with control, stress+lithium group showed a significant decrease depressive symptoms (P< 0.01).Western blotting results show that compared with stress group, protein levels of P-JNK /JNK ,P-C-Jun/C-Jun ,caspase-3 and Bax in PFC of control were significantly increased (P < 0.01), Bcl-2 level significantly decreased (P < 0.01);Compared with the stress group, the protein levels of nerve cells p-JNK/JNK, P-C-Jun/C-Jun, aspase-3 and Bax in prefrontal cortex of mice in stress +lithium group were significantly decreased (P< 0.01), Bcl-2 level increased significantly (P < 0.01).

Conclusions Lithium improve depression symptoms by reducing apoptosis of prefrontal cortex nerve cells through JNK/ C-Jun signaling pathway in depressive mice.

Depression

Lithium carbonate

JNK/c-Jun

Cell apoptosis

Depression is a common mental disease, which is mainly characterized by emotional disorders, lack of pleasure, cognitive dysfunction or increased susceptibility to relapse [1]. According to the World Health Organization (WHO) report in 2017, the number of depression patients worldwide reached 322 million, of which the prevalence rate of depression in China reached 4.2%; It is predicted that depression will become the first factor in the global disease burden by 2030 [2].Depression has become a global neuropsychiatric disease and a major burden on the human medical system. Therefore, research on depression models aims to discover the pathophysiological processes and possible biological mechanisms, providing assistance for therapeutics[34].

The most commonly used methods for animal models of depression include methods as following[5, 6, 7].The Chronic Unpredictable Mild Stress (CUMS) rodent model simulates the diverse and unpredictable physical and mental stimuli encountered in human daily life, and reflects some core symptoms of depression in humans.The Chronic Restraint Stress (CRS) model simulates deprivation of freedom. The Social Frustration Stress (SD) model simulates the pathogenesis of depression at the social level and explores the biological basis of stress recovery behavior that simulates MDD characteristics (referred to as "susceptibility").The learned helplessness (LH) model is exposed to inevitable stress and subsequently affects avoidance or coping abilities, possibly by inducing a "helpless" state.During this process, some biological changes will be observed in the depression model, including changes in indicators related to neural plasticity, such as expression of brain‑derived neurotrophic factor (BDNF)[8, 9]. Some studies have targeted the use of antidepressants for intervention, and the results have found that these indicators have normalized changes. This not only reveals the mechanism of depression, but also reveals the principle of action of antidepressants[8, 9, 10].

In recent years, research related to depression models has also involved mitogen-activated protein kinase (MAPK) family, which are some biological indicators related to cell apoptosis[10, 11]. Changes in these indicators were also found in successfully modeled depression models. More importantly, some antidepressants can also alter these indicators, further indicating that neuronal apoptosis may be related to the occurrence of depression, and also the anti apoptotic effect of antidepressants. These anti-apoptotic mechanisms involve normalization of related express protein[11, 12].

Lithium is a first-line drug and an effective mood stabilizer for bipolar disorder.Until today, lithium salt is still regarded as a classic drug to prevent mania and suicide in bipolar patients [13]. And lithium also have positive efficacy in bipolar depression[14].Many studies have shown that the clinical efficacy of lithium is related to its neuroprotective effect [15], but its mechanism is still unclear. But a study found that LiCl could down-regulate the apoptosis-related genes Caspase-3 and Bax, up-regulate Bcl-2, and down-regulate the inflammatory-related genes (NF-κB, NLRP3, TNF-α, and IL-1β) via inhibiting virus replication[16].

Apoptosis is a programmed cell death to maintain the stability of the internal environment. The occurrence and development of depression is usually accompanied by the apoptosis of nerve cells [17], so how to reduce the apoptosis of nerve cells is an important research direction in the treatment of depression.C-Jun N-terminal kinase (JNK) belongs to a class of kinases in the mitogen-activated protein kinase (MAPK) family [11]. A large number of research results show that JNK is activated to different degrees in the events of nerve atrophy, inflammatory reaction, oxidative stress and psychological stress, and these events are closely related to depression [18],When the JNK pathway is activated, the activated JNK can reactivate a variety of effector proteins, including transcription factors, to produce biological effects.C-Jun is the main downstream factor of JNK. Under activated conditions, JNK phosphorylates c-Jun and induces nerve cell apoptosis.It is worth exploring whether the therapeutic effect of lithium carbonate on depression is related to the nerve cells mediated by JNK/c-Jun pathway.In this study, we discuss whether lithium carbonate can reduce the apoptosis of nerve cells and improve the depressive symptoms of depression model mice through JNK/c-Jun pathway.。

Materials

Experimental Animals

Male C57BL/6 mice (weighing 22 ± 3 g, 8 weeks old) were used in this study. The mice was provided by Beijing Weitong Lihua Experimental Animal Co., Ltd., the production license number of experimental animals is [SCXK (Beijing) 2019-0011], and it is raised by the Experimental Animal Center of Zhejiang University of Traditional Chinese Medicine. The use license number of experimental animals is [SYXK (Zhejiang) 2019-0022].Mice are allowed to freely obtain food and water during a 12 hour light/dark cycle (with lights on at 09:00) in a room at 24 ± 1 ° C and a relative humidity of 50% -60%.All operations during this experiment comply with the Regulations on the Management of Experimental Animals of the People's Republic of China.This study was approved Animal Care and Use Ethic Committee of Zhejiang Chinese Medical University.The animal ethics number 20200622-04.

Thirty mice were randomly divided into three groups, namely blank control group, model group and Lithium carbonate group (model + Lithium carbonate), with 10 mice in each group.

Main Reagents and Drug

Lithium carbonate (Hunan Qianjin Xiangjiang Pharmaceutical Co., Ltd., batch number: H43020372); β- Actin( β- Actin antibody (Immunoway, batch number: YM3028-100ug),

c-Jun N-terminal kinase (JNK) antibody (Hua'an Biological Co., Ltd., batch number: RT1550), phosphorylated c-Jun N-terminal kinase (p-JNK) antibody (Hua'an Biological Co., Ltd., batch number: ET1609-42), c-Jun antibody (Hua'an Biological ,Co., Ltd. batch number: ET1608-3).

Phosphorylated c-Jun (p-c-Jun) antibody (SANTA CRUZ, batch number sc-822),

cysteine aspartic acid protease-3 (Caspase-3) antibody (Hua'an Biological Co., Ltd., batch number ER30804), B cell tumor/leukemia 2 (Bcl-2) antibody (Hua'an Biological Co., Ltd., batch number ER0602), apoptosis related protein Bcl-2 related X protein (Bax) antibody (Hua'an Biological Co., Ltd., batch number ET1603-34).

Main Instruments

SMART 3.0 Spontaneous Activity Video Analysis System Detection (Panlab/Rivald, Spain), SDS-PAGE Vertical Electrophoresis Tank (MP-8001, Beijing Kaiyuan Bole Biotechnology Co., Ltd.).

Methods

Model Establishment and Intervention

The chronic unpredictable mild stress (CUMS) program refers to the modeling method proposed by Chinese researcher et al. [19] and is slightly modified by methods of stress as following:(1) 12 hours of nighttime illumination; (2) abrosia for 24 hours; (3) binding for 4 hours; (4) wet pad material for 24 hours (200ml of water per cage); (5) swimming in ice water for 5 minutes (4 ℃); (6) water prohibition for 24 hours; (7) horizontal shaking of the rat cage for 10 minutes; (8) pinch the tail for 5 minutes (1cn from the end of the tail); (9) tilt the rat cage for 24 hours (45 °).Mice were randomly subjected to one of the above stimulation methods at different times every day, and did not continuously apply the same stimulation for two days. They were continuously stimulated for 8 weeks to establish a depression mouse model.The mice in the lithium carbonate group were given 75 mg/kg lithium carbonate by gavage at the end of the fourth week of modeling once a day to the end of eighth weekend.The mice in the model group were given the same amount of normal saline by gavage, while the mice in the control group did not receive any stimulation treatment, and were given the same amount of normal saline by gavage at the same time.

Behavioral Assessment

Behavioral assessment includes classic sugar water preference test(SPT), open field test (OFT). and forced swimming test(FST).The indicator of sugar preference experiment is sugar preference rate, which is sugar consumption/(sugar consumption + pure water consumption)× 100%. The observation indicators of the open field experiment are the number of times (times) of crossing the middle grid and the total distance (cm).The observation indicator of the forced swimming experiment is to record the time of immobility within 5 minutes after swimming by video camera.

Sample Collection

After the last behavioral test, mice were sacrificed by cervical dislocation. The brain tissue was removed and placed in pre-cooled PBS buffer. After washing off residual blood, the prefrontal cortex was quickly removed on the ice surface. The prefrontal cortex was separated and cut according to the three-dimensional localization map of the mouse brain, and stored in liquid nitrogen for subsequent Western Blot testing.

Western Blot Test

The preparation of total protein in the prefrontal cortex of mice in each group was carried out using 1 ml of cold RIPA buffer and supplemented with 1% PMSF

(phenylmethanesulfonyl flfluoride,Beyotime ST505), a protease inhibitor and phosphatase inhibitors. Before obtaining the protein supernatants, probes were ground and centrifuge at 12000 rpm at 4 ° C for 30 minutes.BCA assay was used the protein concentration was determined.20ug protein was transferred to polyvinylidene difluoride(PVDF) membrane after electrophoretic on 10% SDS-PAGE gel. Then,membranes were incubated with primary antibodies overnight at 4 ° C after blocking with 5% nonfat milk in TBS Tween 20, as follows:Phosphorylated c-Jun (p-c-Jun) antibody (SANTA CRUZ, batch number sc-822), Cysteine aspartic acid protease-3 (Caspase-3) antibody (Hua'an Biological Co., Ltd., batch number ER30804), B cell tumor/leukemia 2 (Bcl-2) antibody (Hua'an Biological Co., Ltd., batch number ER0602), apoptosis related protein Bcl-2 related X protein (Bax) antibody (Hua'an Biological Co., Ltd., batch number ET1603-34).The membrane was washed three times with TBS-Tween 20 (5 minutes each time) before incubating with the secondary antibody goat antirabbit IgG antibody (Biker, 1:5000) and goat anti-mouse IgG antibody (Biker, 1:50000) at room temperature for 2 hours.After the final washing step, an enhanced chemiluminescence reaction was performed on the membrane, and the bands were quantified by a densitometry (Quantity One 4.2, Bio Rad, Hercules, CA).Standardize the density value of the marker to the GAPDH level were normalized. Each experiment should be conducted at least three times. Image Studio Ver2.0 software was used for detection and quantification of each band.

Statistical Analysis

Statistical analysis was completed by Graph Pad Prism8 0 software. All data are mean ± standard deviation (\(\overline{x}\)± s). ANOVAs was used for multi analysis.Single factor analysis of variance was used for overall comparison between multiple groups, and t-test was used for mean comparison between the two groups, with P < 0 05 representing a statistically significant difference.

1.Effect of Lithium carbonate on behavior of stress mice

As shown in Fig. 1 and Table 1, the sugar preference in each group were statistically analyzed(F = 4.96,P = 0.032).The results of the mouse sugar preference experiment showed that compared with the control group, the stress group showed a significant decrease in sugar preference (P < 0.01); Compared with the stress group, the preference for sugar water in the stress + lithium group increased significantly (P < 0.01) (see Fig. 1 and Table 1).

2.Effects of Lithium carbonate on the total distance of exercise and the number of times of crossing in stress mice

The open field experiment includes two parts: the total distance of movement and the number of passes.As shown in Fig. 2A and Table 1, the total distance of movement in each group were statistically analyzed(F = 4.71,P = 0.045).The total exercise distance of mice showed a significant decrease in the stress group compared to the control group (P < 0.01);Compared with the stress group, the total distance of exercise in the Stress + Lithium group increased significantly (P < 0.01) ; As shown in Fig. 2B and Table 1, the number of times of passing through the grid in each group were statistically analyzed(F = 5.06,P = 0.026).The result also show that the number of times of passing through the grid in the stress group is significantly lower than that in the control group (P < 0.01). After treatment with Lithium carbonate, the number of times of passing through the grid in the stress + lithium group is significantly higher than that in the stress group (P < 0.01).see Fig. 2A, Fig. 2B and Table 1.

3.Effect of Lithium carbonate on immobility time in forced swimming of stress mice

As shown in Fig. 3 and Table 1, the immobility time in each group were statistically analyzed(F = 5.01,P = 0.026). The immobility time of the stress group mice was significantly longer than that of the control group (P < 0.01); However, after treatment with Lithium carbonate, the immobility time of mice in the stress + lithium group was significantly shorter than that in the stress group (P < 0.01) ,see Fig. 3 and Table 1.

4.Lithium carbonate on p-JNK/JNK、p-c-Jun/c-Jun in stress mice

As shown in Fig. 4, the p-JNK/JNK and p-c-Jun/c-Jun ratios in each group were statistically analyzed(F = 6.01, P = 0.001). The results showed that compared with the control group, the p-JNK/JNK, p-c-Jun/c-Jun ratios in the prefrontal cortex of the stress group mice were significantly increased (P < 0.01), Compared with the stress group, JNK, c-Jun phosphorylation levels in the prefrontal cortex of mice increase; p-JNK/JNK, p-c-Jun/c-Jun in the Stress + Lithium group decreased (P < 0 01).see Fig. 4 and Table 2.

Table 2

Comparison of p-JNK/JNK and p-cJun/c-Ju expression among three groups(%)
	p-JNK/JNK	p-cJun/c-Ju
Control group	0.29 ± 0.01	0.11 ± 0.05
Stress group	0.77 ± 0.06**	0.78 ± 0.04**
Stress + Lithium group	0.67 ± 0.05*#	0.48 ± 0.03*#
p-JNK/JNK:F = 6.01, P = 0.001;p-cJun/c-Ju:F = 6.66 = 0.001
Compared with the normal control group, ^* P ＜ 0.05, ^** P ＜ 0.01;Compared with the model group, ^#P ＜ 0.01.

5.Effect of Lithium carbonate on apoptosis protein in stress mice

As shown in Fig. 4, the Bcl-2, Bax and Caspase-3 in each group were statistically analyzed(F = 6.01, P = 0.001).Compared with the control group, the expression of Bcl-2 protein in the stress group decreased, while the levels of Bax and Caspase-3 increased (P < 0. 05) 01); Compared with the stress group, the expression of Bcl-2 protein in the stress + Lithium group increased, and the levels of Bax and Caspase-3 decreased (P < 0.01).see Fig. 5 and Table 3

Table 3

Comparison of apoptotic protein expression among three groups(%)
	Bax	Bcl-2	Caspase-3
Control group	0.22 ± 0.0.4	0.92 ± 0.04	0.12 ± 00.1
Stress group	0.61 ± 0.03**	0.10 ± 0.02**	0.71 ± 0.04**
Stress + Lithium group	0.49 ± 0.03*#	0.42 ± 0.07*#	0.41 ± 0.03*#
Bax:F = 5.67, P = 0.018;Bcl-2:F = 6.21, P = 0.001;Caspase-3:F = 5.21, P = 0.011p-cJun/c-Ju
Compared with the normal control group, ^* P ＜ 0.05, ^** P ＜ 0.01;Compared with the model group, ^#P ＜ 0.01.

Depression is one of the most common and prominent mental disorders in the world[1, 2]. At present, the incidence rate of depression is increasing year by year, which has become a research hot spot. In the research process, a reasonable animal model of depression is the key, mainly including environmental stress model, social stimulation model, surgical preparation model, Genetically modified animal model and postpartum depression model [20].Chronic Unpredictable Mild Stress (CUMS) is one of the classic methods for establishing depression models. Through long-term relatively mild and unpredictable human stimuli, animals exhibit depressive like behavior, and its etiology and pathological mechanism are similar to human depression. It has been widely accepted and applied in the establishment of depression animal models [21, 22].Depression like behavior can be detected through behavioral experiments such as sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST) [23,24]. The prefrontal cortex is one of the brain regions that cause mood disorders, and its functional changes play an important role in the pathogenesis of depression[21].

In our present study, we found that lithium carbonate treatment for 4 weeks alleviated depression-like behaviors via decreased the protein levels of nerve cells p-JNK/JNK, P-C-Jun/C-Jun,caspase-3 and Bax and increased Bcl-2 level significantly in the prefrontal cortex of CUMS mice. This means that in addition to the role of lithium in regulating other neurotransmitters, regulating autophagy and JNK/C-Jun signaling pathways may be another mode of action of lithium.This result is similar to LiCl could down-regulate the apoptosis-related genes Caspase-3 and Bax, up-regulate Bcl-2, and down-regulate the inflammatory-related genes (NF-κB, NLRP3, TNF-α, and IL-1β) via inhibiting virus replication[16].Bc1-2 is widely regarded as a major neuroprotective protein, and genetic strategies that increase bc1-2 levels have demonstrated not only robust protection of neurons against diverse insults, but have also demonstrated an increase in the regeneration of mammalian CNS axons[25].

Lithium carbonate is a classic emotional stabilizer. For a long time, lithium has been one of the main drugs for treating bipolar disorder. However, there is not yet a good understanding of the etiology or drug treatment mechanisms of this disease[26].In addition to its current use in patients with bipolar disorder, lithium can also be used to treat acute brain injury, such as stroke and chronic progressive neurodegenerative diseases.Chuang [27] found that lithium in primary neurons can induce cell proliferation near the injury site, accompanied by the loss of proliferating cells in the subventricular area, and some of these proliferating cells show the phenotype of neurons or astrocyte.Tushar Dwivedi et al. confirmed the mechanism of lithium mediated BDNF protection in rat hippocampal neurons [28]. The loss of proximal prefrontal cortex volume in bipolar disorder patients receiving lithium carbonate therapy was suppressed [29].Since the neuroprotective effect of lithium may be related to clinical improvement, Lithium carbonate is closely related to its neuroprotective effect and improvement of depressive symptoms, which is worth studying.

In this experiment, mice were found to experience of anhedonia after being modeled by CUMS, characterized by a significant decrease in the sugar preference index of the model mice; In open field experiments, there is a decrease in autonomous activity, shorter movement distance, and a decrease in the number of grid crossings; In the forced swimming experiment, the time of immobility was prolonged. But these indexes all increased after the treatment with Lithium carbonate, which indicated that Lithium carbonate could improve the depressive symptoms of depressed mice.

At the molecular level, JNK signaling pathway is a member of the Mitogen activated protein kinase (MAPK) family, and can participate in cell proliferation, differentiation, apoptosis, intracellular and extracellular signal transduction and other processes [30].The activation of JNK is common in various neurodegenerative diseases, and recent studies have gradually confirmed the important role of JNK activation in the regulation of depressive behavior [31].YU et al. showed that Curcumin can inhibit cell apoptosis by inhibiting JNK/c-Jun signaling pathway, down regulating caspase-3 protein expression[32] .In recent years, its use in antidepressant treatment has been carried out in clinic or experiment. Evidence-based medicine has more evidence to confirm the antidepressant effect of Curcumin with great effect size[33],which has been considered as a potential antidepressant[34].In many studies, curcumin has shown efficacy in regulating neurotransmitter concentration, inflammatory pathways, excitotoxicity, neural plasticity, hypothalamic pituitary adrenal disorders, insulin resistance, oxidative and nitrous stress, and endogenous cannabinoid systems, all of which can participate in the pathophysiology of MDD[35]. One of more anti-depession mechanism is the activation of JNK.

This study show that lithium carbonate has potential points of action on the JNK/c-Jun pathway. Compared with the control group, the expression levels of apoptotic protein Bax and caspase-3 in the model group were significantly increased, and the level of anti apoptotic protein Bcl-2 was decreased, which all reversed after treatment with Lithium carbonate. The levels of apoptotic protein Bax and caspase-3 were decreased, and the level of anti-apoptotic protein Bcl-2 was increased by lithium carbonate.These results indicate that the antidepressant mechanism of Lithium carbonate is partly through inhibiting JNK/c-Jun, reducing the expression of pro apoptotic protein Bax and Caspase-3, and increasing the level of anti apoptotic protein Bcl-2 that produce reducing neuronal apoptosis.In fact, the effect of Lithium carbonate on depressive symptoms is also reliable in clinical practice[36].

This study also has the following aspects of insufficient. Firstly,as an antidepressant effect study of drugs, a control group of antidepressants should be set up. Unfortunately, this control group was not set up.Secondly,as an antidepressant effect study of mood stabilizer, a control group of a mood stabilizer should be set up. Unfortunately, this control group was also not set up.Thirdly,to study the therapeutic effects of drugs, it is necessary to investigate the differences in effects under different doses. Unfortunately, such a research design has not be designed. Because study found that role of low (0.2 mmol/kg) and high dose (2 mmol/kg) lithium and revealed that high dose lithium group was the most mobile so the least depressed in the tail suspension test[37].

1. Ethics approval and consent to participate

This study was approved Ethic Committee About Animal Study of Zhejiang Chinese Medical University(20200622-04).

2.Consent to publication

All authors agree to publish our paper and no conflict in any interests.

3.Availability of data and material.

The data used to support the findings of this study are available from the corresponding author upon request.

4.Competing interests

There were not any financial and non-financial competing interests.

5.Funding

This study was supported by Peak Subject of Psychiatry,Tongde Hospital of Zhejiang Province,Zhejiang Province mental Health Center(PSP2023-010)

6.Author’s contribution

Our authors have different contributions to this article and study.Prof.JWD participated in project design, some laboratory work, most statistical analysis, writing papers, and seeking funding.Dr.JHY participated in behavior observation work, part statistical analysis, research reference.Dr.CFP and Dr.LJ participated in some behavior observationsl, most laboratory test.Prof.SFL participated in part project design, some laboratory work and some writings and final review of article.

7.Acknowledgment

We thank Prof Fang Marong (Zhejiang University) give us good idea about this study and Mr Wang Zhiqiang(Tsinghua University) help us retrieval of literature. We thank Ms Ren Xin(Zhejiang Province Mental Health Center)help us in part of statistic.We thanks Prof Ma Yongchun(Zhejiang Province Mental Health Center) in final revision of the article.Especially,we thank laboratory of Zhejiang Chinese Medical University in series measures and test of biomarker in this study.

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Lithium Carbonate Alleviate Neuronal Apoptosis to Improve Depression Symptoms in Mice by the JNK/c-Jun Signaling Pathway

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Materials

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Model Establishment and Intervention

Behavioral Assessment

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