Tianeptine, olanzapine and fluoxetine show similar restoring effects on stress induced molecular changes in mice brain: An FT-IR study

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Highlights

  • We investigated UCMS-induced changes and restoring effects of tianeptin, olanzapine and fluoxetine on these alterations on mice brain.

  • We approximated lipid peroxidation, membrane dynamics, packing of membrane lipids and lipid, protein content.

  • we emerged the changes in proteins secondary structure, and relatively obtained information about their performance.

Abstract

Chronic stress which can cause a variety of disorders and illness ranging from metabolic and cardiovascular to mental leads to alterations in content, structure and dynamics of biomolecules in brain. The determination of stress-induced changes along with the effects of antidepressant treatment on these parameters might bring about more effective therapeutic strategies. In the present study, we investigated unpredictable chronic mild stress (UCMS)-induced changes in biomolecules in mouse brain and the restoring effects of tianeptine (TIA), olanzapine (OLZ) and fluoxetine (FLX) on these variations, by Fourier transform infrared (FT-IR) spectroscopy. The results revealed that chronic stress causes different membrane packing and an increase in lipid peroxidation, membrane fluidity. A significant increment for lipid/protein, Cdouble bondO/lipid, CH3/lipid, CH2/lipid, PO2/lipid, COO/lipid and RNA/protein ratios but a significant decrease for lipid/protein ratios were also obtained. Additionally, altered protein secondary structure components were estimated, such as increment in random coils and beta structures. The administration of TIA, OLZ and FLX drugs restored these stress-induced variations except for alterations in protein structure and RNA/protein ratio. This may suggest that these drugs have similar restoring effects on the consequences of stress activity in brain, in spite of the differences in their action mechanisms. All findings might have importance in understanding molecular mechanisms underlying chronic stress and contribute to studies aimed for drug development.

Introduction

Stress, a widely used word in our daily life, is generally defined as the responses to severe demands on the body. It has been well established that chronic stress may trigger biochemical mechanisms that can cause a variety of disorders ranging from metabolic and cardiovascular to mental [1], especially when it is followed by anxiety and depression [2]., Chronic stress has been pointed out as one of the main factors for depression although there are also some other risks for its development [3]. According to depression-related stress statistics of World Health Organization (WHO), 121 million people worldwide are estimated to suffer from depression; and by the year of 2030 depression is projected to be the second factor for the cause of disease burden worldwide [4].

Many different types of medications are available for treatment of depression, potentially caused by stress. Among such agents, fluoxetine, also known by trade names Prozac and Sarafem, (FLX), is a selective serotonin (5-HT) reuptake inhibitor (SSRI) which reverses the effects of stress on brain plasticity. This drug is commonly prescribed for treating major depression due to its tolerability and safety [5], [6]. A typical antidepressant tianeptine, (brand names Stablon, Coaxil, Tatinol, Tianeurax and Salymbra) (TIA) has an opposite action mechanism to SSRIs. It exerts its action by selectively either enhancing or facilitating 5-HT uptake [7], [8]. Both FLX and TIA diminish the neuronal degeneration caused by depression. Olanzapine (originally branded Zyprexa) (OLZ) is an atypical antipsychotic, which is also proposed to have antidepressant-like activity via both serotonergic and dopaminergic receptors [9]. Even though these kinds of agents have been used for many years, 30% of patients do not respond to pharmacological treatment. This may be due to the limited understanding of pathophysiology of stress activity [10]. Thus, further studies are needed to broaden in order to develop novel strategies for stress-related disorders and illness including depression [11].

Stress-based animal models serve for antidepressant drug development. One of these models is unpredictable chronic mild stress (UCMS). Upon exposing to different stressors UCMS-mice/rats exhibit degradation in the physical coat state, a decrease in the grooming behavior and an increase in aggression. All are reflective of clinical depression, most of which can be reversed by antidepressant agents, illustrating a strong predictive validity [6], [12], [13]. Therefore, UCMS model has been accepted as a reliable model to screen antidepressants.

It has been reported that stress can produce some changes in brain structures, which might affect its functions [14], [15], [16]. The alterations in content and structure of biomolecules are probably responsible for these observed structural changes in brain. Accordingly, understanding of these variations provides the identification of stress-induced pathologies, which in turn facilitates development of drug therapies to target these defects.

The evaluation and validation of stress target biomarker might imply costly and lengthy processes. An ideal test providing simultaneous information about biomolecules requires poor sample manipulation and it has to be possibly non-invasive, and reliable. Fourier transform infrared (FT-IR) spectroscopy is a suitable method for this purpose, since it has high sensitivity in detecting changes in the functional groups belonging to tissue components such as lipids, proteins, carbohydrates and nucleic acids, simultaneously [17], [18], [19], [20], [21], [22], [23], [24]. The shift in peak positions, bandwidth and peak area/intensity parameters gives valuable information, all of which can be used for identification of disease-states in a variety of biological samples such as tissues, membranes, cells and biofluids. Therefore, this technique has been widely employed for diagnosis of several diseases and the effects of selected drugs on disease conditions [17], [18], [20], [21], [22], [23], [25], [26], [27], [28], [29], [30], [31], [32]. By taking the advantages of FT-IR spectroscopy, we aimed to acquire an overview about how stress affects content and structure of biomolecules in mice brain and the potency of three different drugs (TIA, OLZ and FLX) to restore these variations, which have not been reported previously to our knowledge. In the current study, we obtained relative information about UCMS-induced alterations in the quantity of lipid, protein and RNA molecules, membrane lipid packing, membrane fluidity, membrane order and lipid peroxidation along with the impacts of TIA, OLZ and FLX on these molecular alterations. Moreover, by detailed analysis of Amide I mode we also predicted the changes in protein secondary structures.

Section snippets

Chemicals

TIA, OLZ and FLX were supplied as gift from Gata University, Biopharma and Deva, in Turkey, respectively. Potassium bromide (KBr) was purchased from Sigma Chemical Company (Sigma Chemical Co., St. Louis, MO, USA). All chemicals were used without further purification.

Animals

Male 7–8 weeks-old BALB/c ByJ mice (MAM TUBITAK, Gebze, Kocaeli, Turkey) weighing 35–45 g were housed five-six per home cages (L30 × W20 × h12.5 cm) in an animal colony facility for 2 weeks before the experiments. At first stage,

Results and discussion

Conne's advantage of FT-IR spectroscopy, which supports spectral interpretation with the aid of post-acquisition data manipulation algorithms, facilitates identification of biomolecules in high resolution because each mode under investigation has the minimum peak interval that can be distinguished. Thus, the vibrations of functional groups present in the biomolecules represent a variety of different modes appeared at distinct wavenumber values in an absorption FT-IR spectrum of brain tissue.

Conclusion

To our knowledge, this study for the first time demonstrated stress-induced alterations at molecular level by monitoring the FT-IR spectral parameters in detail. Our findings revealed that chronic stress caused significant changes in the macromolecular content and structure that may contribute to the development of stress activity. Notably, a significant increase in lipid/protein, Cdouble bondO/lipid, CH3/lipid, CH2/lipid, PO2/lipid, COO /lipid and RNA/protein ratios, lipid peroxidation, membrane

Conflict of interest

Authors declare that there is no conflict of interest.

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