Effects of transcranial photobiomodulation on peripheral biomarkers associated with oxidative stress and complex IV activity in the prefrontal cortex in rats subjected to chronic mild stress

Why this preprint is important:

The search for new therapies is an important step when looking into any health conditions, but I wound say particularly when talking about mood disorders and mental health conditions. The photobiomodulation therapy discussed in this preprint is on the rise due to its non-invasive nature. This article seeks to elucidate if transcranial photobiomodulation is capable to improve mood disorders in a model of chronic mild stress, correlating this with major depressive disorder.  In fact, this study can provide important insights helping us to understand the mechanisms, consequences, safety, and compartmental improvements of photobiomodulation therapy for major depressive disorder.

Background:

Photobiomodulation therapy (tPBM) is based on the application of radiation in the red and infrared wavelengths range emitted by sources, such as lasers and LEDs, at low powers [1]. It has applications in wound healing, pain relief, modulation of inflammatory cytokines and more recently, in mood disorders such major depressive disorder, anxiety disorder and bipolar disorder [2, 3, 4].

Major depressive disorder (MDD) affects approximately 185 million individuals worldwide according the Global Burden of Disease Collaborative Network [5]. Approximately one-third of individuals diagnosed with MDD, fail to achieve a satisfactory clinical response with medical intervention, such as pharmacological drugs and psychotherapies [6]. Therefore, the search for new medical approaches to treat mood disorders is necessary.

In this preprint, the authors aim to verify whether tPBM can be a promising treatment for MDD, and the main objective is to analyze the impact 2 different wavelengths (red 600 nm and NIR 840 nm) on behavioral, peripheral, and central biological parameters related to the pathophysiology of MDD in a Chronic Mild Stress (CMS) model.

Key findings:

tPBM alleviates anhedonic behavior in rats submitted to a chronic stress protocol

In this study, Wistar rats were subjected to 30 days of sucrose consumption. Rats who were then also subjected to the Chronic Mild Stress protocol reduced their sucrose consumption, which is characteristic of anhedonic behavior, that means, the rats lost the interest by activities that gave him gratification [7]. The authors demonstrate that tPBM enhance the sucrose consumption, alleviating the anhedonic behavior of rats submitted to a chronic stress protocol.

tPBM lowers lipid oxidation and thereby oxidative stress

The authors found that rats treated with both red and infrared wavelengths showed lower Thiobarbituric acid reactive substances (TBARS) levels compared to sham stimulation, although only the red wavelength group demonstrated statistical significance (p=0.0048). These findings suggest that tPBM, particularly when using the red wavelenght, lowers lipid peroxidation, indicating an improvement in oxidative stress.

tPBM increases nitric oxide levels in the hippocampus which may be correlated with the increased activity of mitochondrial complex IV

Finally, the authors found that nitric oxide (NO) levels within the hippocampus of rats treated with infrared wavelengths significantly increased compared to the sham stimulated rats (p=0.013). As for cytochrome C oxidase (CCO) activity, the infrared wavelenghts group exhibited higher levels than the red wavelengths group (p=0.012), and it was similar to the control (non-stress) group. However, the red wavelengths group showed lower CCO activity levels than other groups. The authors suggest that tPBM, particularly with infrared wavelenghts, increases NO levels in the hippocampus of treated animals by dissociation from CCO, and this may be correlated with the increased activity of mitochondrial complex IV. Together, these findings suggest that tPBM provides systemic and central nervous system antioxidant properties, improving the metabolism of irradiated area, also contributinf to the antidepressant effect.

Questions and comments:

Major aspects

Q1: Several studies on photobiomodulation raise questions about the characteristics of the devices. One of them is whether lasers and LEDS can induce the photobiomodulation [1]. In the literature, there is a debate regarding the radiation characteristics, such as coherence and collimation (Parallel and in-phase radiation beams, respectively), of lasers and LEDs to promote photobiomodulation. Therefore, could the authors perhaps give more details regarding the choice of using LEDs instead lasers (or both) to promote photobiomodulation in this study?

Q2: Related to question 1, the characteristics of coherence and collimation could be relevant here? This is an interesting discussion, since the scientific community has not yet reached a consensus about that characteristic of lasers and LEDs. Could the authors perhaps considerer this topic briefly in their discussion section.

Q3: The Wistar rats were housed in standard temperature conditions (22 ± 2°C). However, these temperatures do not represent the thermoneutral temperature of these animals (30 ± 2°C). Could this be seen as a potential confounding factor since the difference of temperature can be a stress factor itself.

Q4: In the Materials and Methods section, the authors state that: “stress was induced once or twice daily”. Could the authors might explain what the conditions were for subjecting the rats to stressors twice a day?

Q5: Since this is a study that subjects animals to stress conditions, would it be interesting to evaluate cortisol levels as well?

Q6: The authors correlate the increase of nitric oxide (NO) levels in the hippocampus with the increase of cytochrome c oxidase (CCO) activity in the prefrontal cortex after photobiomodulation with infrared LED in the discussion (p12, last paragraph). However, it is my understanding that the effect observed should be opposite (= increase of NO, reduction of CCO activity) [11]. Could the authors please review this correlation?

Q7: Related to Q6, the tissues analyzed were different (prefrontal cortex vs. hippocampus). Could the authors justify the correlation between the data knowing that the regions of the brain analyzed were different.

Minor aspects

Q8: In preprint figure 1, Could the authors perhaps consider using differently colored lines for the control, sham, red and infrared groups? Also, could you please increase the font size?

Q9: In section 3.3.2 it was stated that: “In contrast, the red group showed lower CCO levels than other groups (p<0.05)”, but this is not represented in figure 6. Could the authors clarify this?

Q10: What could explain the effect observed that red LEDs  reduce CCO activity? This is interesting results since red light is absorbed by CCO and was expected a increase the electron transport, and thereby its activity [10].

Disclaimer

For the redaction of this report, was used the google translate, and Grammarly.

References:

[1] V. Heiskanen, M. R. Hamblin, Photobiomodulation: lasers vs. light emitting diodes? Photochem. Photobiol. Sci. 17(8) (2018) 1003-1017. https://doi.org/10.1039/c8pp90049c

[2] M. F. De Oliveira, D. D. Johnson, T. Demchak, S. S. Tomazoni, E. C. Leal-Junior, Low-intensity LASER and LED (photobiomodulation therapy) for pain control of the most common musculoskeletal conditions, Eur. J. Rehabil. Med. 58(2) (2021) 282-289. doi: 10.23736/S1973-9087.21.07236-1

[3] R. C. Mosca, A. A. Ong, O. Albasha, K. Bass, P. Arany, Photobiomodulation Therapy for Wound Care: A Potent, Noninvasive, Photoceutical Approach, Adv. Skin Wound Care, 32(4) (2019) 157-167 doi: 10.1097/01.ASW.0000553600.97572.d2

[4] K. Montazeri, M. Farhadi, R. Fekrazad, S. Chaibakhsh, S. Mahmoudian, Photobiomodulation therapy in mood disorders: a systematic review, Lasers Med. Sci. 37(9) (2022) 3343-3351. https://doi.org/10.1007/s10103-022-03641-w

[5] W. Marx, B. W. J. H. Penninx, M. Solmi, T. A. Furukawa, J. Firth, A. F. Carvalho, M. Berk, Major depressive disorder, Nat. Rev. Dis. Pri. 44 (2023). https://doi.org/10.1038/s41572-023-00454-1

[6] R.H. McAllister Williams, C. Arango, P. Blier, K. Demyttenaere, P. Falkai, P. Gorwood, M. Hopwood, A. Javed, S. Kasper, G.S. Malhi, J.C. Soares, E. Vieta, A.H. Young, A. Papadopoulos, A.J. Rush, The identification, assessment and management of difficult-to-treat depression: An international consensus statement, J. Affect. Disord. 267 (2020) https://doi.org/10.1016/j.jad.2020.02.023

[7] M. Papp, Models of affective illness: Chronic Mild Stress in the Rat, Curr. Prot. Pharm. 57(1) (2012) https://doi.org/10.1002/0471141755.ph0509s57

[8] J. A. D. De Leon, C. R. Borges, Evaluation of Oxidative Stress in Biological Samples Using the Thiobarbituric Acid Reactive Substances Assay, J. Vis. Exp. 12(159) (2020) doi: 10.3791/61122

[9] M. R. Hamblin, Mechanisms and Mitochondrial Redox Signaling in Photobiomodulation, Photochem. Photobiol, 94(2) (2018) 199-212. https://doi.org/10.1111/php.12864

[10] O. Blanco-Prieto, J. Catalán, L. Trujillo-Rojas, A. Peña, M. M. R. Álamo, M. Llavanera, S. Bonet, J. M. Fernández-Novell, M. Yeste, J. E. Rodríguez-Gil, Red LED Light Acts on the Mitochondrial Electron Chain of Mammalian Sperm via Light-Time Exposure-Dependent Mechanisms, Cells 9(2020) doi:10.3390/cells9122546

Tags: animal behavior, biochemistry, oxidative stress, photobiomodulation

doi: https://doi.org/10.1242/prelights.41684

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