Skip to main content

Advertisement

Log in

Effects of Chronic Photobiomodulation with Transcranial Near-Infrared Laser on Brain Metabolomics of Young and Aged Rats

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Since laser photobiomodulation has been found to enhance brain energy metabolism and cognition, we conducted the first metabolomics study to systematically analyze the metabolites modified by brain photobiomodulation. Aging is often accompanied by cognitive decline and susceptibility to neurodegeneration, including deficits in brain energy metabolism and increased susceptibility of nerve cells to oxidative stress. Changes in oxidative stress and energetic homeostasis increase neuronal vulnerability, as observed in diseases related to brain aging. We evaluated and compared the cortical and hippocampal metabolic pathways of young (4 months old) and aged (20 months old) control rats with those of rats exposed to transcranial near-infrared laser over 58 consecutive days. Statistical analyses of the brain metabolomics data indicated that chronic transcranial photobiomodulation (1) significantly enhances the metabolic pathways of young rats, particularly for excitatory neurotransmission and oxidative metabolism, and (2) restores the altered metabolic pathways of aged rats towards levels found in younger rats, mainly in the cerebral cortex. These novel metabolomics findings may help complement other laser-induced neurocognitive, neuroprotective, anti-inflammatory, and antioxidant effects described in the literature.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Anders JJ, Lanzafame RJ, Arany PR (2015) Low-level light/laser therapy versus photobiomodulation therapy. Photomed Laser Surg 33:183–184

    Article  PubMed  PubMed Central  Google Scholar 

  2. Arany PR (2016) Craniofacial wound healing with photobiomodulation therapy: new insights and current challenges. J Dent Res 95:977–984

    Article  CAS  PubMed  Google Scholar 

  3. Chung H, Dai T, Sharma SK, Huang YY, Carroll JD, Hamblin MR (2012) The nuts and bolts of low-level laser (light) therapy. Ann Biomed Eng 40:516–533

    Article  PubMed  Google Scholar 

  4. Eells JT, Wong-Riley MT, VerHoeve J, Henry M, Buchman EV, Kane MP, Gould LJ, Dias R et al (2004) Mitochondrial signal transduction in accelerated wound and retinal healing by near-infrared light therapy. Mitochondrion. 4:559–567

    Article  CAS  PubMed  Google Scholar 

  5. Rojas JC, Gonzalez-Lima F (2011) Low-level light therapy of the eye and brain. Eye Brain 3:49–67

    PubMed  PubMed Central  Google Scholar 

  6. Shinhmar H, Grewal M, Sivaprasad S, Hogg C, Chong V, Neveu M, Jeffery G (2020) Optically improved mitochondrial function redeems aged human visual decline. J Gerontol Ser A 75:e49–e52

    Article  Google Scholar 

  7. Wong-Riley MT, Liang HL, Eells JT, Chance B, Henry MM, Buchmann E, Kane M, Whelan HT (2005) Photobiomodulation directly benefits primary neurons functionally inactivated by toxins: role of cytochrome c oxidase. J Biol Chem 280:4761–4771

    Article  CAS  PubMed  Google Scholar 

  8. Holanda VM, Chavantes MC, Wu X, Anders JJ (2017) The mechanistic basis for photobiomodulation therapy of neuropathic pain by near infrared laser light. Lasers Surg Med 49:516–524

    PubMed  Google Scholar 

  9. El Khoury H, Mitrofanis J, Henderson LA (2019) Exploring the effects of near infrared light on resting and evoked brain activity in humans using magnetic resonance imaging. Neuroscience. 422:161–171

    Article  PubMed  Google Scholar 

  10. Mitrofanis J, Henderson LA (2020) How and why does photobiomodulation change brain activity? Neural Regen Res 15:2243–2244

    Article  PubMed  PubMed Central  Google Scholar 

  11. Rojas JC, Gonzalez-Lima F (2013) Neurological and psychological applications of transcranial lasers and LEDs. Biochem Pharmacol 86:447–457

    Article  CAS  PubMed  Google Scholar 

  12. Wang X, Tian F, Reddy DD, Nalawade SS, Barrett DW, Gonzalez-Lima F, Liu H (2017) Up-regulation of cerebral cytochrome-c-oxidase and hemodynamics by transcranial infrared laser stimulation: a broadband near-infrared spectroscopy study. J Cereb Blood Flow Metab 37:3789–3802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang X, Dmochowski JP, Zeng L, Kallioniemi E, Husain M, Gonzalez-Lima F, Liu H (2019) Transcranial photobiomodulation with 1064-nm laser modulates brain electroencephalogram rhythms. Neurophotonics. 6:025013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Oron A, Oron U, Streeter J, Taboada L, Alexandrovich A, Trembovler V, Shohami E (2007) Low-level laser therapy applied transcranially to mice following traumatic brain injury significantly reduces long-term neurological deficits. J Neurotrauma 24:651–656

    Article  Google Scholar 

  15. De Taboada L, Yu J, El-Amouri S, Gattoni-Celli S, Richieri S, McCarthy T, Kindy MS (2011) Transcranial laser therapy attenuates amyloid-β peptide neuropathology in amyloid-β protein precursor transgenic mice. J Alzheimers Dis 23:521–535

    Article  PubMed  Google Scholar 

  16. Mitrofanis J, Jeffery G (2018) Does photobiomodulation influence ageing? Aging (Albany NY) 10:2224–2225

    Article  Google Scholar 

  17. Mattson MP, Magnus T (2006) Ageing and neuronal vulnerability. Nat Rev Neurosci 7:278–294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Boveris A, Navarro A (2008) Brain mitochondrial dysfunction in aging. IUBMB Life 60:308–314

    Article  CAS  PubMed  Google Scholar 

  19. Yin F, Boveris A, Cadenas E (2014) Mitochondrial energy metabolism and redox signaling in brain aging and neurodegeneration. Antioxid Redox Signal 20:353–371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Petit-Taboue MC, Landeau B, Desson JF, Desgranges B, Baron JC (1988) Effects of healthy aging on the regional cerebral metabolic rate of glucose assessed with statistical parametric mapping. Neuroimage. 7:176–184

    Article  Google Scholar 

  21. Miccheli A, Puccetti C, Capuani G, Di Cocco ME, Giardino L, Calzà L, Bettaglia A, Battistin L et al (2003) [1-13C] Glucose entry in neuronal and astrocytic intermediary metabolism of aged rats: a study of the effects of nicergoline treatment by 13C NMR spectroscopy. Brain Res 966:116–125

    Article  CAS  PubMed  Google Scholar 

  22. Martínez A, Portero-Otin M, Pamplona R, Ferrer I (2010) Protein targets of oxidative damage in human neurodegenerative diseases with abnormal protein aggregates. Brain Pathol 20:281–297

    Article  PubMed  Google Scholar 

  23. Dubey A, Forster MJ, Lal H, Sohal RS (1996) Effect of age and caloric intake on protein oxidation in different brain regions and on behavioral functions of the mouse. Arch Biochem Biophys 333:189–197

    Article  CAS  PubMed  Google Scholar 

  24. Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA (2004) Gene regulation and DNA damage in the ageing human brain. Nature. 429:883–891

    Article  CAS  PubMed  Google Scholar 

  25. Butterfield DA, Perluigi M, Reed T, Muharib T, Hughes CP, Robinson RA, Sultana R (2012) Redox proteomics in selected neurodegenerative disorders: from its infancy to future applications. Antioxid Redox Signal 17:1610–1655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Vargas E, Barrett DW, Saucedo CL, Huang LD, Abraham JA, Tanaka H, Haley AP, Gonzalez-Lima F (2017) Beneficial neurocognitive effects of transcranial laser in older adults. Lasers Med Sci 32:1153–1162

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, Lewis GD, Fox CS et al (2011) Metabolite profiles and the risk of developing diabetes. Nat Med 17:448–453

    Article  PubMed  PubMed Central  Google Scholar 

  28. Xia J, Sinelnikov IV, Han B, Wishart DS (2015) MetaboAnalyst 3.0--making metabolomics more meaningful. Nucleic Acids Res 43:W251–W257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. CIOMS (1985) International guiding principles for biomedical research involving animals. Altern Lab Anim 12:ii

    Google Scholar 

  30. Paxinos G, Watson C (2006) The rat brain in stereotaxic coordinates. Ed 6. Academic, Amsterdam

  31. Almeida P, Lopes-Martins RÁ, Tomazoni SS, Albuquerque-Pontes GM, Santos LA, Vanin AA, Frigo L, Vieira RP et al (2013) Low-level laser therapy and sodium diclofenac in acute inflammatory response induced by skeletal muscle trauma: effects in muscle morphology and mRNA gene expression of inflammatory markers. Photochem Photobiol 89:501–507

    Article  PubMed  Google Scholar 

  32. Haslerud S, Lopes-Martins RA, Frigo L, Bjordal JM, Marcos RL, Naterstad IF, Magnussen LH, Joensen J (2017) Low-level laser therapy and cryotherapy as mono- and adjunctive therapies for Achilles tendinopathy in rats. Photomed Laser Surg 35:32–42

    Article  CAS  PubMed  Google Scholar 

  33. Naterstad IF, Rossi RP, Marcos RL, Parizzoto NA, Frigo L, Joensen J, Lopes Martins PSL, Bjordal JM et al (2018) Comparison of photobiomodulation and anti-inflammatory drugs on tissue repair on collagenase-induced Achilles tendon inflammation in rats. Photomed Laser Surg 36:137–145

    Article  CAS  PubMed  Google Scholar 

  34. Tomazoni SS, Leal-Junior EC, Pallotta RC, Teixeira S, de Almeida P, Lopes-Martins RÁ (2017) Effects of photobiomodulation therapy, pharmacological therapy, and physical exercise as single and/or combined treatment on the inflammatory response induced by experimental osteoarthritis. Lasers Med Sci 32:101–108

    Article  PubMed  Google Scholar 

  35. Morries LD, Cassano P, Henderson TA (2015) Treatments for traumatic brain injury with emphasis on transcranial near-infrared laser phototherapy. Neuropsychiatr Dis Treat 11:2159–2175

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Henderson TA, Morries LD (2015) Near-infrared photonic energy penetration: can infrared phototherapy effectively reach the human brain? Neuropsychiatr Dis Treat 11:2191–2208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Carreras AL, Mattos-Dutra A, Meirelles R, Rocha BB, Wannmacher CMD, Pessoa-Pureur R (2000) Phenylalanine inhibition of the phosphorylation of cytoskeletal proteins from cerebral cortex of young rats is prevented by alanine. Eur J Clin Investig 30:536–542

    Article  CAS  Google Scholar 

  38. Katsuki H, Watanabe Y, Fujimoto S, Kume T, Akaike A (2007) Contribution of endogenous glycine and d-serine to excitotoxic and ischemic cell death in rat cerebrocortical slice cultures. Life Sci 81:740–749

    Article  CAS  PubMed  Google Scholar 

  39. Meldrum BS (2000) Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr 130:1007S–1015S

    Article  CAS  PubMed  Google Scholar 

  40. Stefanic P, Dolenc MS (2004) Aspartate and glutamate mimetic structures in biologically active compounds. Curr Med Chem 11:945–968

    Article  CAS  PubMed  Google Scholar 

  41. Ault B, Wang CM, Yawn BC (1987) L-proline depolarizes rat spinal motoneurones by an excitatory amino acid antagonist-sensitive mechanism. Br J Pharmacol 92:319–326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Henzi V, Reichling DB, Helm SW, MacDermott AB (1992) L-proline activates glutamate and glycine receptors in cultured rat dorsal horn neurons. Mol Pharmacol 41:793–801

    CAS  PubMed  Google Scholar 

  43. Martin D, Ault B, Nadler JV (1992) NMDA receptor-mediated depolarizing action of proline on CA1 pyramidal cells. Eur J Pharmacol 219:59–66

    Article  CAS  PubMed  Google Scholar 

  44. Pace JR, Brian M, Paul SM, Rogawski MA (1992) High concentrations of neutral amino acids activate NMDA receptor currents in rat hippocampal neurons. Neurosci Lett 141:97–100

    Article  CAS  PubMed  Google Scholar 

  45. Konstantinović LM, Jelić MB, Jeremić A, Stevanović VB, Milanović SD, Filipović SR (2013) Transcranial application of near-infrared low-level laser can modulate cortical excitability. Lasers Surg Med 45:648–653

    Article  PubMed  Google Scholar 

  46. Aoyama K, Nakaki T (2015) Glutathione in cellular redox homeostasis: association with the excitatory amino acid carrier 1 (EAAC1). Molecules. 20:8742–8758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rae CD, Williams SR (2017) Glutathione in the human brain: review of its roles and measurement by magnetic resonance spectroscopy. Anal Biochem 529:127–143

    Article  CAS  PubMed  Google Scholar 

  48. Puig MV, Antzoulatos EG, Miller EK (2014) Prefrontal dopamine in associative learning and memory. Neuroscience. 282:217–229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shnitko TA, Taylor SC, Stringfield SJ, Zandy SL, Cofresí RU, Doherty JM, Lynch WB, Boettiger CA et al (2016) Acute phenylalanine/tyrosine depletion of phasic dopamine in the rat brain. Psychopharmacology. 233:2045–2054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rojas JC, Gonzalez-Lima F (2017) Transcranial low-level laser light therapy for neurocognitive enhancement. In: Hamblin MR, Sousa MV, Agrawal T (eds) Handbook of low-level laser therapy. Pan Stanford Publishing, Singapore, pp. 1057–1076

    Google Scholar 

  51. Rojas JC, Bruchey AK, Gonzalez-Lima F (2012) Low-level light therapy improves cortical metabolic capacity and memory retention. J Alzheimers Dis 32:741–752

    Article  PubMed  Google Scholar 

  52. Wong-Riley MT (2012) Bigenomic regulation of cytochrome c oxidase in neurons and the tight coupling between neuronal activity and energy metabolism. Adv Exp Med Biol 748:283–304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Banik D, Kundu S, Banerjee P, Dutta R, Sarkar N (2017) Investigation of fibril forming mechanisms of l-phenylalanine and l-tyrosine: microscopic insight toward phenylketonuria and tyrosinemia type II. J Phys Chem B 121:1533–1543

    Article  CAS  PubMed  Google Scholar 

  54. Blau N, van Spronsen FJ, Levy HL (2010) Phenylketonuria. Lancet 376:1417–1427

    Article  CAS  PubMed  Google Scholar 

  55. Francis DEM, Kirby DM, Thompson GN (1992) Maternal tyrosinaemia II: management and successful outcome. Eur J Pediatr 151:196–199

    Article  CAS  PubMed  Google Scholar 

  56. Huttenlocher PR (2000) The neuropathology of phenylketonuria: human and animal studies. Eur J Pediatr 159:S102–S106

    Article  PubMed  Google Scholar 

  57. Gabbita SP, Lovell MA, Markesbery WR (1998) Increased nuclear DNA oxidation in the brain in Alzheimer’s disease. J Neurochem 71:2034–2040

    Article  CAS  PubMed  Google Scholar 

  58. Lyras L, Cairns NJ, Jenner A, Jenner P, Halliwell B (1997) An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer’s disease. J Neurochem 68:2061–2069

    Article  CAS  PubMed  Google Scholar 

  59. Abbracchio MP, Burnstock G (1998) Purinergic signalling: pathophysiological roles. Jpn J Pharmacol 78:113–145

    Article  CAS  PubMed  Google Scholar 

  60. Sims B, Powers RE, Sabina RL, Theibert AB (1998) Elevated adenosine monophosphate deaminase activity in Alzheimer’s disease brain. Neurobiol Aging 19:385–391

    Article  CAS  PubMed  Google Scholar 

  61. Matsumoto S, Häberle J, Kido J, Mitsubuchi H, Endo F, Nakamura K (2019) Urea cycle disorders—update. J Hum Genet 64:833–847

    Article  PubMed  Google Scholar 

  62. Holmes O, Paturi S, Ye W, Wolfe MS, Selkoe DJ (2012) Effects of membrane lipids on the activity and processivity of purified γ-secretase. Biochemistry. 51:3565–3575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ledesma MD, Martin MG, Dotti CG (2012) Lipid changes in the aged brain: effect on synaptic function and neuronal survival. Prog Lipid Res 51:23–35

    Article  CAS  PubMed  Google Scholar 

  64. Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1:623–634

    Article  CAS  PubMed  Google Scholar 

  65. Du Y, Bales KR, Dodel RC, Hamilton-Byrd E, Horn JW, Czilli DL, Simmons LK, Ni B et al (1997) Activation of a caspase 3-related cysteine protease is required for glutamate-mediated apoptosis of cultured cerebellar granule neurons. Proc Natl Acad Sci 94:11657–11662

    Article  CAS  PubMed  Google Scholar 

  66. Nicholls D, Attwell D (1990) The release and uptake of excitatory amino acids. Trends Pharmacol Sci 11:462–468

    Article  PubMed  Google Scholar 

  67. Rush T, Liu X, Lobner D (2012) Synergistic toxicity of the environmental neurotoxins methylmercury and β-N-methylamino-L-alanine. Neuroreport. 23:216–219

    Article  CAS  PubMed  Google Scholar 

  68. Pontes ZL, Oliveira LS, Franzon R, Wajner M, Wannmacher CMD, Souza Wyse AT (2001) Inhibition of Na+, K+-ATPase activity from rat hippocampus by proline. Neurochem Res 26:1321–1326

    Article  CAS  PubMed  Google Scholar 

  69. An Y, Varma VR, Varma S, Casanova R, Dammer E, Pletnikova O, Chia CW, Egan JM et al (2018) Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimers Dement 14:318–329

    Article  PubMed  Google Scholar 

  70. Rebrin I, Kamzalov S, Sohal RS (2003) Effects of age and caloric restriction on glutathione redox state in mice. Free Radic Biol Med 35:626–635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rebrin I, Forster MJ, Sohal RS (2007) Effects of age and caloric intake on glutathione redox state in different brain regions of C57BL/6 and DBA/2 mice. Brain Res 1127:10–18

    Article  CAS  PubMed  Google Scholar 

  72. Wu G, Fang YZ, Yang S, Lupton JR, Turner ND (2004) Glutathione metabolism and its implications for health. J Nutr 134:489–492

    Article  CAS  PubMed  Google Scholar 

  73. Wallin G, Kamerlin SC, Åqvist J (2013) Energetics of activation of GTP hydrolysis on the ribosome. Nat Commun 4:1–10

    Article  Google Scholar 

  74. Lu Y, Wang R, Dong Y, Tucker D, Zhao N, Ahmed ME, Zhu L, Liu TCY et al (2017) Low-level laser therapy for beta amyloid toxicity in rat hippocampus. Neurobiol Aging 49:165–182

    Article  CAS  PubMed  Google Scholar 

  75. Xuan W, Vatansever F, Huang L, Hamblin MR (2014) Transcranial low-level laser therapy enhances learning, memory, and neuroprogenitor cells after traumatic brain injury in mice. J Biomed Opt 19:108003

    Article  PubMed  PubMed Central  Google Scholar 

  76. Xuan W, Agrawal T, Huang L, Gupta GK, Hamblin MR (2015) Low-level laser therapy for traumatic brain injury in mice increases brain derived neurotrophic factor (BDNF) and synaptogenesis. J Biophotonics 8:502–511

    Article  CAS  PubMed  Google Scholar 

  77. Xu Z, Guo X, Yang Y, Tucker D, Lu Y, Xin N, Zhang Q (2017) Low-level laser irradiation improves depression-like behaviors in mice. Mol Neurobiol 54:4551–4559

    Article  CAS  PubMed  Google Scholar 

  78. Ahmed NAEH, Radwan NM, Ibrahim KM, Khedr ME, El Aziz MA, Khadrawy YA (2008) Effect of three different intensities of infrared laser energy on the levels of amino acid neurotransmitters in the cortex and hippocampus of rat brain. Photomed Laser Surg 26:479–488

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the Nuclear Magnetic Resonance (NMR) Facility at Brazilian Biosciences National Laboratory (LNBio) and Brazilian Center for Research in Energy and Materials (CNPEM) for the use of the NMR spectrometer.

Funding

This study was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Centros de Pesquisa, Inovação e Difusão (CEPID; 2013/08028-1 and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; #2017/16443-0). Francisco Gonzalez-Lima was supported by the Oskar Fischer Project Fund. Rodrigo Álvaro Brandão Lopes-Martins was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; 307839/2015-0).

Author information

Authors and Affiliations

Authors

Contributions

All authors read and approved the final manuscript.

Corresponding author

Correspondence to Sérgio Gomes da Silva.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Highlights

(1) Photobiomodulation increases the brain metabolic pathways of young rats.

(2) Photobiomodulation restores the brain metabolic pathways of aged rats towards the levels of younger rats.

Supplementary Information

ESM 1

(DOCX 34 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

dos Santos Cardoso, F., dos Santos, J.C.C., Gonzalez-Lima, F. et al. Effects of Chronic Photobiomodulation with Transcranial Near-Infrared Laser on Brain Metabolomics of Young and Aged Rats. Mol Neurobiol 58, 2256–2268 (2021). https://doi.org/10.1007/s12035-020-02247-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-020-02247-z

Keywords

Navigation