Experimental Brain Research

, Volume 235, Issue 10, pp 3081–3092 | Cite as

No evidence for toxicity after long-term photobiomodulation in normal non-human primates

  • Cécile Moro
  • Napoleon Torres
  • Katerina Arvanitakis
  • Karen Cullen
  • Claude Chabrol
  • Diane Agay
  • Fannie Darlot
  • Alim-Louis Benabid
  • John Mitrofanis
Research Article

Abstract

In this study, we explored the effects of a longer term application, up to 12 weeks, of photobiomodulation in normal, naïve macaque monkeys. Monkeys (n = 5) were implanted intracranially with an optical fibre device delivering photobiomodulation (red light, 670 nm) to a midline midbrain region. Animals were then aldehyde-fixed and their brains were processed for immunohistochemistry. In general, our results showed that longer term intracranial application of photobiomodulation had no adverse effects on the surrounding brain parenchyma or on the nearby dopaminergic cell system. We found no evidence for photobiomodulation generating an inflammatory glial response or neuronal degeneration near the implant site; further, photobiomodulation did not induce an abnormal activation or mitochondrial stress in nearby cells, nor did it cause an abnormal arrangement of the surrounding vasculature (endothelial basement membrane). Finally, because of our interest in Parkinson’s disease, we noted that photobiomodulation had no impact on the number of midbrain dopaminergic cells and the density of their terminations in the striatum. In summary, we found no histological basis for any major biosafety concerns associated with photobiomodulation delivered by our intracranial approach and our findings set a key template for progress onto clinical trial on patients with Parkinson’s disease.

Keywords

Tyrosine hydroxylase Substantia nigra Striatum Macaque monkeys Behaviour 670 nm 

Notes

Acknowledgements

We are forever grateful to Michael J. Fox Foundation, Credit Agricole Sud Rhones Alpes, Fondation Philanthropique Edmond J Safra, Fondation Avenir, France Parkinson and the French National Research Agency (ANR Carnot Institute), Tenix corp and Salteri family and our industry partners for funding this work. We thank Darryl Cameron, Sharon Spana, Guillaume Barboux, Clément Perrin, Cyril Zenga and Mylène D’Orchymont for excellent technical assistance. The authors declare no conflict of interest with this work. All authors contributed to the experiments and analysis of the results and CM, ALB and JM to the writing of the manuscript.

References

  1. Anderson KJ, Fugaccia I, Scheff SW (2003) Fluoro-jade B stains quiescent and reactive astrocytes in the rodent spinal cord. J Neurotrauma 20:1223–1231. doi:10.1089/089771503770802899 CrossRefPubMedGoogle Scholar
  2. Ando T, Xuan W, Xu T et al (2011) Comparison of therapeutic effects between pulsed and continuous wave 810-nm wavelength laser irradiation for traumatic brain injury in mice. PLoS One 6:e26212. doi:10.1371/journal.pone.0026212 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Barrett DW, Gonzalez-Lima F (2013) Transcranial infrared laser stimulation produces beneficial cognitive and emotional effects in humans. Neuroscience 230:13–23. doi:10.1016/j.neuroscience.2012.11.016 CrossRefPubMedGoogle Scholar
  4. Darlot F, Moro C, El Massri N et al (2016) Near-infrared light is neuroprotective in a monkey model of Parkinson disease. Ann Neurol 79:59–75. doi:10.1002/ana.24542 CrossRefPubMedGoogle Scholar
  5. de Olmos J (1994) Use of an amino-cupric-silver technique for the detection of early and semiacute neuronal degeneration caused by neurotoxicants, hypoxia, and physical trauma. Neurotoxicol Teratol 16:545–561CrossRefPubMedGoogle Scholar
  6. Eells JT, Wong-Riley MTT, VerHoeve J et al (2004) Mitochondrial signal transduction in accelerated wound and retinal healing by near-infrared light therapy. Mitochondrion 4:559–567. doi:10.1016/j.mito.2004.07.033 CrossRefPubMedGoogle Scholar
  7. El Massri N, Johnstone DM, Peoples CL et al (2016) The effect of different doses of near infrared light on dopaminergic cell survival and gliosis in MPTP-treated mice. Int J Neurosci 126:76–87. doi:10.3109/00207454.2014.994063 CrossRefPubMedGoogle Scholar
  8. Giller CA, Liu H, German DC et al (2009) A stereotactic near-infrared probe for localization during functional neurosurgical procedures: further experience. J Neurosurg 110:263–273. doi:10.3171/2008.8.JNS08728 CrossRefPubMedGoogle Scholar
  9. Hamblin MR (2016) Shining light on the head: photobiomodulation for brain disorders. BBA Clin 6:113–124. doi:10.1016/j.bbacli.2016.09.002 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Ilic S, Leichliter S, Streeter J et al (2006) Effects of power densities, continuous and pulse frequencies, and number of sessions of low-level laser therapy on intact rat brain. Photomed Laser Surg 24:458–466. doi:10.1089/pho.2006.24.458 CrossRefPubMedGoogle Scholar
  11. Johnstone DM, Moro C, Stone J et al (2016) Turning on lights to stop neurodegeneration: the potential of near infrared light therapy in Alzheimer’s and Parkinson’s disease. Front Neurosci 9:500. doi:10.3389/fnins.2015.00500 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Keller E, Ishihara H, Nadler A et al (2002) Evaluation of brain toxicity following near infrared light exposure after indocyanine green dye injection. J Neurosci Methods 117:23–31CrossRefPubMedGoogle Scholar
  13. Kordorwer J, Muller S, Marck K et al (2015) Photobiomodulation in aged non-human primates. Society for Neuroscience, Chicago. Poster 217.20/C80Google Scholar
  14. Lampl Y, Zivin JA, Fisher M et al (2007) Infrared laser therapy for ischemic stroke: a new treatment strategy: results of the neurothera effectiveness and safety trial-1 (NEST-1). Stroke 38:1843–1849. doi:10.1161/STROKEAHA.106.478230 CrossRefPubMedGoogle Scholar
  15. Liang HL, Whelan HT, Eells JT, Wong-Riley MTT (2008) Near-infrared light via light-emitting diode treatment is therapeutic against rotenone- and 1-methyl-4-phenylpyridinium ion-induced neurotoxicity. Neuroscience 153:963–974. doi:10.1016/j.neuroscience.2008.03.042 CrossRefPubMedPubMedCentralGoogle Scholar
  16. McCarthy TJ, De Taboada L, Hildebrandt PK et al (2010) Long-term safety of single and multiple infrared transcranial laser treatments in Sprague-Dawley rats. Photomed Laser Surg 28:663–667. doi:10.1089/pho.2009.2581 CrossRefPubMedGoogle Scholar
  17. Merry G, Dotson R, Devenyi R et al (2012) Photobiomodulation as a new treatment for dry age related macular degeneration. Results from the Toronto and Oak Ridge photobiomodulation study in AMD (TORPA). Invest Ophthalmol Vis Sci 53:2049Google Scholar
  18. Moro C, El Massri N, Torres N et al (2014) Photobiomodulation inside the brain: a novel method of applying near-infrared light intracranially and its impact on dopaminergic cell survival in MPTP-treated mice. J Neurosurg 120:670–683. doi:10.3171/2013.9.JNS13423 CrossRefPubMedGoogle Scholar
  19. Moro C, El Massri N, Darlot F et al (2016) Effects of a higher dose of near-infrared light on clinical signs and neuroprotection in a monkey model of Parkinson’s disease. Brain Research 1648(Part A):19–26. doi:10.1016/j.brainres.2016.07.005 CrossRefPubMedGoogle Scholar
  20. Muili KA, Gopalakrishnan S, Meyer SL et al (2012) Amelioration of experimental autoimmune encephalomyelitis in C57BL/6 mice by photobiomodulation induced by 670 nm light. PLoS One 7:e30655. doi:10.1371/journal.pone.0030655 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Naeser MA, Saltmarche A, Krengel MH et al (2011) Improved cognitive function after transcranial, light-emitting diode treatments in chronic, traumatic brain injury: two case reports. Photomed Laser Surg 29:351–358. doi:10.1089/pho.2010.2814 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Paxinos G, Huang X, Toga A (1998) The Rhesus monkey brain in stereotaxic coordinates. Academic Press, USAGoogle Scholar
  23. Peoples C, Spana S, Ashkan K et al (2012) Photobiomodulation enhances nigral dopaminergic cell survival in a chronic MPTP mouse model of Parkinson’s disease. Parkinsonism Relat Disord 18:469–476. doi:10.1016/j.parkreldis.2012.01.005 CrossRefPubMedGoogle Scholar
  24. Powner MB, Sim DA, Zhu M et al (2016) Evaluation of nonperfused retinal vessels in ischemic retinopathy persistent retinal vasculature basement membrane. Invest Ophthalmol Vis Sci 57:5031–5037. doi:10.1167/iovs.16-20007 CrossRefPubMedGoogle Scholar
  25. Reinhart F, El Massri N, Darlot F et al (2015) Evidence for improved behaviour and neuroprotection after intracranial application of near infrared light in a hemi-parkinsonian rat model. J Neurosurg 27:1–13Google Scholar
  26. Rinne JO (1993) Nigral degeneration in Parkinson’s disease. Mov Disord 8(Suppl 1):S31–S35CrossRefPubMedGoogle Scholar
  27. Saltmarche AE, Naeser MA, Ho KF et al (2017) Significant improvement in cognition in mild to moderately severe dementia cases treated with transcranial plus intranasal photobiomodulation: case series report. Photomed Laser Surg. doi:10.1089/pho.2016.4227 PubMedPubMedCentralGoogle Scholar
  28. Schiffer F, Johnston AL, Ravichandran C et al (2009) Psychological benefits 2 and 4 weeks after a single treatment with near infrared light to the forehead: a pilot study of 10 patients with major depression and anxiety. Behav Brain Funct 5:46. doi:10.1186/1744-9081-5-46 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Shaw VE, Spana S, Ashkan K et al (2010) Neuroprotection of midbrain dopaminergic cells in MPTP-treated mice after near-infrared light treatment. J Comp Neurol 518:25–40. doi:10.1002/cne.22207 CrossRefPubMedGoogle Scholar
  30. Tata D, Waynant R (2012) Laser therapy: a review of its mechanism of action and potential medical applications. Laser Photonics Rev 1:1–12. doi:10.1002/lpor.200900032 CrossRefGoogle Scholar
  31. Wallace BA, Ashkan K, Heise CE et al (2007) Survival of midbrain dopaminergic cells after lesion or deep brain stimulation of the subthalamic nucleus in MPTP-treated monkeys. Brain 130:2129–2145. doi:10.1093/brain/awm137 CrossRefPubMedGoogle Scholar
  32. Ying R, Liang HL, Whelan HT et al (2008) Pretreatment with near-infrared light via light-emitting diode provides added benefit against rotenone- and MPP+-induced neurotoxicity. Brain Res 1243:167–173. doi:10.1016/j.brainres.2008.09.057 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Cécile Moro
    • 1
  • Napoleon Torres
    • 1
  • Katerina Arvanitakis
    • 2
  • Karen Cullen
    • 2
  • Claude Chabrol
    • 1
  • Diane Agay
    • 1
  • Fannie Darlot
    • 1
  • Alim-Louis Benabid
    • 1
  • John Mitrofanis
    • 2
  1. 1.University of Grenoble Alpes, CEA, LETI, CLINATEC, MINATEC CampusGrenobleFrance
  2. 2.Department of Anatomy F13University of SydneyCamperdownAustralia

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