Skip to main content

Advertisement

SpringerLink
Log in

Photobiomodulation Therapy Attenuates Hypoxic-Ischemic Injury in a Neonatal Rat Model

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Photobiomodulation (PBM) has been demonstrated as a neuroprotective strategy, but its effect on perinatal hypoxic-ischemic encephalopathy is still unknown. The current study was designed to shed light on the potential beneficial effect of PBM on neonatal brain injury induced by hypoxia ischemia (HI) in a rat model. Postnatal rats were subjected to hypoxic-ischemic insult, followed by a 7-day PBM treatment via a continuous wave diode laser with a wavelength of 808 nm. We demonstrated that PBM treatment significantly reduced HI-induced brain lesion in both the cortex and hippocampal CA1 subregions. Molecular studies indicated that PBM treatment profoundly restored mitochondrial dynamics by suppressing HI-induced mitochondrial fragmentation. Further investigation of mitochondrial function revealed that PBM treatment remarkably attenuated mitochondrial membrane collapse, accompanied with enhanced ATP synthesis in neonatal HI rats. In addition, PBM treatment led to robust inhibition of oxidative damage, manifested by significant reduction in the productions of 4-HNE, P-H2AX (S139), malondialdehyde (MDA), as well as protein carbonyls. Finally, PBM treatment suppressed the activation of mitochondria-dependent neuronal apoptosis in HI rats, as evidenced by decreased pro-apoptotic cascade 3/9 and TUNEL-positive neurons. Taken together, our findings demonstrated that PBM treatment contributed to a robust neuroprotection via the attenuation of mitochondrial dysfunction, oxidative stress, and final neuronal apoptosis in the neonatal HI brain.

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

Access this article

Log in via an institution

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
Fig. 7

Similar content being viewed by others

References

  • Ahmed ME, Tucker D, Dong Y, Lu Y, Zhao N, Wang R, Zhang Q (2016) Methylene blue promotes cortical neurogenesis and ameliorates behavioral deficit after photothrombotic stroke in rats. Neuroscience 336:39–48

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ahmed ME, Dong Y, Lu Y, Tucker D, Wang R, Zhang Q (2017) Beneficial effects of a CaMKIIalpha inhibitor TatCN21 peptide in global cerebral ischemia. J Mol Neurosci: MN 61:42–51

    Article  PubMed  CAS  Google Scholar 

  • Akbar M, Essa MM, Daradkeh G, Abdelmegeed MA, Choi Y, Mahmood L, Song BJ (2016) Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress. Brain Res 1637:34–55

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Albrecht J, Hanganu IL, Heck N, Luhmann HJ (2005) Oxygen and glucose deprivation induces major dysfunction in the somatosensory cortex of the newborn rat. Eur J Neurosci 22:2295–2305

    Article  PubMed  Google Scholar 

  • Baburamani AA, Hurling C, Stolp H, Sobotka K, Gressens P, Hagberg H, Thornton C (2015) Mitochondrial optic atrophy (OPA) 1 processing is altered in response to neonatal hypoxic-ischemic brain injury. Int J Mol Sci 16:22509–22526

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Berman MH, Halper JP, Nichols TW, Jarrett H, Lundy A, Huang JH (2017) Photobiomodulation with near infrared light helmet in a pilot, placebo controlled clinical trial in dementia patients testing memory and cognition. J Neurol Neurosci 8

  • Bertholet AM, Delerue T, Millet AM, Moulis MF, David C, Daloyau M, Arnaune-Pelloquin L, Davezac N, Mils V, Miquel MC, Rojo M, Belenguer P (2016) Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity. Neurobiol Dis 90:3–19

    Article  PubMed  CAS  Google Scholar 

  • Blennow M, Ingvar M, Lagercrantz H, Stone-Elander S, Eriksson L, Forssberg H, Ericson K, Flodmark O (1995) Early [18F]FDG positron emission tomography in infants with hypoxic-ischaemic encephalopathy shows hypermetabolism during the postasphyctic period. Acta Paediatr 84:1289–1295

    Article  PubMed  CAS  Google Scholar 

  • Blomgren K, Hagberg H (2006) Free radicals, mitochondria, and hypoxia-ischemia in the developing brain. Free Radic Biol Med 40:388–397

    Article  PubMed  CAS  Google Scholar 

  • Chao de la Barca JM, Prunier-Mirebeau D, Amati-Bonneau P, Ferre M, Sarzi E, Bris C, Leruez S, Chevrollier A, Desquiret-Dumas V, Gueguen N, Verny C, Hamel C, Milea D, Procaccio V, Bonneau D, Lenaers G, Reynier P (2016) OPA1-related disorders: diversity of clinical expression, modes of inheritance and pathophysiology. Neurobiol Dis 90:20–26

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Colver A, Fairhurst C, Pharoah PO (2014) Cerebral palsy. Lancet 383:1240–1249

    Article  PubMed  Google Scholar 

  • Datta V (2017) Therapeutic hypothermia for birth asphyxia in neonates. Indian J Pediatr 84:219–226

    Article  PubMed  Google Scholar 

  • van de Looij Y, Chatagner A, Quairiaux C, Gruetter R, Huppi PS, Sizonenko SV (2014) Multi-modal assessment of long-term erythropoietin treatment after neonatal hypoxic-ischemic injury in rat brain. PLoS One 9:e95643

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Goodrich-Hunsaker NJ, Hunsaker MR, Kesner RP (2008) The interactions and dissociations of the dorsal hippocampus subregions: how the dentate gyrus, CA3, and CA1 process spatial information. Behav Neurosci 122:16–26

    Article  PubMed  Google Scholar 

  • Ham PB 3rd, Raju R (2017) Mitochondrial function in hypoxic ischemic injury and influence of aging. Prog Neurobiol 157:92–116

    Article  PubMed  CAS  Google Scholar 

  • Han D, Scott EL, Dong Y, Raz L, Wang R, Zhang Q (2015) Attenuation of mitochondrial and nuclear p38alpha signaling: a novel mechanism of estrogen neuroprotection in cerebral ischemia. Mol Cell Endocrinol 400:21–31

    Article  PubMed  CAS  Google Scholar 

  • Juul SE, Ferriero DM (2014) Pharmacologic neuroprotective strategies in neonatal brain injury. Clin Perinatol 41:119–131

    Article  PubMed  Google Scholar 

  • Kim YM, Yim HW, Jeong SH, Klem ML, Callaway CW (2012) Does therapeutic hypothermia benefit adult cardiac arrest patients presenting with non-shockable initial rhythms?: A systematic review and meta-analysis of randomized and non-randomized studies. Resuscitation 83:188–196

    Article  PubMed  Google Scholar 

  • Kim HN, Pak ME, Shin MJ, Kim SY, Shin YB, Yun YJ, Shin HK, Choi BT (2017) Comparative analysis of the beneficial effects of treadmill training and electroacupuncture in a rat model of neonatal hypoxia-ischemia. Int J Mol Med 39:1393–1402

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lee HI, Lee SW, Kim NG, Park KJ, Choi BT, Shin YI, Shin HK (2017) Low-level light emitting diode therapy promotes long-term functional recovery after experimental stroke in mice. J Biophotonics 10:1761–1771

    Article  PubMed  CAS  Google Scholar 

  • Li L, Yang R, Li P, Lu H, Hao J, Tucker D, Zhang Q (2018) Combination treatment with methylene blue and hypothermia in global cerebral ischemia. Mol Neurobiol 55:2042–2055

    Article  PubMed  CAS  Google Scholar 

  • Lu Y, Tucker D, Dong Y, Zhao N, Zhuo X, Zhang Q (2015) Role of mitochondria in neonatal hypoxic-ischemic brain injury. J Neurosci Rehabil 2:1–14

    PubMed  PubMed Central  Google Scholar 

  • Lu Q, Tucker D, Dong Y, Zhao N, Zhang Q (2016) Neuroprotective and functional improvement effects of methylene blue in global cerebral ischemia. Mol Neurobiol 53:5344–5355

    Article  PubMed  CAS  Google Scholar 

  • Lu Y, Wang R, Dong Y, Tucker D, Zhao N, Ahmed ME, Zhu L, Liu TC, Cohen RM, Zhang Q (2017) Low-level laser therapy for beta amyloid toxicity in rat hippocampus. Neurobiol Aging 49:165–182

    Article  PubMed  CAS  Google Scholar 

  • McQuillen PS, Sheldon RA, Shatz CJ, Ferriero DM (2003) Selective vulnerability of subplate neurons after early neonatal hypoxia-ischemia. J Neurosci 23:3308–3315

    Article  PubMed  CAS  Google Scholar 

  • Niatsetskaya ZV, Sosunov SA, Matsiukevich D, Utkina-Sosunova IV, Ratner VI, Starkov AA, Ten VS (2012) The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice. J Neurosci 32:3235–3244

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nolan JP et al. (2008) Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A scientific statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke. Resuscitation 79:350–379

  • Odorcyk FK, Kolling J, Sanches EF, Wyse ATS, Netto CA (2017) Experimental neonatal hypoxia ischemia causes long lasting changes of oxidative stress parameters in the hippocampus and the spleen. J Perinat Med

  • Oron A, Oron U (2016) Low-level laser therapy to the bone marrow ameliorates neurodegenerative disease progression in a mouse model of Alzheimer's disease: a minireview. Photomed Laser Surg 34:627–630

    Article  PubMed  CAS  Google Scholar 

  • Otera H, Ishihara N, Mihara K (2013) New insights into the function and regulation of mitochondrial fission. Biochim Biophys Acta 1833:1256–1268

    Article  PubMed  CAS  Google Scholar 

  • Rice JE 3rd, Vannucci RC, Brierley JB (1981) The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol 9:131–141

    Article  PubMed  Google Scholar 

  • Rumajogee P, Bregman T, Miller SP, Yager JY, Fehlings MG (2016) Rodent hypoxia-ischemia models for cerebral palsy research: a systematic review. Front Neurol 7:57

    Article  PubMed  PubMed Central  Google Scholar 

  • Salehpour F, Ahmadian N, Rasta SH, Farhoudi M, Karimi P, Sadigh-Eteghad S (2017) Transcranial low-level laser therapy improves brain mitochondrial function and cognitive impairment in D-galactose-induced aging mice. Neurobiol Aging 58:140–150

    Article  PubMed  CAS  Google Scholar 

  • Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ (2013) Brain development in rodents and humans: identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol 106-107:1–16

    Article  PubMed  Google Scholar 

  • Smith J, Wells L, Dodd K (2000) The continuing fall in incidence of hypoxic-ischaemic encephalopathy in term infants. BJOG: Int J Obstet Gynaecol 107:461–466

    Article  CAS  Google Scholar 

  • Sosunov SA, Ameer X, Niatsetskaya ZV, Utkina-Sosunova I, Ratner VI, Ten VS (2015) Isoflurane anesthesia initiated at the onset of reperfusion attenuates oxidative and hypoxic-ischemic brain injury. PLoS One 10:e0120456

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Suen DF, Norris KL, Youle RJ (2008) Mitochondrial dynamics and apoptosis. Genes Dev 22:1577–1590

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Thornton C, Rousset CI, Kichev A, Miyakuni Y, Vontell R, Baburamani AA, Fleiss B, Gressens P, Hagberg H (2012) Molecular mechanisms of neonatal brain injury. Neurol Res Int 2012:506320

    Article  PubMed  PubMed Central  Google Scholar 

  • Toet MC, Hellstrom-Westas L, Groenendaal F, Eken P, de Vries LS (1999) Amplitude integrated EEG 3 and 6 hours after birth in full term neonates with hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 81:F19–F23

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vannucci SJ, Hagberg H (2004) Hypoxia-ischemia in the immature brain. J Exp Biol 207:3149–3154

    Article  PubMed  CAS  Google Scholar 

  • Vannucci RC, Connor JR, Mauger DT, Palmer C, Smith MB, Towfighi J, Vannucci SJ (1999) Rat model of perinatal hypoxic-ischemic brain damage. J Neurosci Res 55:158–163

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X (2014) Oxidative stress and mitochondrial dysfunction in Alzheimer's disease. Biochim Biophys Acta 1842:1240–1247

    Article  PubMed  CAS  Google Scholar 

  • Wyatt JS (1994) Noninvasive assessment of cerebral oxidative metabolism in the human newborn. J R Coll Physicians Lond 28:126–132

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Xuan W, Huang L, Hamblin MR (2016) Repeated transcranial low-level laser therapy for traumatic brain injury in mice: biphasic dose response and long-term treatment outcome. J Biophotonics 9:1263–1272

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang L, Tucker D, Dong Y, Wu C, Lu Y, Li Y, Zhang J, Liu TC, Zhang Q (2018) Photobiomodulation therapy promotes neurogenesis by improving post-stroke local microenvironment and stimulating neuroprogenitor cells. Exp Neurol 299:86–96

    Article  PubMed  CAS  Google Scholar 

  • Zhang QG, Raz L, Wang R, Han D, De Sevilla L, Yang F, Vadlamudi RK, Brann DW (2009) Estrogen attenuates ischemic oxidative damage via an estrogen receptor alpha-mediated inhibition of NADPH oxidase activation. J Neurosci 29:13823–13836

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang QG, Wang RM, Scott E, Han D, Dong Y, Tu JY, Yang F, Reddy Sareddy G, Vadlamudi RK, Brann DW (2013) Hypersensitivity of the hippocampal CA3 region to stress-induced neurodegeneration and amyloidogenesis in a rat model of surgical menopause. Brain: J Neurol 136:1432–1445

    Article  Google Scholar 

  • Zhang J, Tucker LD, DongYan LY, Yang L, Wu C, Li Y, Zhang Q (2018) Tert-butylhydroquinone post-treatment attenuates neonatal hypoxic-ischemic brain damage in rats. Neurochem Int 116:1–12

    Article  PubMed  CAS  Google Scholar 

  • Zivin JA et al. (2009) Effectiveness and safety of transcranial laser therapy for acute ischemic stroke. Stroke 40:1359–1364

Download references

Funding

This study was supported by Research Grant NS086929 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, USA.

Author information

Author notes

  1. Lorelei Donovan Tucker and Yujiao Lu contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA

    Lorelei Donovan Tucker, Yujiao Lu, Yan Dong, Luodan Yang, Yong Li, Ningjun Zhao & Quanguang Zhang

Authors
  1. Lorelei Donovan Tucker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yujiao Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luodan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ningjun Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Quanguang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Quanguang Zhang.

Ethics declarations

All procedures were approved by the local ethical committee and were in accordance with the National Institutes of Health guidelines. All efforts were made to minimize the suffering and the number of pups used in the surgical and experimental procedures.

Conflict of Interest

The author declares that there is no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tucker, L.D., Lu, Y., Dong, Y. et al. Photobiomodulation Therapy Attenuates Hypoxic-Ischemic Injury in a Neonatal Rat Model. J Mol Neurosci 65, 514–526 (2018). https://doi.org/10.1007/s12031-018-1121-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-018-1121-3

Keywords

Search

Navigation