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Photobiomodulation for Global Cerebral Ischemia: Targeting Mitochondrial Dynamics and Functions

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Abstract

Hypothermia is currently the only approved therapy for global cerebral ischemia (GCI) after cardiac arrest; however, it unfortunately has multiple adverse effects. As a noninvasive procedure, photobiomodulation (PBM) therapy has emerged as a potential novel treatment for brain injury. PBM involves the use of low-level laser light therapy to influence cell behavior. In this study, we evaluated the therapeutic effects of PBM treatment with an 808-nm diode laser initiated 6 h after GCI. It was noted that PBM dose-dependently protected against GCI-induced neuronal death in the vulnerable hippocampal CA1 subregion. Functional assessments demonstrated that PBM markedly preserved both short-term (a week) and long-term (6 months) spatial learning and memory function following GCI. Further mechanistic studies revealed that PBM post-treatment (a) preserved healthy mitochondrial dynamics and suppressed substantial mitochondrial fragmentation of CA1 neurons, by reducing the detrimental Drp1 GTPase activity and its interactions with adaptor proteins Mff and Fis1 and by balancing mitochondrial targeting fission and fusion protein levels; (b) reduced mitochondrial oxidative damage and excessive mitophagy and restored mitochondrial overall health status and preserved mitochondrial function; and (c) suppressed mitochondria-dependent apoptosome formation/caspase-3/9 apoptosis-processing activities. Additionally, we validated, in an in vitro ischemia model, that cytochrome c oxidase served as a key PBM target for mitochondrial function preservation and neuroprotection. Our findings suggest that PBM serves as a promising therapeutic strategy for the functional recovery after GCI, with mechanisms involving PBM’s preservation on mitochondrial dynamics and functions and the inhibition of delayed apoptotic neuronal death in GCI.

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Funding

This study was supported by Research Grants NS086929 (to QZ) and NS088058 (to DW) from the National Institute of Neurological Disorders and Stroke, National Institutes of Health USA and by National Natural Science Foundation Grants of China: 30970664 and 31171354 (to RMW).

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  1. Ruimin Wang and Yan Dong contributed equally to this work.

Authors and Affiliations

  1. Neurobiology Institute of Medical Research Center, North China University of Science and Technology, Tangshan, 063000, China

    Ruimin Wang & Wenli Zhang

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

    Yan Dong, Yujiao Lu, Darrell W. Brann & Quanguang Zhang

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  1. Ruimin Wang
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Correspondence to Ruimin Wang, Darrell W. Brann or Quanguang Zhang.

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All animal surgery protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of the local university and were carried out in compliance with National Institutes of Health guidelines.

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The authors declare that they have no competing interests.

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Wang, R., Dong, Y., Lu, Y. et al. Photobiomodulation for Global Cerebral Ischemia: Targeting Mitochondrial Dynamics and Functions. Mol Neurobiol 56, 1852–1869 (2019). https://doi.org/10.1007/s12035-018-1191-9

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