DOI: 10.37212/jcnos.1946738 ISSN: 2149-7222

Translational Failure of Photobiomodulation in Ischemic Stroke: A Systematic Review of Oxidative Stress and Dosimetric Limitations

Anang Maulana Yusuf, Prananda Surya Airlangga, Hamzah Hamzah
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Photobiomodulation (PBM) has demonstrated substantial neuroprotective potential in experimental models of ischemic stroke; however, clinical trials have not demonstrated consistent therapeutic efficacy, raising concerns regarding its clinical translation. This review critically evaluates the discrepancy between predominantly favorable preclinical findings and inconclusive clinical outcomes, with particular emphasis on oxidative stress modulation, mitochondrial bioenergetics, neuroinflammation, neurovascular regulation, and dosimetric limitations. A structured literature search was conducted for studies published up to March 2026. Most experimental studies demonstrated that PBM improves neurological recovery, reduces infarct volume, enhances mitochondrial function, restores redox balance, modulates inflammatory signaling pathways, and promotes neurovascular responses following ischemic injury. Several studies also reported improved endothelial nitric oxide synthase activation, enhanced cerebral perfusion, and facilitation of neuronal repair processes. Although most preclinical studies reported favorable outcomes, some investigations demonstrated limited or non significant effects, highlighting heterogeneity within the available experimental evidence. Despite these promising mechanistic effects, translation into human stroke therapy remains limited. Emerging evidence suggests that insufficient intracranial photon penetration caused by attenuation through the scalp, skull, and cerebrospinal tissues may result in subtherapeutic fluence at target brain regions, representing a major barrier to clinical efficacy. This review highlights that the translational limitations of PBM are more likely attributable to inadequate intracranial light delivery and dosimetric mismatch rather than absence of biological activity. PBM remains a promising but investigational adjunctive neuroprotective strategy for ischemic stroke, warranting further optimization of light delivery systems and treatment protocols before widespread clinical application.

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