Abstract
Brain photobiomodulation (PBM) is an innovative treatment for a variety of neurological conditions, including cerebral ischemia. However, the capability of PBM for ischemic stroke needs to be further explored and its mechanisms of action remain currently unclear. The aim of the present research was to identify a treatment protocol capable of inducing neuroprotection and to investigate the molecular mechanisms activated by a dual-wavelength near infrared (NIR) laser source in an organotypic hippocampal slice model of hypoxia/ischemia. Hippocampal slices were exposed to oxygen and glucose deprivation (OGD) for 30 min followed by NIR laser light (fluence 3.71, 7.42, or 14.84 J/cm2; wavelengths 808 nm and 905 nm) delivered immediately or 30 min or 60 min after OGD, in order to establish a therapeutic window. Neuronal injury was assessed by propidium iodide fluorescence 24 h later. Our results show that NIR laser irradiation attenuates OGD neurotoxicity once applied immediately or 30 min after OGD. Western blot analysis of proteins involved in neuroinflammation (iNOS, COX-2, NFkB subunit p65, and Bcl-2) and in glutamatergic-mediated synaptic activity (vGluT1, EAAT2, GluN1, and PSD95) showed that the protein modifications induced by OGD were reverted by NIR laser application. Moreover, CA1 confocal microscopy revealed that the profound morphological changes induced by OGD were reverted by NIR laser radiation. In conclusion, NIR laser radiation attenuates OGD neurotoxicity in organotypic hippocampal slices through attenuation of inflammatory mechanisms. These findings shed light on molecular definition of NIR neuroprotective mechanisms, thus underlining the potential benefit of this technique for the treatment of cerebral ischemia.
Highlights
Cerebral ischemia is the third leading cause of death in Europe and North America and, in 70% of non-fatal cases, is the first cause of severe disability [1]
Organotypic hippocampal slices exposed to 30 min oxygen and glucose deprivation (OGD) had a selective injury in CA1 pyramidal neurons 24 h later [15, 16]
Our results show that 30 min OGD significantly increased High Density Nucleus (HDN) neurons in CA1 region (Fig. 5E), confirming the neuronal damage detected by propidium iodide (PI) staining
Summary
Cerebral ischemia is the third leading cause of death in Europe and North America and, in 70% of non-fatal cases, is the first cause of severe disability [1]. The pathophysiology of cerebral ischemia has been extensively studied and many drugs that appeared to be promising in animal models did not show the same efficacy in clinical studies [2]. The only possible therapeutic approach is to restore the cerebral flow as soon as possible. The tissue plasminogen activator (tPA) is the only drug in use, but it must be administered within 3 h from ischemic attack to be effective and, very often, patients do not arrive on time for treatment. TPA shows strict rules for inclusion criteria and could be burdened by serious adverse drug reactions [3]. Novel therapeutic approaches with a wider therapeutic
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