Multi-Wavelength Photobiomodulation Ameliorates Sodium Iodate-Induced Age-Related Macular Degeneration in Rats.

Age-related macular degeneration (AMD) is a global health challenge. AMD causes visual impairment and blindness, particularly in older individuals. This multifaceted disease progresses through various stages, from asymptomatic dry to advanced wet AMD, driven by various factors including inflammation and oxidative stress. Current treatments are effective mainly for wet AMD; the therapeutic options for dry AMD are limited. Photobiomodulation (PBM) using low-energy light in the red-to-near-infrared range is a promising treatment for retinal diseases. This study investigated the effects of multi-wavelength PBM (680, 780, and 830 nm) on sodium iodate-induced oxidatively damaged retinal tissue. In an in vivo rat model of AMD induced by sodium iodate, multi-wavelength PBM effectively protected the retinal layers, reduced retinal apoptosis, and prevented rod bipolar cell depletion. Furthermore, PBM inhibited photoreceptor degeneration and reduced retinal pigment epithelium toxicity. These results suggest that multi-wavelength PBM may be a useful therapeutic strategy for AMD, mitigating oxidative stress, preserving retinal integrity, and preventing apoptosis.

The Anti-Inflammatory Effect of Multi-Wavelength Light-Emitting Diode Irradiation Attenuates Dry Eye Symptoms in a Scopolamine-Induced Mouse Model of Dry Eye.

Dry eye disease is a common condition in patients of all ages, causing discomfort and potential visual problems. Current treatments, including artificial tears and anti-inflammatory drugs, have certain limitations, encouraging research into alternative therapies. We investigated the therapeutic potential of multi-wavelength light-emitting diode (LED) irradiation of mice with dry eye. First, we showed that multi-wavelength LED irradiation was non-toxic to human corneal epithelial cells and improved cell viability. We then used a scopolamine-induced mouse model of dry eye to assess the effects of multi-wavelength LED irradiation on various clinical parameters. This treatment increased the tear volume and reduced corneal irregularity, thus improving dry eye. Histological analysis revealed that multi-wavelength LED irradiation protected against corneal epithelial damage and the associated reduction in epithelial thickness and would thus improve the corneal health of dry eye patients. Multi-wavelength LED irradiation significantly reduced the corneal levels of pro-inflammatory cytokines IL-6, IL-1ß, and TNF-α; the treatment was thus anti-inflammatory. Our results suggest that multi-wavelength LED irradiation may serve as a safe and effective treatment for dry eye, alleviating symptoms, reducing inflammation, and promoting corneal health.

Photobiomodulation improves the synapses and cognitive function and ameliorates epileptic seizure by inhibiting downregulation of Nlgn3.

BACKGROUND: Temporal lobe epilepsy (TLE) remains one of the most drug-resistant focal epilepsies. Glutamate excitotoxicity and neuroinflammation which leads to loss of synaptic proteins and neuronal death appear to represent a pathogen that characterizes the neurobiology of TLE. Photobiomodulation (PBM) is a rapidly growing therapy for the attenuation of neuronal degeneration harboring non-invasiveness benefits. However, the detailed effects of PBM on excitotoxicity or neuroinflammation remain unclear. We investigated whether tPBM exerts neuroprotective effects on hippocampal neurons in epilepsy mouse model by regulating synapse and synapse-related genes. METHODS: In an in vitro study, we performed imaging analysis and western blot in primary hippocampal neurons from embryonic (E17) rat pups. In an in vivo study, RNA sequencing was performed to identify the gene regulatory by PBM. Histological stain and immunohistochemistry analyses were used to assess synaptic connections, neuroinflammation and neuronal survival. Behavioral tests were used to evaluate the effects of PBM on cognitive functions. RESULTS: PBM was upregulated synaptic connections in an in vitro. In addition, it was confirmed that transcranial PBM reduced synaptic degeneration, neuronal apoptosis, and neuroinflammation in an in vivo. These effects of PBM were supported by RNA sequencing results showing the relation of PBM with gene regulatory networks of neuronal functions. Specifically, Nlgn3 showed increase after PBM and silencing the Nlgn3 reversed the positive effect of PBM in in vitro. Lastly, behavioral alterations including hypoactivity, anxiety and impaired memory were recovered along with the reduction of seizure score in PBM-treated mice. CONCLUSIONS: Our findings demonstrate that PBM attenuates epileptic excitotoxicity, neurodegeneration and cognitive decline induced by TLE through inhibition of the Nlgn3 gene decrease induced by excitotoxicity.

Photobiomodulation Attenuated Cognitive Dysfunction and Neuroinflammation in a Prenatal Valproic Acid-Induced Autism Spectrum Disorder Mouse Model.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication and interaction disorders, as well as repetitive and restrictive behaviors. To date, no effective treatment strategies have been identified. However, photobiomodulation (PBM) is emerging as a promising treatment for neurological and neuropsychiatric disorders. We used mice exposed to valproic acid (VPA) as a model of ASD and found that pathological behavioral and histological changes that may have been induced by VPA were attenuated by PBM treatment. Pregnant mice that had been exposed to VPA were treated with PBM three times. Thereafter, we evaluated the offspring for developmental disorders, motor function, hyperactivity, repetitive behaviors, and cognitive impairment. PBM attenuated many of the pathological behaviors observed in the VPA-induced ASD mouse model. In addition, pathophysiological analyses confirmed that the increase in activated microglia and astrocytes observed in the VPA-induced ASD mouse model was attenuated by PBM treatment. This suggests that PBM can counteract the behavioral changes caused by neuroinflammation in ASD. Therefore, our data show that PBM has therapeutic potential and may reduce the prevalence of neurodevelopmental disorders such as ASD.

Photobiomodulation regulates adult neurogenesis in the hippocampus in a status epilepticus animal model.

Status epilepticus (SE) refers to a single seizure that lasts longer than typical seizures or a series of consecutive seizures. The hippocampus, which is vulnerable to the effects of SE, has a critical role in memory storage and retrieval. The trisynaptic loop in the hippocampus connects the substructures thereof, namely the dentate gyrus (DG), CA3, and CA1. In an animal model of SE, abnormal neurogenesis in the DG and aberrant neural network formation result in sequential neural degeneration in CA3 and CA1. Photobiomodulation (PBM) therapy, previously known as low-level laser (light) therapy (LLLT), is a novel therapy for the treatment of various neurological disorders including SE. However, the effects of this novel therapeutic approach on the recovery process are poorly understood. In the present study, we found that PBM transformed SE-induced abnormal neurogenesis to normal neurogenesis. We demonstrated that PBM plays a key role in normal hippocampal neurogenesis by enhancing the migration of maturing granular cells (early neuronal cells) to the GCL, and that normal neurogenesis induced by PBM prevents SE-induced hippocampal neuronal loss in CA1. Thus, PBM is a novel approach to prevent seizure-induced neuronal degeneration, for which light devices may be developed in the future.

Synapto-protective effect of lithium on HIV-1 Tat-induced synapse loss in rat hippocampal cultures.

Human immunodeficiency virus type I (HIV-1) infection of the CNS produces synapse loss which correlates with cognitive decline in patients with HIV-associated neurocognitive disorders (HAND). Lithium is mood stabilizer of unknown mechanism used to treat bipolar disorder and is known to exhibit neuroprotective properties. Here, we studied the effects of lithium on HIV-1 Tat-induced synapses between rat hippocampal neurons. The number of synapses was quantified to detect clusters of the scaffold protein postsynaptic density 95 (PSD95) which is clustered at glutamatergic synapses on cultured rat hippocampal neurons in vitro. Lithium protected synapses from HIV-1 Tat-induced synapse loss and subsequent neuronal death. This synaptic protection was prevented by both the activation of NMDA receptor leading to intracellular signaling and the regulatory pathway of lithium including inositol depletion and glycogen synthase kinase-3ß (GSK-3ß). These results suggest that mood stabilizers might be effective drugs to treat neurodegenerative disorders including HAND.

Treatment with Light-Emitting Diodes of Wavelength 863 nm Delays DMBA/TPA-Induced Skin Tumor Formation and Decreases Proinflammatory Cytokine Levels in ICR Mice.

The popularity of light/energy devices for cosmetic purposes (e.g., skin care) is increasing. However, the effects and underlying mechanisms remain poorly understood. Commencing in the 1960s, various studies have evaluated the beneficial effects of a light source on cells and tissues. The techniques evaluated include low-level light (laser) therapy and photobiomodulation (PBM). Most studies on PBM used red light sources, but, recently, many studies have employed near-infrared light sources including those of wavelength 800 nm. Here, we used a light-emitting diode (LED) array with a wavelength of 863 nm to treat DMBA/TPA-induced mouse skin tumors; treatment with the array delayed tumor development and reduced the levels of systemic inflammatory cytokines. These results suggest that light therapy could be beneficial. However, the effects were small. Further studies on different skin tumors using an optimized LED setup are required. Combination therapies (conventional methods and an LED array) may be useful.

Photobiomodulation with a 660-Nanometer Light-Emitting Diode Promotes Cell Proliferation in Astrocyte Culture.

Astrocytes act as neural stem cells (NSCs) that have the potential to self-renew and differentiate into other neuronal cells. The protein expression of these astrocytes depends on the stage of differentiation, showing sequential expression of multiple proteins such as octamer-binding transcription factor 4 (Oct4), nestin, glial fibrillary acidic protein (GFAP), and aldehyde dehydrogenase 1 family member L1 (aldh1L1). Photobiomodulation (PBM) affects cell apoptosis, proliferation, migration, and adhesion. We hypothesized that astrocyte proliferation and differentiation would be modulated by PBM. We used an optimized astrocyte culture method and a 660-nanometer light-emitting diode (LED) to enhance the biological actions of many kinds of cells. We determined that the 660-nanometer LED promoted the biological actions of cultured astrocytes by increasing the reactive oxygen species levels. The overall viability of the cultured cells, which included various cells other than astrocytes, did not change after LED exposure; however, astrocyte-specific proliferation was observed by the increased co-expression of GFAP and bromodeoxyuridine (BrdU)/Ki67. Furthermore, the 660-nanometer LED provides evidence of differentiation, as shown by the decreased Oct4 and GFAP co-expression and increased nestin and aldh1L1 expression. These results demonstrate that a 660-nanometer LED can modify astrocyte proliferation, which suggests the efficacy of the therapeutic application of LED in various pathological states of the central nervous system.

Combined treatment of low-level laser therapy and phloroglucinol for inhibition of fibrosis.

BACKGROUND AND OBJECTIVES: Fibrosis is a highly prevalent disease, which is responsible for 45% of deaths through pathological effects in developed countries. Previous studies have reported that low-level laser therapy (LLLT) can modulate fibrotic activity, but significant enhancement of therapeutic efficacy is still required for clinical translation. The aim of this study is to evaluate the feasible effect of LLLT combined with phloroglucinol (PHL) on the inhibition of fibrosis in vitro. STUDY DESIGN/MATERIALS AND METHODS: NIH/3T3 murine embryonic fibroblasts cells were cultured and transforming growth factor-ß1 (TGF-ß1) was treated for transition of fibroblasts. After TGF-ß1 treatment, LLLT and PHL were used, respectively, and in combination to suppress fibrosis. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and BrdU assays were performed to estimate the cell viability and proliferation. To evaluate the expression of fibrotic markers, we used confocal immunofluorescence and western blot. RESULTS: When compared with respectively treated groups, the group with the combined treatment of LLLT and PHL significantly reduced cell viability and proliferation. Immunofluorescence staining showed that the combined group minimized more α-smooth muscle actin (α-SMA) and type I collagen than the other groups. Western blot analysis showed that the combined treatment had significant decreases in α-SMA, TGF-ß1, and type I collagen. CONCLUSIONS: PHL-assisted LLLT may be an effective treatment to inhibit fibrosis due to its additive effects. The combined treatment has a potential to be an alternative treatment for fibrosis. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Photobiomodulation as a treatment for neurodegenerative disorders: current and future trends.

Photobiomodulation (PBM) is a rapidly growing as an innovative therapeutic modality for various types of diseases in recent years. Neuronal degeneration is irreversible process and it is proven to be difficult to slow down or stop the progression. Pharmacologic approaches to slow neuronal degeneration have been studied, but are limited due to concerns about the side effects. Therefore, it is necessary to develop a new therapeutic approach to stabilize neuronal degeneration and achieve neuronal protection against several neurodegenerative diseases. In this review, we have introduced several previous studies showing the positive effect of PBM over neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and different types of epilepsy. Despite excellent outcomes of animal researches, not many clinical studies are conducted or showed positive outcome of PBM against neurodegenerative disease. To achieve clinical application of PBM against neurodegenerative disorder, determination of exact mechanism and establishment of effective clinical protocol seems to be necessary.

The co-expression of Neogenin with SOX2 in hippocampal neurons.

Dementia has been shown to be closely related with neuronal degeneration and/or a decrease in the activity of neural stem cells in many brain regions, including the hippocampus. It has been recently established that Neogenin is involved in the cell fate determination by regulating Oct3/4, SOX and Nanog, notable embryonic cell markers, expressions in pre-implantation mouse embryos. Further, Neogenin expression at both mRNA and protein levels is manifest in many brain regions in mice, but it remains unclear whether Neogenin expression is prerequisite for the maintenance of neural stem cells, particularly, playing a critical role in the hippocampus, a brain region known to be involved in memory generation and consolidation. Here, we provide evidence that supports that Neogenin is implicated in the maintenance of neural stem cells in the hippocampus by enhancing PCNA expressions. We have performed RT-PCR analysis, Western blotting, and immunohistochemistry with fetal rat brain tissues at E18 for Neogenin mRNA and protein profiling. Neuronal cells obtained from the hippocampus were subjected to FACS analysis for the identification of Neogenin-positive and/or neuronal stem cell marker-positive cells. Western blotting results showed that Neogenin expression was higher in the hippocampal region compared to the cortical region. FACS analysis results indicated that a significant population of fetal rat neuronal cells exhibiting Neogenin expression also displayed SOX2 expression, implying co-expression of Neogenin and SOX2 in the hippocampus. Next, we investigated the role of Neogenin through gain- and loss-of-function studies with cultured rat hippocampal neurons. Neogenin down-regulation by small hairpin RNAs led to a dramatic decrease in SOX2 expression while its up-regulation by overexpression caused an increase in PCNA expression, a cell proliferation marker, compared with none-transfected cells. From this study, we propose a model whereby Neogenin could maintain neural stem cell population and control cell proliferation.

Neuroprotective effect of lithium after pilocarpine-induced status epilepticus in mice.

Status epilepticus is the most common serious neurological condition triggered by abnormal electrical activity, leading to severe and widespread cell loss in the brain. Lithium has been one of the main drugs used for the treatment of bipolar disorder for decades, and its anticonvulsant and neuroprotective properties have been described in several neurological disease models. However, the therapeutic mechanisms underlying lithium's actions remain poorly understood. The muscarinic receptor agonist pilocarpine is used to induce status epilepticus, which is followed by hippocampal damage. The present study was designed to investigate the effects of lithium post-treatment on seizure susceptibility and hippocampal neuropathological changes following pilocarpine-induced status epilepticus. Status epilepticus was induced by administration of pilocarpine hydrochloride (320 mg/kg, i.p.) in C57BL/6 mice at 8 weeks of age. Lithium (80 mg/kg, i.p.) was administered 15 minutes after the pilocarpine injection. After the lithium injection, status epilepticus onset time and mortality were recorded. Lithium significantly delayed the onset time of status epilepticus and reduced mortality compared to the vehicle-treated group. Moreover, lithium effectively blocked pilocarpine-induced neuronal death in the hippocampus as estimated by cresyl violet and Fluoro-Jade B staining. However, lithium did not reduce glial activation following pilocarpine-induced status epilepticus. These results suggest that lithium has a neuroprotective effect and would be useful in the treatment of neurological disorders, in particular status epilepticus.