Article

Neuroprotective Effects of Near-Infrared Light in an In Vivo Model of Mitochondrial Optic Neuropathy

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Abstract

Near-infrared light (NIL) promotes a wide range of biological effects including enhancement of energy production, gene expression and prevention of cell death. This is the first report of the in vivo neuroprotective effects of NIL against optic neuropathy induced by mitochondrial complex I inhibition. Subjects were pigmented rats that received single bilateral intravitreal doses of rotenone, a mitochondrial complex I inhibitor, or rotenone plus one of three different doses of NIL. Treatment effects were evaluated at behavioral, structural and neurochemical levels. Rotenone induced a decrease in visual function, as determined by changes in the dark-adapted illuminance sensitivity threshold, escape latency and rate of successful trials in a two-choice visual task, compared with vehicle-treated controls. Behavioral impairment correlated with a decrease in retinal and visual pathway metabolic activity, retinal nerve fiber layer thickness and ganglion cell layer cell density. These changes were prevented by NIL treatments in a dose-dependent manner. Whole-brain cytochrome oxidase and superoxide dismutase activities were also increased in NIL-treated subjects in a dose-dependent manner, suggesting an in vivo transcranial effect of NIL. In whole-brain membrane isolates, NIL prevented the rotenone-induced decrease in cell respiration. The results show that NIL treatment can effectively prevent the neurotoxic effects of rotenone and that it might be used in the treatment of neurodegenerative disorders associated with mitochondrial dysfunction.

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... It has been shown to produce a wide range of biological effects including the enhancement of cellular metabolic energy (ATP production) and gene expression (Rojas & Gonzalez-Lima, 2013). The primary mechanism of action of photobiomodulation is the photonic activation of cytochrome oxidase (Karu et al. 2005;Rojas & Gonzalez-Lima, 2011;Rojas, Lee, John, & Gonzalez-Lima, 2008;Wong-Riley et al. 2005), which is the mitochondrial enzyme that catalyzes oxygen consumption in cellular respiration for metabolic energy production (Wong-Riley et al. 2005), and the primary cellular photoacceptor of red-to-near-infrared light energy (Karu et al. 2005). In animal studies, there is evidence that both the enzyme activity and the protein levels of cytochrome oxidase are increased by photobiomodulation (Rojas et al., 2008;Hayworth et al., 2010). ...
... The primary mechanism of action of photobiomodulation is the photonic activation of cytochrome oxidase (Karu et al. 2005;Rojas & Gonzalez-Lima, 2011;Rojas, Lee, John, & Gonzalez-Lima, 2008;Wong-Riley et al. 2005), which is the mitochondrial enzyme that catalyzes oxygen consumption in cellular respiration for metabolic energy production (Wong-Riley et al. 2005), and the primary cellular photoacceptor of red-to-near-infrared light energy (Karu et al. 2005). In animal studies, there is evidence that both the enzyme activity and the protein levels of cytochrome oxidase are increased by photobiomodulation (Rojas et al., 2008;Hayworth et al., 2010). In human studies, broad-band near-infrared spectroscopy (Wang et al., 2016) has demonstrated that the 1064 nm laser used in the present study affects cytochrome oxidase enzyme activity, as shown by increased oxidized cytochrome oxidase 5 during and shortly after light stimulation. ...
... Previous work has shown that non-invasive transcranial photobiomodulation can increase cytochrome oxidase activity in the rat brain (Rojas et al. 2008), which can provide neuroprotection and improve behavioral performance (Rojas & Gonzalez-Lima, 2011. In particular, Rojas et al. (2012) demonstrated that transcranial photobiomodulation can improve prefrontal cortex oxygen consumption and metabolic energy, and thereby increase prefrontal cortex-based memory functions in rats. ...
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This is the first randomized, controlled study comparing the cognitive effects of transcranial laser stimulation on category learning tasks. Transcranial infrared laser stimulation is a new non-invasive form of brain stimulation that shows promise for wide-ranging experimental and neuropsychological applications. It involves using infrared laser to enhance cerebral oxygenation and energy metabolism through upregulation of the respiratory enzyme cytochrome oxidase, the primary infrared photon acceptor in cells. Previous research found that transcranial infrared laser stimulation aimed at the prefrontal cortex can improve sustained attention, short-term memory, and executive function. In this study, we directly investigated the influence of transcranial infrared laser stimulation on two neurobiologically dissociable systems of category learning: a prefrontal cortex mediated reflective system that learns categories using explicit rules, and a striatally mediated reflexive learning system that forms gradual stimulus-response associations. Participants (n = 118) received either active infrared laser to the lateral prefrontal cortex or sham (placebo) stimulation, and then learned one of two category structures-a rule-based structure optimally learned by the reflective system, or an information-integration structure optimally learned by the reflexive system. We found that prefrontal rule-based learning was substantially improved following transcranial infrared laser stimulation as compared to placebo (treatment X block interaction: F(1, 298)=5.117, p=0.024), while information-integration learning did not show significant group differences (treatment X block interaction: F(1, 288)=1.633, p=0.202). These results highlight the exciting potential of transcranial infrared laser stimulation for cognitive enhancement and provide insight into the neurobiological underpinnings of category learning.
... Interestingly, high intensity NR has the ability to penetrate deeply through tissues of different types, and to ameliorate traumatic brain injury (Wu et al. 2012) as well as to induce nerve regeneration (Ishiguro et al. 2010) and brain neuronal damage (Peoples et al. 2012;Moro et al. 2013) in situ. In the case of the eye, NR has been shown to protect against photoreceptor death in situ (Rojas et al. 2008;Natoli et al. 2010;Albarracin et al. 2011;Albarracin & Valter 2012) as well as mitigate oxygeninduced degeneration (Albarracin et al. 2013). The underlying mechanism behind the positive effects of NR therapy is that it acts on mitochondrial cytochrome oxidase (COX), and induces the activation of transcription factors to elicit beneficial effects that include the reduction of oxidative stress, inflammation and cell death (Karu 1999;Eells et al. 2003;Wong-Riley et al. 2005;Begum et al. 2013). ...
... The use of NR therapy clinically to enhance mitochondrial function in these cell types noninvasively and to attenuate retinal malfunctions is therefore worthy of consideration. This idea is supported by the successful use of NR to attenuate histopathological changes to animal retinas in situ (Eells et al. 2004;Wong-Riley et al. 2005;Rojas et al. 2008;Natoli et al. 2010;Albarracin et al. 2011;Albarracin & Valter 2012;Albarracin et al. 2013;Begum et al. 2013). ...
... Impressive evidence exists to show the beneficial effects of long wavelength NR light in a variety of central nervous system injuries and disorders (Fitzgerald et al. 2013;Osborne et al. 2014). Animal studies have specifically shown that red light can attenuate retinal dysfunctions (Eells et al. 2003;Rojas et al. 2008;Natoli et al. 2010;Albarracin et al. 2011;Albarracin & Valter 2012;Rutar et al. 2012;Albarracin et al. 2013;Begum et al. 2013;Kokkinopoulos et al. 2013), but we are not aware of any reports related to clinical observations. This might be because of the lack of information related to optimum treatment conditions for red light therapy and a possible harmful influence on vision (Fitzgerald et al. 2013;Kokkinopoulos et al. 2013). ...
Article
Purpose: To ascertain whether red light, known to enhance mitochondrial function, can blunt chemical insults to cell cultures and ischaemic insults to the rat retina. Methods: Raised intraocular pressure (IOP, 140 mmHg, 60 min) or ischaemia was delivered in complete darkness or in the presence of low intensity red light (16.5 watts/m(2) , 3000 lux, 625-635 nm) to one eye of each rat. Animals were killed at specific times after ischemia and retinas analysis for ganglion cell numbers, the localization of specific antigens or for changes in defined RNAs. RGC-5 cell cultures were also exposed to various chemical insults in the presence or absence of red light. Significant differences were determined by t-test and anova. Results: Elevation of IOP causes changes in the localization of glial fibrillary acid protein (GFAP), calretinin, calbindin, choline acetyltransferase, ganglion cell numbers and an elevation (GFAP, vimentin, HO-1 and mTORC1) or reduction (Thy-1 and Brn3a) of mRNAs in the rat retina. These negative effects to the rat retina caused by ischaemia are reduced by red light. Moreover, chemical insults to cell cultures are blunted by red light. Conclusions: Low, non-toxic levels of red light focussed on the retina for a short period of time are sufficient to attenuate an insult of raised IOP to the rat retina. Since mitochondrial dysfunctions are thought to play a major role in ganglion cell death in glaucoma, we propose the potential use of red light therapy for the treatment of the disease.
... 2016; Liang et al., 2006;Wong-Riley et al., 2005;Ying et al., 2008). Specifically in the eye, red light protects against photoreceptor death (Albarracin et al., 2011;Albarracin and Valter, 2012;Natoli et al., 2010;Osborne et al., 2016aOsborne et al., , 2016bRojas et al., 2008), ameliorates diabetic retinopathy (Saliba et al., 2015;Tang et al., 2013), reduces dendropathy (Beirne et al., 2016), mitigates oxygeninduced degeneration (Albarracin et al., 2013) and attenuates histopathological changes in the retina induced by a variety of insults (Albarracin et al., 2011(Albarracin et al., , 2013Albarracin and Valter, 2012;Begum et al., 2013;Eells et al., 2004;Natoli et al., 2010;Rojas et al., 2008;Wong-Riley et al., 2005). It has also been reported that red light can ameliorate injury to the brain and spinal cord Ishiguro et al., 2010;Moro et al., 2013;Peoples et al., 2012;Wu et al., 2012) in animals. ...
... 2016; Liang et al., 2006;Wong-Riley et al., 2005;Ying et al., 2008). Specifically in the eye, red light protects against photoreceptor death (Albarracin et al., 2011;Albarracin and Valter, 2012;Natoli et al., 2010;Osborne et al., 2016aOsborne et al., , 2016bRojas et al., 2008), ameliorates diabetic retinopathy (Saliba et al., 2015;Tang et al., 2013), reduces dendropathy (Beirne et al., 2016), mitigates oxygeninduced degeneration (Albarracin et al., 2013) and attenuates histopathological changes in the retina induced by a variety of insults (Albarracin et al., 2011(Albarracin et al., , 2013Albarracin and Valter, 2012;Begum et al., 2013;Eells et al., 2004;Natoli et al., 2010;Rojas et al., 2008;Wong-Riley et al., 2005). It has also been reported that red light can ameliorate injury to the brain and spinal cord Ishiguro et al., 2010;Moro et al., 2013;Peoples et al., 2012;Wu et al., 2012) in animals. ...
... The retina has been a key target of this treatment in mammals because of its high energy demand and the fact that with ageing there is significant reduced function and high cell loss [11,12,13,14]. However, it has also proved highly effective in the brain where energy demands are also high [18]. Recently, it has been used successfully in diverse situations including treatment of experimental Parkinson's disease. ...
... However, as with some previous mouse studies [12,13], we made no attempt to restrain animals, rather they were free to move within their housing and in relation to the light source. Hence, effective dosing energy and time of exposure probably have a relatively wide spectrum, although there is evidence that excess exposure has reduced efficacy [18]. These features are important as we are prototyping economic 670nm light source devices for colonies and we have confirmed that the overall pattern of protection we reveal here can be obtained when insecticide exposed colonies are illuminated with 670nm as in the video data shown in the supplementary material. ...
Article
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Global pollination is threatened by declining insect pollinator populations that may be linked to neonicotinoid pesticide use. Neonicotinoids over stimulate neurons and depolarize their mitochondria, producing immobility and death. However, mitochondrial function can be improved by near infrared light absorbed by cytochrome c oxidase in mitochondrial respiration. In flies, daily exposure to 670nm light throughout life increases average lifespan and aged mobility, and reduces systemic inflammation. Here we treat bumble bees with Imidacloprid a common neonicotinoid. This undermined ATP and rapidly induced immobility and reduced visual function and survival. Bees exposed to insecticide and daily to 670nm light showed corrected ATP levels and significantly improved mobility allowing them to feed. Physiological recordings from eyes revealed that light exposure corrected deficits induced by the pesticide. Overall, death rates in bees exposed to insecticide but also given 670nm light were indistinguishable from controls. When Imidacloprid and light exposure were withdrawn, survival was maintained. Bees and insects generally cannot see deep red light so it does not disturb their behaviour. Hence, we show that deep red light exposure that improves mitochondrial function, reverses the sensory and motor deficits induced by Imidacloprid. These results may have important implications as light delivery is economic and can be placed in hives/colonies.
... The positive effects of red light includes promoting wound healing, cause complement propagation, and reducing oxidative stress, inflammation and cell death (Del Olmo-Aguado et al., 2012;Liang et al., 2006;Wong-Riley et al., 2005;Ying et al., 2008)) as well as improving recovery rates of soft tissue injuries and myocardial infarction (Oron et al., 2001;Simunovic et al., 2000). In the case of the eye, red light stimulates COX and ATP synthesis in the retina (Begum et al., 2013;Gkotsi et al., 2014) and protects against photoreceptor death in situ (Albarracin et al., 2011;Albarracin and Valter, 2012;Natoli et al., 2010;Rojas et al., 2008), ameliorates lesions in diabetic retinopathy (Saliba et al., 2015;Tang et al., 2013), reduces dendropathy as occurs in glaucoma (Beirne et al., 2016), mitigates oxygen-induced degeneration (Albarracin et al., 2013) and attenuates histopathological changes in animal retinas in situ (Albarracin et al., 2011;Albarracin et al., 2013;Albarracin and Valter, 2012;Begum et al., 2013;Eells et al., 2004;Natoli et al., 2010;Rojas et al., 2008;Wong-Riley et al., 2005). While the precise action of the many positive effects of red light is incompletely understood, the present evidence favours the view that it acts on mitochondrial chromophores, particularly COX, to cause an increase in ATP production and ROS, including nitric oxide, and a subsequent action on cellular DNA (Fig. 3). ...
... The positive effects of red light includes promoting wound healing, cause complement propagation, and reducing oxidative stress, inflammation and cell death (Del Olmo-Aguado et al., 2012;Liang et al., 2006;Wong-Riley et al., 2005;Ying et al., 2008)) as well as improving recovery rates of soft tissue injuries and myocardial infarction (Oron et al., 2001;Simunovic et al., 2000). In the case of the eye, red light stimulates COX and ATP synthesis in the retina (Begum et al., 2013;Gkotsi et al., 2014) and protects against photoreceptor death in situ (Albarracin et al., 2011;Albarracin and Valter, 2012;Natoli et al., 2010;Rojas et al., 2008), ameliorates lesions in diabetic retinopathy (Saliba et al., 2015;Tang et al., 2013), reduces dendropathy as occurs in glaucoma (Beirne et al., 2016), mitigates oxygen-induced degeneration (Albarracin et al., 2013) and attenuates histopathological changes in animal retinas in situ (Albarracin et al., 2011;Albarracin et al., 2013;Albarracin and Valter, 2012;Begum et al., 2013;Eells et al., 2004;Natoli et al., 2010;Rojas et al., 2008;Wong-Riley et al., 2005). While the precise action of the many positive effects of red light is incompletely understood, the present evidence favours the view that it acts on mitochondrial chromophores, particularly COX, to cause an increase in ATP production and ROS, including nitric oxide, and a subsequent action on cellular DNA (Fig. 3). ...
Article
Light of different wave-lengths have the potential to interact with four major mitochondrial protein complexes that are involved in the generation of ATP. Neurones of the central nervous system have an absolute dependence on mitochondrial generated ATP. Laboratory studies show that short-wave or blue light (400–480 nm) that impinges on the retina affect flavin and cytochrome constituents associated with mitochondria to decrease the rate of ATP formation, stimulate ROS and results in cell death. This suggests that blue light could potentially have a negative influence on retinal ganglion cell (RGC) mitochondria that are abundant and not shielded by macular pigments as occurs for photoreceptor mitochondria. This might be of significance in glaucoma where it is likely that RGC mitochondria are already affected and therefore be more susceptible to blue light. Thus simply filtering out some natural blue light from entering the eye might be beneficial for the treatment of glaucoma.
... The biphasic dose-response of PBM, also known as hormetic or inverted U-shaped dose-response, is a phenomenon characterized by lower doses that have stimulating effects and higher doses that have inhibitory or even detrimental effects (Rojas et al., 2008;Huang et al., 2009;Rojas and Gonzalez-Lima, 2011;Hamblin, 2016;Salehpour et al., 2018a). Several studies have demonstrated these hormetic effects (Sharma et al., 2011;Rojas et al. 2012). ...
... This evidence is important since during aging a chronic inflammation has been observed which contributes to a modulation of the glial cells to a pro-inflammatory response(Franceschi et al., 2000, Franceschi and Campisi, 2014, Goldeck et al., 2016, Harrison, 2016, Pizza et al., 2011. In addition, studies using animals treated with lipopolysaccharide (LPS) have provided alternatives for answering certain questions involving inflammation and cognitive impairment(Lee et al., 2008; Gong et al., 2010; Au et al., 2016, Hauss-Wegrzyniak et al., 2002, Vereker et al., 2000, because LPS decreases the post-synaptic excitatory potential in brainregions fundamental to memory consolidation (Au et al., 2016). For example, Lee et al. (2008) observed that animals treated with LPS had impaired learning and memory, accompanied by neuronal death in the cortex and hippocampus. ...
Article
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Longevity is one of the great triumphs of humanity. Worldwide, the elderly is the fastest growing segment of the population. As a consequence, the number of cases of age-related cognitive decline and neurological diseases associated with aging, such as Alzheimer's and Parkinson's, has been increasing. Among the non-pharmacological interventions studied for the treatment or prevention of age-related neurocognitive impairment, photobiomodulation (PBM) has gained prominence for its beneficial effects on brain functions relevant to aging brains. In animal models, the neuroprotective and neuromodulatory capacity of PBM has been observed. Studies using both animals and humans have shown promising metabolic and hemodynamic effects of PBM on the brain, such as improved mitochondrial and vascular functions. Studies in humans have shown that PBM can improve electrophysiological activity and cognitive functions such as attention, learning, memory and mood in older people. In this paper we will review the main brain effects of PBM during aging, discuss its mechanisms of action relevant to the aging brain, and call for more controlled studies in older populations.
... LED light at wavelengths of 670 and 830 nm remarkably upregulated mitochondrial COX activity in cultured visual cortical neurons (Wong-Riley et al., 2005). Also, an 633 nm LED light irradiation of rat head was able to significantly increase the COX activity in the whole brain (Rojas et al., 2008) as well as-in case of selective irradiation-in specific brain regions such as PFC (Rojas et al., 2012) and superior colliculus (Rojas et al., 2008). Likewise, the restoration of mitochondrial COX expression patterns in the neocortex and hippocampus have been shown in mouse AD model, following long-term LED therapy (at 670 nm) (Purushothuman et al., 2014). ...
... LED light at wavelengths of 670 and 830 nm remarkably upregulated mitochondrial COX activity in cultured visual cortical neurons (Wong-Riley et al., 2005). Also, an 633 nm LED light irradiation of rat head was able to significantly increase the COX activity in the whole brain (Rojas et al., 2008) as well as-in case of selective irradiation-in specific brain regions such as PFC (Rojas et al., 2012) and superior colliculus (Rojas et al., 2008). Likewise, the restoration of mitochondrial COX expression patterns in the neocortex and hippocampus have been shown in mouse AD model, following long-term LED therapy (at 670 nm) (Purushothuman et al., 2014). ...
... Photobiomodulation involves the absorption of photons and the subsequent modulation of metabolic processes in cells, including neurons [1,2]. For red to near-infrared light, the major intracellular molecule absorbing photons is cytochrome c oxidase [3], a mitochondrial respiratory enzyme that can be upregulated in vitro and in vivo [4][5][6][7]. Upregulation of cytochrome c oxidase serves to convert high-energy photons into a source for ATP-based metabolic energy production in the brain [8]. Photobiomodulation of neural functions has been successful at 633-1070-nm wavelengths (for reviews, see [9][10][11]). ...
... Also, a repeated measures ANOVA on the DMS data (Fig. 2b), using six data points (baseline + 5 weeks of treatment), using percentage change from baseline as the dependent variable, showed that the effect of the within-subject variable (session) was significant: F(5, 40) = 3.5799, p < 0.01. Figure 3 illustrates mean cognitive scores for baseline vs. acute (after a single session at week 1) pair-wise comparisons, where paired t tests indicated significant improvements for PVT lapses (p < 0.001), but not for PVT reaction time (p = 0.12) and borderline for DMS correct responses (p = 0.05). However, paired t tests conducted on baseline vs. chronic (after repeated sessions at weeks [2][3][4][5] showed that all improvements were significant for PVT reaction time (p < 0.001), PVT lapses (p < 0.001), and DMS correct responses (p < 0.05). ...
Article
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Transcranial infrared laser stimulation (TILS) at 1064 nm, 250 mW/cm² has been proven safe and effective for increasing neurocognitive functions in young adults in controlled studies using photobiomodulation of the right prefrontal cortex. The objective of this pilot study was to determine whether there is any effect from TILS on neurocognitive function in older adults with subjective memory complaint at risk for cognitive decline (e.g., increased carotid artery intima-media thickness or mild traumatic brain injury). We investigated the cognitive effects of TILS in older adults (ages 49–90, n = 12) using prefrontal cortex measures of attention (psychomotor vigilance task (PVT)) and memory (delayed match to sample (DMS)), carotid artery intima-media thickness (measured by ultrasound), and evaluated the potential neural mechanisms mediating the cognitive effects of TILS using exploratory brain studies of electroencephalography (EEG, n = 6) and functional magnetic resonance imaging (fMRI, n = 6). Cognitive performance, age, and carotid artery intima-media thickness were highly correlated, but all participants improved in all cognitive measures after TILS treatments. Baseline vs. chronic (five weekly sessions, 8 min each) comparisons of mean cognitive scores all showed improvements, significant for PVT reaction time (p < 0.001), PVT lapses (p < 0.001), and DMS correct responses (p < 0.05). The neural studies also showed for the first time that TILS increases resting-state EEG alpha, beta, and gamma power and promotes more efficient prefrontal blood-oxygen-level-dependent (BOLD)-fMRI response. Importantly, no adverse effects were found. These preliminary findings support the use of TILS for larger randomized clinical trials with this non-invasive approach to augment neurocognitive function in older people to combat aging-related and vascular disease-related cognitive decline.
... It is claimed that laser acts on photoreceptor molecules (chromophores) of cytochrome c oxidase complex (Complex IV, cytochrome c oxidase), which is a transmembrane protein found in the mitochondria, playing an important role in energy metabolism. [52][53][54] LLLT may stimulate the respiratory chain activity of cytochrome c oxidase, leading to an increase in oxygen consumption and ATP production, with the potential of modifying a variety of biological processes. [52][53][54] Hayworth et al. 55 found a 30% increase in the activity of cytochrome c oxidase in the temporal muscle of healthy rats 24 h after a single irradiation of LLLT compared with a control group. ...
... [52][53][54] LLLT may stimulate the respiratory chain activity of cytochrome c oxidase, leading to an increase in oxygen consumption and ATP production, with the potential of modifying a variety of biological processes. [52][53][54] Hayworth et al. 55 found a 30% increase in the activity of cytochrome c oxidase in the temporal muscle of healthy rats 24 h after a single irradiation of LLLT compared with a control group. Importantly, irradiation occurred in a healthy tissue, so values found after irradiation were higher than actual levels. ...
Article
Background: Tendinopathy is characterized by pain, edema, and structural changes in tendon tissue. Objective: In this animal study we decided to compare the short- and medium-term effects of low-level laser therapy (LLLT), dexamethasone, and diclofenac on inflammation and tendon tissue repair in collagenase-induced tendinitis. Materials and methods: Two hundred five female Wistar rats were randomly divided into five groups. Animals in the control group were given a saline injection and the experimental groups received a collagenase injection (100 μg/tendon) in the peritendinous Achilles and received no treatment, LLLT (3 J, 810 nm, 100 mW), diclofenac (1.1 mg/kg), or dexamethasone (0.02 mg/kg). Histological analyses were performed at 10 time points up to 60 days (n = 5/group each time point), and included an assessment of the severity of inflammation, collagen fiber content, and organization. Results: Collagenase injection induced a severe inflammatory reaction with significant reduction in collagen content for 48 h, and disorientation of collagen fibers lasting between 14 and 21 days. Diclofenac and dexamethasone reduced inflammatory signs during the first 2 days, although there was prolongation of the inflammatory phase and slower normalization of tendon quality, particularly in the dexamethasone group. LLLT prevented hemorrhage, reduced inflammation severity, and preserved tendon morphology compared with the other groups. Conclusions: LLLT showed a significant superiority over commonly used anti-inflammatory pharmaceutical agents in acute collagenase-induced tendinitis.
... More recently, low-level light therapy in the far-red (FR) to near-infrared (NIR) range of the spectrum (~600-1000 nm), collectively termed photobiomodulation (PBM), has gained worldwide attention in recent years as a novel tool for experimental therapeutic applications in a variety of medical conditions. For instance, applications of PBM to medical disorders, has been shown to restore functions of damaged mitochondria by upregulating cytoprotective factors and protecting against damage [1]. These findings suggest laser therapy may inhibit inflammation and promote immune response and wound healing for various tissues (reviewed in [2]). ...
... Remarkably, NIR light may reduce death of photoreceptors by 70% [91]. NIR light can also inhibit cell degeneration of retinal ganglion cells caused by inhibitor rotenone to the mitochondrial complex I [1]. NIR light treatment can also promote drusen, yellow deposits from macular degeneration due to aging, lower intraocular pressure as long as several months [6], indicating that NIR light can have beneficiaries in retinal and optic nerves. ...
Article
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Near infrared (NIR) light therapy, or photobiomodulation therapy (PBMT), has gained persistent worldwide attention in recent years as a new novel scientific approach for therapeutic applications in ophthalmology. This ongoing therapeutic adoption of NIR therapy is largely propelled by significant advances in the fields of photobiology and bioenergetics, such as the discovery of photoneuromodulation by cytochrome c oxidase and the elucidation of therapeutic biochemical processes. Upon transcranial delivery, NIR light has been shown to significantly increase cytochrome oxidase and superoxide dismutase activities which suggests its role in inducing metabolic and antioxidant beneficial effects. Furthermore, NIR light may also boost cerebral blood flow and cognitive functions in humans without adverse effects. In this review, we highlight the value of NIR therapy as a novel paradigm for treatment of visual and neurological conditions, and provide scientific evidence to support the use of NIR therapy with emphasis on molecular and cellular mechanisms in eye diseases.
... [36][37][38] This mechanism is supported by previously reported animal experiments, which identified increases in cytochrome c oxidase and metabolic capacity following PBM. 37,39,40 Other studies using various mouse models showed that PBM effectively provided neuroprotection, 41,42 improved memory function, 43 and reduced brain tissue loss. 22 ...
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Objectives The frontal lobe hypothesis of age‐related cognitive decline suggests that the deterioration of the prefrontal cortical regions that occurs with aging leads to executive function deficits. Photobiomodulation (PBM) is a newly developed, non‐invasive technique for enhancing brain function, which has shown promising effects on cognitive function in both animals and humans. This randomized, sham‐controlled study sought to examine the effects of PBM on the frontal brain function of older adults. Methods/Designs Thirty older adults without a neuropsychiatric history performed cognitive tests of frontal function (i.e., the Eriksen flanker and category fluency tests) before and after a single 7.5‐min session of real or sham PBM. The PBM device consisted of three separate light‐emitting diode cluster heads (633 nm and 870 nm), which were applied to both sides of the forehead and posterior midline, and delivered a total energy of 1349 J. Results Significant group (experimental, control) × time (pre‐PBM, post‐PBM) interactions were found for the flanker and category fluency test scores. Specifically, only the older adults who received real PBM exhibited significant improvements in their action selection, inhibition ability, and mental flexibility after vs. before PBM. Conclusions Our findings support that PBM may enhance the frontal brain functions of older adults in a safe and cost‐effective manner.
... Low-level laser therapy, a recently developed intervention, regulates neuronal function in neuronal cultures, animals, and clinical conditions [110] and rescues the neuronal loss and dendritic atrophy in cultured hippocampal neurons treated with Aβ and hippocampal neurons from the APP/PS1 mice via increasing BDNF expression [111]. As mentioned above, there is accumulating evidence for a potential use of 7,8-DHF, a small-molecule of TrkB agonist, in the therapeutic effect for AD patients. ...
Article
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It is well known that brain-derived neurotrophic factor, BDNF, has an important role in a variety of neuronal aspects, such as differentiation, maturation, and synaptic function in the central nervous system (CNS). BDNF stimulates mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), phosphoinositide-3kinase (PI3K), and phospholipase C (PLC)-gamma pathways via activation of tropomyosin receptor kinase B (TrkB), a high affinity receptor for BDNF. Evidence has shown significant contributions of these signaling pathways in neurogenesis and synaptic plasticity in in vivo and in vitro experiments. Importantly, it has been demonstrated that dysfunction of the BDNF/TrkB system is involved in the onset of brain diseases, including neurodegenerative and psychiatric disorders. In this review, we discuss actions of BDNF and related signaling molecules on CNS neurons, and their contributions to the pathophysiology of brain diseases.
... NIR also stimulates neurite outgrowth mediated by nerve growth factor and promotes axonal protection [91]. Neuroprotective effects of red light (670 nm) were documented in in vivo models of mitochondrial optic neuropathy [92]. Red light close to NIR spectrum (670 nm) has also been shown to protect neuronal cells against cyanide toxicity [93]. ...
Chapter
Photobiomodulation (PBM) is a novel device-based treatment for major depressive disorder (MDD). PBM delivers near-infrared (NIR) or red light transcranially or systemically, aiming to modulate mitochondrial bioenergetics metabolism via the delivery of energy to the cytochrome c oxidase (CCO) enzyme. This primary action on mitochondria can lead to secondary effects on other pathways relevant for MDD such as oxidative stress, inflammation, and neurogenesis. Evidence supports that a fraction of the light delivered transcranially can reach the brain and modulate cortical activity and that light delivered in the periphery can exert systemic effects that include the brain. Preclinical studies indicate that PBM can treat depression-like behaviors in animal models of depression and also give some guidance on the optimal stimulation parameters. According to these studies, repeated sessions are more effective than a single session, and pulsed wave is more effective than continuous wave. Clinical studies also support the antidepressant effect of PBM and reinforce the need of repeated sessions. Clinical evidence also indicates that PBM can induce mild adverse effects, but the incidence of serious adverse effects is not different from that observed in sham (i.e., placebo) treatment. At this moment, PBM is an over-the-counter treatment for MDD and can be considered an alternative for patients who do not respond, tolerate, or accept antidepressant medication, evidence-based psychotherapies, or other FDA-approved device-based treatments.
... Red light (670 nm) also stimulates neurite outgrowth mediated by nerve growth factor, and promotes axonal protection (Giuliani et al., 2009). Neuroprotective effects of red light (670 nm) were documented in-vivo models of mitochondrial optic neuropathy (Rojas et al., 2008). Red light close to NIR spectrum (670 nm) has also been shown to protect neuronal cells against cyanide toxicity (Wong-Riley et al., 2005). ...
Article
Background: Photobiomodulation (PBM) with red and near-infrared light (NIR) -also known as Low-Level Light Therapy-is a low risk, inexpensive treatment-based on non-retinal exposure-under study for several neuropsychiatric conditions. The aim of this paper is to discuss the proposed mechanism of action and to perform a systematic review of pre-clinical and clinical studies on PBM for major depressive disorder (MDD). Methods: A search on MEDLINE and EMBASE databases was performed in July 2017. No time or language restrictions were used. Studies with a primary focus on MDD and presenting original data were included (n = 17). References on the mechanisms of action of PBM also included review articles and studies not focused on MDD. Results: Red and NIR light penetrate the skull and modulate brain cortex; an indirect effect of red and NIR light, when delivered non-transcranially, is also postulated. The main proposed mechanism for PBM is the enhancement of mitochondrial metabolism after absorption of NIR energy by the cytochrome C oxidase; however, actions on other pathways relevant to MDD are also reported. Studies on animal models indicate a benefit from PBM that is comparable to antidepressant medications. Clinical studies also indicate a significant antidepressant effect and good tolerability. Limitations: Clinical studies are heterogeneous for population and treatment parameters, and most lack an appropriate control. Conclusions: Preliminary evidence supports the potential of non-retinal PBM as a novel treatment for MDD. Future studies should clarify the ideal stimulation parameters as well as the overall efficacy, effectiveness and safety profile of this treatment.
... The early studies by Wong-Riley et al. in cultured rat visual cortical neurons revealed that irradiation using LED light (4 J/cm 2 ) at wavelengths of 670 and 830 nm was more effective than 770 nm and 880 nm in the upregulation of CCO activity [106], while 670 nm light significantly reversed the downregulation of CCO activity induced by tetrodotoxin [107]. LED light irradiation at 633 nm resulted in augmentation of CCO activity in the prefrontal cortex (PFC) of naive rats by 14% (10.9 J/cm 2 ) [18], in the superior colliculus by 26% and in the whole brain by 60% (3.6 J/cm 2 ) in a rat model of rotenoneinduced neurotoxicity [108]. Recent studies conducted by Zhang and his research team show that transcranial LED therapy (808 nm) significantly increased the CCO activity in the PFC in a mouse stress model (41 J/cm 2 ) [30], as well as in the hippocampus of a murine Aβinduced Alzheimer's disease (AD) model (3 J/cm 2 ) [21]. ...
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Brain photobiomodulation (PBM) therapy using red to near-infrared (NIR) light is an innovative treatment for a wide range of neurological and psychological conditions. Red/NIR light is able to stimulate complex IV of the mitochondrial respiratory chain (cytochrome c oxidase) and increase ATP synthesis. Moreover, light absorption by ion channels results in release of Ca²⁺ and leads to activation of transcription factors and gene expression. Brain PBM therapy enhances the metabolic capacity of neurons and stimulates anti-inflammatory, anti-apoptotic, and antioxidant responses, as well as neurogenesis and synaptogenesis. Its therapeutic role in disorders such as dementia and Parkinson’s disease, as well as to treat stroke, brain trauma, and depression has gained increasing interest. In the transcranial PBM approach, delivering a sufficient dose to achieve optimal stimulation is challenging due to exponential attenuation of light penetration in tissue. Alternative approaches such as intracranial and intranasal light delivery methods have been suggested to overcome this limitation. This article reviews the state-of-the-art preclinical and clinical evidence regarding the efficacy of brain PBM therapy.
... The effects include an increase in mitochondrial respiration, ATP synthesis [12][13][14], and nerve cell proliferation [15], among others. Through the analysis of increased cytochrome oxidase, Rojas et al. [16] reported that PBM induces brain metabolic and antioxidant effects. In another study, these authors reported an increase in memory retention and oxygen consumption as the result of cytochrome oxidase stimulation in the frontal cortex of rats [17]. ...
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Excessive Aβ deposition in the brain is associated with the formation of senile plaques, and their diffuse distribution is related to Alzheimer’s disease. Thirty rats (EG) were irradiated with light-emitting diode (photobiomodulation (PBM)) in the frontal region of the skull after being inoculated with the Aβ toxin in the hippocampus; 30 rats were used as the control group (CG). The analysis was conducted at 7, 14, and 21 days after irradiation. We observed a decreased in Aβ deposits in treated animals compared with animals in the CG. The behavioral and motor assessment revealed that the EG group covered a larger ground distance and explored the open field than the CG group on days 14 and 21 (p < 0.05). The EG group was statistically significant in the spatial memory test compared to the CG group on day 14. The use of PBM significantly reduced the presence of Aβ plaques and improved spatial memory and behavioral and motor skills in treated animals on day 21.
... Apart from that, it not only promotes recovery from ischemia in cardiomyocytes (Zhang et al. 2009), but also enables muscle regeneration (Weiss and Oron 1992) and aids wound and retinal healing (Conlan et al. 1996;Eells et al. 2004). In neuronal cells, red/NIR light prevents neurotoxic effect of cyanide and azide (Desmet et al. 2006;Wong-Riley et al. 2005), restores axonal transport in Parkinson's disease (Trimmer et al. 2009), and exerts a neuroprotective effect against optic neuropathies (Rojas et al. 2008). ...
Chapter
Tissue engineering techniques, to replace wounded or missing tissue, are advancing rapidly to ensure the speedy recovery of patients. However, this field faces limitations of cells and biomaterials which prevents the acceleration of regeneration. Low level light therapy, a physical therapy, shows potential in enhancing and supporting the existing medicinal treatments. Visible light in the red and near-infrared range has shown to have positive stimulatory effects on various types of cells involved in wound healing and tissue regeneration. As angiogenesis is an essential part of this process, light therapy was investigated in multiple studies to see its beneficial effect on vessel formation. In vitro, in vivo, and in a clinical setup, LLLT therapy proved that it is capable of stimulating not only endothelial cells but other cells such as fibroblasts, smooth muscle cells, and lymphocytes which are involved in the vessel formation process. It triggers the activation of cytochrome c oxidase, which leads to the production of NO, ROS, and ATP in the mitochondria. These molecules appear to act as secondary messengers initiating ERK/Sp1 and PI3K signaling pathway, which in turn leads to proliferation, migration, and the synthesis of proangiogenic factors. This data indicates that LLLT could be a promising adjuvant treatment in the future.
... It can regulate neural functions (13,18), modulate gene expression (19), and protect cells from death after ischemic stroke (20) and neurotoxicity (21). It can also promote the cell's energy production (22) by increasing mitochondrial respiration (23,24). An increase in the brain cerebral blood flow has also been observed after light irradiation (25). ...
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Background: Transcranial light therapy (TCLT) is a new noninvasive interventional method, which applies red to near infrared spectrum laser or light emitting diode (LED) source on the head, transcranially. This spectrum can penetrate the skull and could improve the brain pathological conditions and cognitive functions. Despite relative advantages of the LED upon laser sources, TCLT research has been limited on the beneficial effects of LED source on human cognitive performances. Objectives: This study aimed at investigating the effectiveness of the TCLT with LED source on brain attentional performance as an important cognitive ability. Methods: This experimental intervention study was conducted in Tabriz, Iran, from September to October 2016. The study samples were selected by the convenience sampling method. Thirty-four healthy individuals (age: 18 to 24; 17 males and 17 females) were randomly assigned to sham (n = 17) or real intervention (n = 17) groups. We applied 850 nm LED with irradiation energy density 60 J/cm² upon the frontal cortex, the brain region involved in attentional activities. Before and after TCLT, participants completed a cognitive task (Level-1 of parametric Go/No-task), which measures attentional performance. Results: Our results revealed improvement of efficiency score as the main parameter of attentional performance in the real intervention group versus sham-TCLT group. The interaction of group × time was significant (P = 0.004). Mean change of the efficiency score was higher in the real intervention group (mean = 4.6 ± 3) than the sham group (mean = 0.8 ± 3) after TCLT (P = 0.001). Conclusions: Applying the TCLT by LED source over the PFC, promotes attentional performance as an important cognitive function.
... Photobiomodulation (PBM) involves the use of visible to near-infrared (NIR) light (500-1000 nm) produced by a laser or non-coherent light sources such as light emitting diodes (LEDs) applied to the body to produce beneficial cellular effects. Light in this range penetrates tissue depending on the wavelength and stimulates cellular function via activation of photoacceptors (Rojas et al. 2008;Tata & Waynant 2010;Rojas & Gonzalaz-Lima 2011). ...
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Purpose: To evaluate the efficacy of photobiomodulation (PBM) treatment for patients with dry age-related macular degeneration (AMD). Methods: Assessments on 42 eyes with dry AMD (age related eye disease study (AREDS) 2-4) were conducted. Multiwavelength light emitting diode (LED) light comprising of yellow (590 nm), red (670 nm) and near-infrared (790 nm) bandwidths was applied to subjects' eyes for a treatment course of 3 weeks. Outcome measures were changes in best-corrected visual acuity (BCVA), contrast sensitivity (CS), drusen volume and central drusen thickness. Results: Significant improvement in mean BCVA of 5.90 letters (p < 0.001) was seen on completion of the 3-week treatment and 5.14 letters (p < 0.001) after 3 months. Contrast sensitivity improved significantly (log unit improvement of 0.11 (p = 0.02) at 3 weeks and 3 months (log unit improvement of 0.16 (p = 0.02) at three cycles per degree. Drusen volume decreased by 0.024 mm(3) (p < 0.001) and central drusen thickness was significantly reduced by a mean of 3.78 μm (p < 0.001), while overall central retinal thickness and retinal volume remained stable. Conclusion: This is the first study demonstrating improvements in functional and anatomical outcomes in dry AMD subjects with PBM therapy. These findings corroborate an earlier pilot study that looked at functional outcome measures. The addition of anatomical evidence contributes to the basis for further development of a non-invasive PBM treatment for dry AMD.
... NIR also stimulates neurite outgrowth mediated by nerve growth factor, and this effect could also have positive implications for axonal protection [5]. Neuroprotective effects of incoherent red light, 670 nm light emitting diode (LED) and 630 nm narrow angle LED, have been documented in in vivo models of mitochondrial optic neuropathy [6,7]. In vivo bioenergetic changes with coherent NIR (810 nm diode laser) were observed at McLean Hospital (Belmont, MA) in beagle dogs, where a shift towards greater bioenergetic efficiency (PCr/ -NTP ratio) occurred in the anterior cingulate cortex after transcranial NIR exposure (3 times/week for 2 weeks) (Mintzopoulos et al., unpublished). ...
... However, due to their nonspecific interactions with multiple receptors and the so-called treatment resistance that happens in about 41 % of patients with depression during drug administration, anti-depressants still show limited success and are associated with a number of adverse effects [13,14]. Lowlevel laser treatment (LLLT) has been reported to modulate a variety of biological processes, like anti-oxidation, anti-inflammation, cell proliferation, and angiogenesis [15][16][17]. Compelling evidences have demonstrated that LLLT can preserve mitochondrial function by increasing cytochrome c oxidase activity and ATP synthesis [18,19]. In addition, Lapchak et al. demonstrated the efficacy of LLLT in facilitating ATP synthesis in cerebral cortex [20], suggesting its potential improvement on neurodegenerative disorders. ...
Article
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Major depressive disorder (MDD) is one of the leading forms of psychiatric disorders, characterized by aversion to mobility, neurotransmitter deficiency, and energy metabolic decline. Low-level laser therapy (LLLT) has been investigated in a variety of neurodegenerative disorders associated with mitochondrial dysfunction and functional impairments. The goal of this study was to examine the effect of LLLT on depression-like behaviors and to explore the potential mechanism by detecting mitochondrial function following LLLT. Depression models in space restriction mice and Abelson helper integration site-1 (Ahi1) knockout (KO) mice were employed in this work. Our results revealed that LLLT effectively improved depression-like behaviors, in the two depression mice models, by decreasing immobility duration in behavioral despair tests. In addition, ATP biosynthesis and the level of mitochondrial complex IV expression and activity were significantly elevated in prefrontal cortex (PFC) following LLLT. Intriguingly, LLLT has no effects on ATP content and mitochondrial complex I-IV levels in other tested brain regions, hippocampus and hypothalamus. As a whole, these findings shed light on a novel strategy of transcranial LLLT on depression improvement by ameliorating neurotransmitter abnormalities and promoting mitochondrial function in PFC. The present work provides concrete groundwork for further investigation of LLLT for depression treatment.
... 76 Neuroprotective effects of red light (670 nm) were documented in in vivo models of mitochondrial optic neuropathy. 77,78 Red light close to NIR spectrum (670 nm) has also been shown to protect neuronal cells against cyanide. 79 In animal models of TBI, NIR (810nm) appears to be an effective treatment and improves neurogenesis and synaptogenesis, via increase of brain-derived neurotrophic factor (BDNF). ...
Article
We examined the use of near-infrared and red radiation (photobiomodulation, PBM) for treating major depressive disorder (MDD). While still experimental, preliminary data on the use of PBM for brain disorders are promising. PBM is low-cost with potential for wide dissemination; further research on PBM is sorely needed. We found clinical and preclinical studies via PubMed search (2015), using the following keywords: "near-infrared radiation," "NIR," "low-level light therapy," "low-level laser therapy," or "LLLT" plus "depression." We chose clinically focused studies and excluded studies involving near-infrared spectroscopy. In addition, we used PubMed to find articles that examine the link between PBM and relevant biological processes including metabolism, inflammation, oxidative stress, and neurogenesis. Studies suggest the processes aforementioned are potentially effective targets for PBM to treat depression. There is also clinical preliminary evidence suggesting the efficacy of PBM in treating MDD, and comorbid anxiety disorders, suicidal ideation, and traumatic brain injury. Based on the data collected to date, PBM appears to be a promising treatment for depression that is safe and well-tolerated. However, large randomized controlled trials are still needed to establish the safety and effectiveness of this new treatment for MDD.
... Other studies have demonstrated similar effects of PBM on CCO activity in excitable cells in the retina, muscle and brain (Rojas et al., 2008(Rojas et al., , 2012Hayworth et al., 2010;Wang et al., 2016Wang et al., , 2017a. For instance, Hayworth et al. (2010) observed that PBM increases CCO activity in rat skeletal muscle, and Wang et al. (2016) found similar effects in the human forearm. ...
Article
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In cellular bioenergetics, cytochrome c oxidase (CCO) is the enzyme responsible for oxygen consumption in the mitochondrial electron transport chain, which drives oxidative phosphorylation for adenosine triphosphate (ATP) production. CCO is also the major intracellular acceptor of photons in the light wavelengths used for photobiomodulation (PBM). Brain function is critically dependent on oxygen consumption by CCO for ATP production. Therefore, our objectives were (1) to conduct the first detailed brain mapping study of the effects of PBM on regional CCO activity, and (2) to compare the chronic effects of PBM on young and aged brains. Specifically, we used quantitative CCO histochemistry to map the differences in CCO activity of brain regions in healthy young (4 months old) and aged (20 months old) rats from control groups with sham stimulation and from treated groups with 58 consecutive days of transcranial laser PBM (810 nm wavelength and 100 mW power). We found that aging predominantly decreased regional brain CCO activity and systems-level functional connectivity, while the chronic laser stimulation predominantly reversed these age-related effects. We concluded that chronic PBM modified the effects of aging by causing the CCO activity on brain regions in laser-treated aged rats to reach levels similar to those found in young rats. Given the crucial role of CCO in bioenergetics, PBM may be used to augment brain and behavioral functions of older individuals by improving oxidative energy metabolism.
... Photo-biomodulation therapy (PBMT) is a novel and noninvasive therapy based on delivering photons in the range of red to near-infrared (NIR) spectra (600-1,100 nm) inside tissues (83,84). PBMT can efficiently penetrate biological tissues including the CNS and produce beneficial photo-biomodulation effects; some of the proposed mechanisms of action are the increase in ATP synthesis, neurogenesis stimulation, increase on brain perfusion, and decrease of inflammation (85). ...
Article
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Depressive disorders are among the most common psychiatric conditions and contribute to significant morbidity. Even though the use of antidepressants revolutionized the management of depression and had a tremendous positive impact on the patient's outcome, a significant proportion of patients with major depressive disorder (MDD) show no or partial or response even with adequate treatment. Given the limitations of the prevailing monoamine hypothesis-based pharmacotherapy, glutamate and glutamatergic related pathways may offer an alternative and a complementary option for designing novel intervention strategies. Over the past few decades, there has been a growing interest in understanding the neurobiological underpinnings of glutamatergic dysfunctions in the pathogenesis of depressive disorders and the development of new pharmacological and non-pharmacological treatment options. There is a growing body of evidence for the efficacy of neuromodulation techniques, including transcranial magnetic stimulation, transcutaneous direct current stimulation, transcranial alternating current stimulation, and photo-biomodulation on improving connectivity and neuroplasticity associated with depression. This review attempts to revisit the role of glutamatergic neurotransmission in the etiopathogenesis of depressive disorders and review the current neuroimaging, neurophysiological and clinical evidence of these neuromodulation techniques in the pathophysiology and treatment of depression.
... The positive effects of red light include improving recovery rates of soft tissue injuries and myocardial infarction [35,36] and promoting wound healing, cause complement propagation, and reducing oxidative stress, inflammation and cell death [18,37,38]. In the case of the eye, rednear infrared light stimulates cytochrome c oxidase (COX) and ATP synthesis in the retina, mitigates oxygen-induced degeneration [39], protects against photoreceptor death in situ and attenuates histopathological changes in animal retinas in situ [37,[39][40][41][42][43][44][45][46]. ...
... Photobiomodulation therapy (PBMT), as a novel, drug-free, and noninvasive physiotherapy strategy, has shown to regulate neuronal functions in cell cultures, animal models, and clinical conditions (Eells et al., 2004;Rojas, Lee, John, & Gonzalez-Lima, 2008). Previous studies have shown that the application of PBMT could provide effective neuroprotection from Aβ-induced neuronal cell apoptosis, decrease neuronal loss, and ameliorate dendrite atrophy (Liang, Liu, & Xing, 2012;Meng, He, & Xing, 2013;Zhang, Wu, & Xing, 2012). ...
Article
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A hallmark of Alzheimer's disease (AD) is the accumulation of amyloid‐β (Aβ), which correlates significantly with progressive cognitive deficits. Although photobiomodulation therapy (PBMT), as a novel noninvasive physiotherapy strategy, has been proposed to improve neuronal survival, decrease neuron loss, ameliorate dendritic atrophy, and provide overall AD improvement, it remains unknown whether and how this neuroprotective process affects Aβ levels. Here, we report that PBMT reduced Aβ production and plaque formation by shifting amyloid precursor protein (APP) processing toward the nonamyloidogenic pathway, thereby improving memory and cognitive ability in a mouse model of AD. More importantly, a pivotal protein, SIRT1, was involved in this process by specifically up‐regulating ADAM10 and down‐regulating BACE1, which is dependent on the cAMP/PKA pathway in APP/PS1 primary neurons and SH‐SY5Y cells stably expressing human APP Swedish mutation (APPswe). We further found that the activity of the mitochondrial photoacceptor cytochrome c oxidase (CcO) was responsible for PBMT‐induced activation of PKA and SIRT1. Together, our research suggests that PBMT as a viable therapeutic strategy has great potential value in improving cognitive ability and combatting AD. Aβ overproduction plays a pivotal role in the pathogenesis of AD. Herein, we firstly revealed that photobiomodulation therapy (PBMT) as a drug‐free and noninvasive physiotherapy strategy was capable of lowering Aβ levels by shifting APP processing toward the nonamyloidogenic pathway, which is dependent on SIRT1 deacetylase activity. Photoactivation of mitochondrial photoacceptor cytochrome c oxidase (CcO) is responsible for the activation of PKA/SIRT1 signaling pathway.
... Numerous physical interventions have been used to slow down the progression of AD, such as laser therapy, repetitive transcranial magnetic stimulation (rTMS) and exercise [369][370][371][372]. Low-level laser treatment has been shown to alleviate Aβ-induced neuronal loss and dendritic atrophy by enhancing BDNF via ERK/CREB pathway activation [32]. ...
Article
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Synaptic abnormalities are a cardinal feature of Alzheimer’s disease (AD) that are known to arise as the disease progresses. A growing body of evidence suggests that pathological alterations to neuronal circuits and synapses may provide a mechanistic link between amyloid β (Aβ) and tau pathology and thus may serve as an obligatory relay of the cognitive impairment in AD. Brain-derived neurotrophic factors (BDNFs) play an important role in maintaining synaptic plasticity in learning and memory. Considering AD as a synaptic disorder, BDNF has attracted increasing attention as a potential diagnostic biomarker and a therapeutical molecule for AD. Although depletion of BDNF has been linked with Aβ accumulation, tau phosphorylation, neuroinflammation and neuronal apoptosis, the exact mechanisms underlying the effect of impaired BDNF signaling on AD are still unknown. Here, we present an overview of how BDNF genomic structure is connected to factors that regulate BDNF signaling. We then discuss the role of BDNF in AD and the potential of BDNF-targeting therapeutics for AD.
... For red to NIR light, the major intracellular moleculeabsorbing photons is CCO (19), a mitochondrial respiratory enzyme that can be upregulated in vitro and in vivo (3,11,20,21). Upregulation of CCO serves to convert high-energy photons into a source for ATP-based metabolic energy production in the brain (22). PBM of neural functions has been successfully demonstrated at 633-nm to 1,070-nm wavelengths (2,23,24). ...
Article
Safe, noninvasive, and effective treatments for brain conditions are everyone's dream. Low-level light therapy (LLLT) based on the photobiomodulation (PBM) phenomenon has recently been adopted in practice, with solid scientific evidence. Optogenetics provides high spatiotemporal resolution to precisely switch on and off a particular circuitry in the brain. However, there are currently no human trials of optogenetics on the human brain. These two approaches-PBM and optogenetics-are promising photonic treatments that target the brain using completely different technologies. PBM is based on the mitochondrial reaction to the photons for up- or downregulation on the cytochrome c oxidase synthase in cellular respiration. It is safe, noninvasive, and good for long-term treatments, with wide applications using light wavelengths ranging from 650 nm to ≈1,100 nm, the red to near-infrared range. Optogenetics is based on the expression of engineered opsins on targeted tissues through viral vectors. The opsins are engineered to be sensors, actuators, or switches and could be precisely controlled by light wavelength ranging from 450 nm to ≈650 nm, the visible light range. The penetration of visible light is limited, and thus the photons cannot be applied directly outside the head without surgical means to create a physical window. PBM using near-infrared light could reach deeper tissues for light directly applied outside the head. Detailed scientific foundations and the state of the art for both technologies are reviewed. Ongoing developments are discussed to provide insight for future research and applications.
... [35][36][37][38] LLLT could stimulate neuron regeneration and induce the proliferation of Schwann cells. 39 LLLT also increased the BDNF which is a crucial growth factor for neuronal survival and growth. It was shown that LLL had beneficial effects on Alzheimer's disease through the inhibition of Aβ-induced neurotoxicity and neurons loss. ...
Article
Introduction: Multiple sclerosis (MS) is an autoimmune disease. Inflammatory cells, cytokines and chemokines play a major role in the pathogenesis of the disease. Low-level laser therapy (LLLT) as a photobiostimulation approach could affect a wide range of cellular responses. LLLT inhibits the inflammatory signaling pathway, improves cell viability, inhibits apoptosis, modulates immune responses and induces the production of growth factors. Methods: In this review, we discuss the effect of LLLT on cellular responses and its application in the treatment of MS. Such keywords as "low-level laser therapy", "photobiomodulation" and "multiple sclerosis" were used to find studies related to laser therapy in MS in Google scholar, PubMed and Medline databases. Results: LLLT reduced the inflammatory immune cells and mediators. It also enhanced the regeneration of neurons. Conclusion: Investigations showed that besides current treatment strategies, LLLT could be a promising therapeutic approach for the treatment of MS.
... For example, Vargas et al. [23] submitted healthy elderly people to PBMT and observed an improvement in cognitive functions in the psychomotor vigilance task (PVT), the test of sustained attention and the delayed match-to-sample (DMS), a test of visual working memory. Many studies using animal models have also shown interesting results of PBM on the brain (e.g., [11,[25][26][27][28]. For instance, Lu et al. [11] injected beta amyloid (Aβ) in the hippocampus of rats that were treated with laser PBM for 5 days. ...
Article
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Photobiomodulation is a non-pharmacological tool widely used to reduce inflammation in many tissues. However, little is known about its effects on the inflammatory response in the aged brain. We conducted the study to examine anti-inflammatory effects of photobiomodulation in aging brains. We used aged rats (20 months old) with control (handled, laser off) or transcranial laser (660 nm wavelength, 100 mW power) treatments for 10 consecutive days and evaluated the level of inflammatory cytokines and chemokines, and the expression and activation of intracellular signaling proteins in the cerebral cortex and the hippocampus. Inflammatory analysis showed that aged rats submitted to transcranial laser treatment had increased levels of IL-1alpha and decreased levels of IL-5 in the cerebral cortex. In the hippocampus, the laser treatment increased the levels of IL-1alpha and decreased levels of IL-5, IL-18, and fractalkine. Regarding the intracellular signaling proteins, a reduction in the ERK and p38 expression and an increase in the STAT3 and ERK activation were observed in the cerebral cortex of aged rats from the laser group. In addition, the laser treatment increased the hippocampal expression of p70S6K, STAT3, and p38 of aged rats. Taken together, our data indicate that transcranial photobiomodulation can improve the inflammatory response and the activation of intracellular signaling proteins linked to vascular function and cell survival in the aged brain.
... Using D-galactose-induced aging mice, Salehpour and collaborators (Salehpour et al., 2017) noted that red (660 nm) and near-infrared (810 nm) laser for 6 weeks attenuated the impairment in spatial and episodic-like memories. One hypothesis to explain these effects may be related to the capacity of PBM to regulate neuronal functions (Eells et al., 2003;Rojas et al., 2008;Freitas and Hamblin, 2016), including cell proliferation (Shefer et al., 2002;Gao et al., 2006), DNA and protein synthesis (Feng et al., 2012), and oxidative energy metabolism (Wang et al., 2017b). ...
Article
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Aging is often accompanied by exacerbated activation of cell death-related signaling pathways and decreased energy metabolism. We hypothesized that transcranial near-infrared laser may increase intracellular signaling pathways beneficial to aging brains, such as those that regulate brain cell proliferation, apoptosis, and energy metabolism. To test this hypothesis, we investigated the expression and activation of intracellular signaling proteins in the cerebral cortex and hippocampus of aged rats (20 months old) treated with the transcranial near-infrared laser for 58 consecutive days. As compared to sham controls, transcranial laser treatment increased intracellular signaling proteins related to cell proliferation and cell survival, such as signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p70 ribosomal protein S6 kinase (p70S6K) and protein kinase B (PKB), also known as Akt that is linked to glucose metabolism. In addition, ERK is linked to memory, while ERK and JNK signaling pathways regulate glucose metabolism. Specifically, the laser treatment caused the activation of STAT3, ERK, and JNK signaling proteins in the cerebral cortex. In the hippocampus, the laser treatment increased the expression of p70S6K and STAT3 and the activation of Akt. Taken together, the data support the hypothesis that transcranial laser photobiomodulation improves intracellular signaling pathways linked to cell survival, memory, and glucose metabolism in the brain of aged rats.
... [127][128][129] PBM with 670 nm light provided neuroprotection of RGC dendrites following axotomy 130 and in an in vivo model of mitochondrial optic neuropathy. 131 Therefore, it may be a possible treatment to inhibit the RGC dendropathy seen in mitochondrial optic neuropathies, particularly considering that the mechanism of PBM is thought to augment mitochondrial efficiency. 132 ...
Article
Mitochondrial optic neuropathies are a group of optic nerve atrophies exemplified by the two commonest conditions in this group, autosomal dominant optic atrophy (ADOA) and Leber’s hereditary optic neuropathy (LHON). Their clinical features comprise reduced visual acuity, colour vision deficits, centro-caecal scotomas and optic disc pallor with thinning of the retinal nerve fibre layer. The primary aetiology is genetic, with underlying nuclear or mitochondrial gene mutations. The primary pathology is owing to retinal ganglion cell dysfunction and degeneration. There is currently only one approved treatment and no curative therapy is available. In this review we summarise the genetic and clinical features of ADOA and LHON and then examine what new avenues there may be for therapeutic intervention. The therapeutic strategies to manage LHON and ADOA can be split into four categories: prevention, compensation, replacement and repair. Prevention is technically an option by modifying risk factors such as smoking cessation, or by utilising pre-implantation genetic diagnosis, although this is unlikely to be applied in mitochondrial optic neuropathies due to the non-life threatening and variable nature of these conditions. Compensation involves pharmacological interventions that ameliorate the mitochondrial dysfunction at a cellular and tissue level. Replacement and repair are exciting new emerging areas. Clinical trials, both published and underway, in this area are likely to reveal future potential benefits, since new therapies are desperately needed.
... The association between PBM and mitochondrial function implicates it as a putative treatment of RGC degeneration caused by mitochondrial pathology such as that found in ADOA patients. It has already demonstrated therapeutic benefits following rotenone-induced mitochondrial dysfunction [37,38]. Furthermore, we previously showed that ex vivo PBM treatment of retinal flat-mounts inhibited axotomy-induced dendropathy of retinal ganglion cells (RGCs) [39]. ...
Article
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Retinal ganglion cells (RGCs) undergo dendritic pruning in a variety of neurodegenerative diseases, including glaucoma and autosomal dominant optic atrophy (ADOA). Axotomising RGCs by severing the optic nerve generates an acute model of RGC dendropathy, which can be utilized to assess the therapeutic potential of treatments for RGC degeneration. Photobiomodulation (PBM) with red light provided neuroprotection to RGCs when administered ex vivo to wild-type retinal explants. In the current study, we used aged (13–15-month-old) wild-type and heterozygous B6;C3-Opa1Q285STOP (Opa1+/−) mice, a model of ADOA exhibiting RGC dendropathy. These mice were pre-treated with 4 J/cm2 of 670 nm light for five consecutive days before the eyes were enucleated and the retinas flat-mounted into explant cultures for 0-, 8- or 16-h ex vivo. RGCs were imaged by confocal microscopy, and their dendritic architecture was quantified by Sholl analysis. In vivo 670 nm light pretreatment inhibited the RGC dendropathy observed in untreated wild-type retinas over 16 h ex vivo and inhibited dendropathy in ON-center RGCs in wild-type but not Opa1+/− retinas. Immunohistochemistry revealed that aged Opa1+/− RGCs exhibited increased nitrosative damage alongside significantly lower activation of NF-κB and upregulation of DJ-1. PBM restored NF-κB activation in Opa1+/− RGCs and enhanced DJ-1 expression in both genotypes, indicating a potential molecular mechanism priming the retina to resist future oxidative insult. These data support the potential of PBM as a treatment for diseases involving RGC degeneration.
... Apart from that, it not only promotes recovery from ischemia in cardiomyocytes (Zhang et al. 2009), but also enables muscle regeneration (Weiss and Oron 1992) and aids wound and retinal healing (Conlan et al. 1996;Eells et al. 2004). In neuronal cells, red/NIR light prevents neurotoxic effect of cyanide and azide (Desmet et al. 2006;Wong-Riley et al. 2005), restores axonal transport in Parkinson's disease (Trimmer et al. 2009), and exerts a neuroprotective effect against optic neuropathies (Rojas et al. 2008). ...
... Studies have shown that light therapy can produce antidepressant effects by increasing serotonin levels [44]. As a novel and noninvasive therapy based on irradiating tissues with photons in the range of red to near-infrared (NIR) spectra (600-1100 nm), photobiomodulation therapy (PBMT) has shown the role of regulating neuronal functions in cell cultures, animal models, and clinical conditions [45,46]. PBMT can efficiently penetrate into biological tissues including the CNS and produce beneficial photobiomodulation effects such as increasing ATP synthesis and stimulating neurogenesis [47]. ...
Article
Full-text available
Accumulating evidence indicates that dysfunction of the glutamatergic neurotransmission has been widely involved in the pathophysiology and treatment of depression. Photobiomodulation therapy (PBMT) has been demonstrated to regulate neuronal function both in vitro and in vivo. Herein, we aim to investigate whether the antidepressant phenotype of PBMT is associated with the improvement of glutamatergic dysfunction and to explore the mechanisms involved. Results showed that PBMT decreased extracellular glutamate levels via upregulation of glutamate transporter-1 (GLT-1) and rescued astrocyte loss in the cerebral cortex and hippocampus, which also alleviated dendritic atrophy and upregulated the expression of AMPA receptors on the postsynaptic membrane, ultimately exhibiting behaviorally significant antidepressant effects in mice exposed to chronic unpredictable mild stress (CUMS). Notably, PBMT also obtained similar antidepressant effects in a depressive mouse model subcutaneously injected with corticosterone (CORT). Evidence from in vitro mechanistic experiments demonstrated that PBMT treatment significantly increased both the GLT-1 mRNA and protein levels via the Akt/NF-κB signaling pathway. NF-κB-regulated transcription was in an Akt-dependent manner, while inhibition of Akt attenuated the DNA-binding efficiency of NF-κB to the GLT-1 promoter. Importantly, in vitro, we further found that PKA activation was responsible for phosphorylation and surface levels of AMPA receptors induced by PBMT, which is likely to rescue excitatory synaptic transmission. Taken together, our research suggests that PBMT as a feasible therapeutic approach has great potential value to control the progression of depression.
... NIR also stimulates neurite outgrowth mediated by nerve growth factor and promotes axonal protection [55]. Neuroprotective effects of far-red light (670 nm) were documented in in vivo models of mitochondrial optic neuropathy [56]. This wavelength has also been shown to protect neuronal cells against cyanide toxicity [57]. ...
Chapter
Major depressive disorder (MDD) is associated with prefrontal hypometabolism and mitochondrial dysfunction. Photobiomodulation (PBM) is a novel treatment under development for MDD. PBM uses near-infrared (NIR) or red light to modulate metabolism and functioning of different tissues and organs, including the brain. NIR and red light are nonionizing electromagnetic irradiations and can be delivered by noninvasive procedures. Most PBM studies evaluated the direct effect of light on the brain when it is delivered transcranially (t-PBM). However, an indirect effect has also been proposed when light is delivered to other parts of the body (other than the head). The suggested primary mechanism of action of PBM for MDD is the absorption of light energy by a mitochondrial enzyme, the cytochrome C oxidase, resulting in the increase of adenosine triphosphate production. Initial evidence on PBM for MDD indicates it is a safe and effective treatment option.
... 60 Second, it was recently demonstrated that low-light level therapy could contribute to increased intracellular Ca 2þ , which is a versatile second messenger 61,62 involved in transcriptional regulation via protein kinase A (PKA), MAPK, and calmodulin-stimulated protein kinase. 63 Moreover, an increase in Ca 2þ intracellular concentration can initiate the Ras/ERK cascade, 27 followed by increased c-Fos expression. Finally, PBM has been found to trigger retrograde mitochondrial signaling. ...
Article
Significance: Transcranial photobiomodulation (PBM) is a noninvasive neuromodulation technique capable of producing changes in the mitochondrial cytochrome c-oxidase (CCO) activity of neurons. Although the application of PBM in clinical practice and as a neurophysiological tool is increasing, less is known about how different treatment time intervals may result in different outcomes. Aim: We evaluated the effects of different PBM treatment intervals on brain metabolic activity through the CCO and proto-oncogene expression (c-Fos). Approach: We studied PBM effects on brain CCO and c-Fos expression in three groups of animals: Control (CN, n = 8 ), long interval PBM treatment (LI, n = 5 ), and short interval PBM treatment (SI, n = 5 ). Results: Increased CCO activity in the LI group, compared to the SI and CN groups, was found in the prefrontal cortices, dorsal and ventral striatum, and hippocampus. Regarding c-Fos expression, we found a significant increase in the SI group compared to LI and CN, whereas LI showed increased c-Fos expression compared to CN in the cingulate and infralimbic cortices. Conclusions: We show the effectiveness of different PBM interval schedules in increasing brain metabolic activity or proto-oncogene expression.
... Since the early 1980s numerous studies have shown increased intracellular ATP synthesis after irradiation with low level infrared laser. Enhanced energetic metabolism has been observed in cells and tissue under conditions of ischemia, intoxication and intense physical exercises by up to 200-300% [45][46][47][48][49][50][51][52][53]. ...
Article
In developing an effective clinical tool against COVID-19, we need to consider why SARS-CoV-2 infections develop along remarkably different trajectories: from completely asymptomatic to a severe course of disease. In this paper we hypothesize that the progressive exhaustion and loss of lymphocytes associated with severe stages of COVID-19 result from an intracellular energy deficit in an organism which has already been depleted by preexisting chronic diseases, acute psychological stress and the aging process. A bioenergetics view of COVID-19 immunopathology opens a new biophysical opportunity to enhance impaired immune function via proposed pathways of photomagnetic catalysis of ATP synthesis, regenerative photobiomodulation and the ultrasonic acceleration of cell restructuring. Moreover, we suggest that a coherent application of multiple biophysical radiances (coMra) may synergistically enhance energy-matter-information kinetics of basal self-regeneration of cells and thus improve immune function and accelerate recovery.
... Это предположение поддерживают также ранее полученные факты, что терапия низкоинтенсивным лазерным светом в длинноволновом диапазоне электромагнитного спектра (600-1000 нм) защищает от повреждения нейроны и другие клетки сетчатки [36]. Использование красного света 670 нм в качестве прекондиционирующего стимула может оказывать мощный нейропротекторный эффект против последующего повреждения, вызванного интенсивным светом [37,38] и токсическими агентами [39]. ...
Article
In premature babies, plastic changes develop in the neural retina, which, depending on the severity of retinopathy of prematurity (ROP), are a manifestation of adaptive or non-adaptive plasticity. In various experimental studies on animal ROP models, the conditioning effects of intermittent white light stimulation and various mechanisms of the positive effect of red and ultraviolet radiation on the plasticity of the retina have been demonstrated, which allows phototherapy to be considered as a promising modifying treatment for ROP supplementing the main therapy. Taking into account that light-dependent processes are involved in the pathogenesis of ROP, we also hypothesize that fractal phototherapy with complex-structured optical stimuli, as a method of activating adaptive neuroplasticity, can be most effective in the complex of methods for preventing and treating ROP.
... Previously, it was shown that LED irradiation with wavelength of 633 nm has neuroprotective effects in rotenone-induced neurotoxic model. 22 Near-infrared PBM was shown to protect dopaminergic cells both in acute and chronic in vivo models of Parkinson's disease 23,24 and can be beneficial for mice with parkinsonism both at cellular and behavioral levels. [25][26][27] Infrared irradiation is a helpful tool for tissue therapies or three-dimensional scaffolds application. ...
... Furthermore, lowlevel light therapy, recently renamed photobiomodulation, has been suggested to provide neuroprotection against Parkinson's and other neurodegenerative diseases, and to provide beneficial effects in wound healing after traumatic events and in psychiatric disorders (Schiffer et al., 2009;Hamblin, 2016;Johnstone et al., 2016). The suggested mechanism of action entails increasing cytochrome oxidase and superoxide dismutase activities (Rojas et al., 2008), which increase cytochrome c oxidation, oxygen consumption, and mitochondrial membrane potential, thereby altering electron flow (Rojas and Gonzalez-Lima, 2011). Though these effects are modulated by a photoacceptor and not a photoreceptor per se, the wide range of NIR light that has been shown to elicit the beneficial effects of photobiomodulation suggest that other photoacceptors/photoreceptors might be involved (Hamblin, 2016). ...
Article
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Sensory receptors that detect and respond to light, taste, and smell primarily belong to the G-protein-coupled receptor (GPCR) superfamily. In addition to their established roles in the nose, tongue, and eyes, these sensory GPCRs have been found in many ‘non-sensory' organs where they respond to different physicochemical stimuli, initiating signaling cascades in these extrasensory systems. For example, taste receptors in the airway, and photoreceptors in vascular smooth muscle cells, both cause smooth muscle relaxation when activated. In addition, olfactory receptors are present within the vascular system, where they play roles in angiogenesis as well as in modulating vascular tone. By better understanding the physiological and pathophysiological roles of sensory receptors in non-sensory organs, novel therapeutic agents can be developed targeting these receptors, ultimately leading to treatments for pathological conditions and potential cures for various disease states.
Preprint
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Photobiomodulation is a non-pharmacological tool widely used to reduce inflammation in many tissues. However, little is known about its effects on the inflammatory response in the aged brain. We conducted the study to examine anti-inflammatory effects of photobiomodulation in aging brains. We used aged rats (20 months old) with control (handled, laser off) or transcranial laser (660 nm wavelength, 100 mW power) treatments for 10 consecutive days and evaluated the level of inflammatory cytokines and chemokines, and the expression and activation of intracellular signaling proteins in the cerebral cortex and the hippocampus. Inflammatory analysis showed that aged rats submitted to transcranial laser treatment had increased levels of IL-1alpha and decreased levels of IL-5 in the cerebral cortex. In the hippocampus, the laser treatment increased the levels of IL-1alpha and decreased levels of IL-5, IL-18 and fractalkine. Regarding the intracellular signaling proteins, a reduction in the ERK and p38 expression and an increase in the STAT3 and ERK activation were observed in the cerebral cortex of aged rats from the laser group. In addition, the laser treatment increased the hippocampal expression of p70S6K, STAT3 and p38 of aged rats. Taken together, our data indicate that transcranial photobiomodulation can improve the inflammatory response and the activation of intracellular signaling proteins linked to vascular function and cell survival in the aged brain.
Chapter
Tissue engineering techniques, to replace wounded or missing tissue, are advancing rapidly to ensure the speedy recovery of patients. However, this field faces limitations of cells and biomaterials which prevents the acceleration of regeneration. Low level light therapy, a physical therapy, shows potential in enhancing and supporting the existing medicinal treatments. Visible light in the red and near-infrared range has shown to have positive stimulatory effects on various types of cells involved in wound healing and tissue regeneration. As angiogenesis is an essential part of this process, light therapy was investigated in multiple studies to see its beneficial effect on vessel formation. In vitro, in vivo, and in a clinical setup, LLLT therapy proved that it is capable of stimulating not only endothelial cells but other cells such as fibroblasts, smooth muscle cells, and lymphocytes which are involved in the vessel formation process. It triggers the activation of cytochrome c oxidase, which leads to the production of NO, ROS, and ATP in the mitochondria. These molecules appear to act as secondary messengers initiating ERK/Sp1 and PI3K signaling pathway, which in turn leads to proliferation, migration, and the synthesis of proangiogenic factors. This data indicates that LLLT could be a promising adjuvant treatment in the future.
Working Paper
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Mild and moderate traumatic brain injury, including post concussion syndrome, (mTBI) have been a subject of increasing interest in medicine. It is now recognized that the severity of the initial physical trauma presentation may not indicate the extent of impact on neurons or the significance of both short and long term consequences of the injury. The initial injury and resulting cascade of neuronal responses to injury have consequences that can be manifested by overt symptoms such as chronic headaches, anxiety, depression, insomnia, social withdrawal, and seizures. Additionally, there often are more subtly manifested symptoms that may include impairment in working memory and information processing speed, dysautonomia, or other indications of CNS dysfunction. The unfortunate impact of unrecognized or undertreated mTBI is that it may lead to long term disability for the patient in the form of impaired ADL capacity or employability. There is also an additional concern of neurodegeneration in some subsets of mTBI patients.
Book
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Pain is a concept that is clinically and pathogenetically complex and heterogeneous. It varies in intensity, localization and subjective manifestations (shooting, pressing, pulsating, pricking, cutting, aching, etc.), can be permanent or periodic, which is largely due to localization and what causes it. Some well-recognised types of pain include muscle or joint-muscle pain. An example of this type of pain is fibromyalgia, a rheumatic disease of unknown etiology, is characterized by generalized muscle weakness and painful palpation in limited areas of the body, designated as trigger points. Effective methods of treatment of patients with this disease have not yet been developed. Some medications allow the patient some form of short-term relief, however, even this is not always the case. Using a complex approach, which involves a wide range of laser therapy methods, it allows the human body to restore itself and any abnormalities in the functioning of various organs and systems, which, as well as providing direct analgesia, ensures the elimination of the causes of the disease. In addition, laser therapy methods are simple and safe, and unlike analgesics do not cause side effects, as well as there being no contraindications. Laser illumination doesn’t only affect one link of the painful reception, but essentially the whole hierarchy of mechanisms in the appearance of pain. Due to this, the curative effect persists for a long period of time. This “versatility” predetermines the exceptional effectiveness of laser therapy, all while using adequate techniques and appropriate equipment. Laser therapeutic devices in the LASMIK series have a frequency of up to 10.000Hz, and a unique set of laser emitting attachments and nozzles. These are the most suitable for implementing methods of pain management. The book is intended for specialists in rehabilitation, rheumatologists, traumatologists, general practitioners and physiotherapists.
Article
Jedes Jahr erleiden mehr als 600 000 Europäer/Innen einen Schlaganfall. Dies ist mit enormen Belastungen für das Gesundheitssystem verbunden und es muss davon ausgegangen werden, dass die Häufigkeit von Schlaganfällen in den nächsten Jahrzehnten ansteigen wird. Zusätzlich zu der konventionellen medikamentösen Therapie wird der Schlaganfall manchmal mit hoch-invasiven Methoden behandelt. Nicht-invasive Lasermethoden werden hingegen durch den Schädelknochen angewandt. In Laserstudien weltweit konnte die Penetration des Laserstrahls durch den Knochen noch nicht sicher festgestellt werden. Derzeit ist es niemandem im Detail bekannt, welche Laser Parameter am intakten Schädel ausgewählt werden müssen, sodass das Laserlicht seine potentielle Wirkung innerhalb des menschlichen Schädelknochens entfalten kann. Die vorliegende Studie demonstriert, dass die Werte für die Wellenlängen 810 nm und 658 nm gut mit bereits vorhandenen Werten aus vorangehenden Experimenten korrelieren. Allerdings muss erwähnt werden, dass die Informationen über den gelben Laser um eine Zehnerpotenz abweichen und somit inkorrekt angegeben wurden. Weitere Forschungen zur Auswahl korrekter Wellenlängen und Parameter könnten die gesamte Lasertherapie positiv beeinflussen.
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This chapter describes our animal and human studies using red to near-infrared lasers and LEDs, a noninvasive and relatively inexpensive intervention, which we are investigating for neuroprotection and for the augmentation of cognitive brain functions. The first part deals with animal studies on the prevention of neurodegeneration and behavioral deficits by photobiomodulation. We describe light parameters that prevent optic neuropathy in vivo. These include fractionated exposure to light wavelengths that correspond to the absorption spectrum of the mitochondrial respiratory enzyme cytochrome oxidase. We show that such light stimulates cell respiration and upregulates cytochrome oxidase activity and the antioxidant enzyme superoxide dismutase. The human studies in the second part of the chapter demonstrate that photobiomodulation may be translated from animals to humans as a noninvasive, safe, nonpharmacological, and cost-effective method for augmentation of brain functions. The translation to human studies shows that transcranial infrared laser stimulation of the forehead causes cognitive enhancement associated with cerebrovascular oxygenation of the prefrontal cortex. Noninvasive methods such as near-infrared spectroscopy, magnetic resonance imaging, and electroencephalography were able to monitor metabolic, hemodynamic, and electrophysiological effects on human brains in real time. Combining photobiomodulation with such neurophysiological monitoring allows for calibration of the laser dose for individuals based on their own particular cerebrovascular response. This approach might also permit identifying potential candidates for photobiomodulation before clinical presentation of neurodegenerative effects. This research may have a broad impact, not only relevant for cognitive enhancement in healthy people but also potential for the noninvasive treatment of neurodegenerative and neurocognitive disorders.
Book
In this book, the authors have provided the latest and most in-depth information on one of clinical medicine's most useful tools: Low-Level Laser Therapy (LLLT). Written by over a dozen experts from five continents, from Jerusalem to Johannesburg and San Diego to Sao Paolo, the breadth of knowledge provided herein expands not only the globe, but many medical fields. LLLT is an inexpensive, easily employed therapeutic strategy that has validated clinical utility in dermatology, oncology, dentistry, veterinary field, wound healing and many other medical arenas. This book provides the most up-to-date information on recent clinical trials as well as catalogs the optimal therapeutic settings for a myriad of disease states. In the past, biochemical mechanisms associated with LLLT therapy have not been well-described; however, this book provides comprehensive and simple biochemical processes pieced together from theories provided by the most recent and reputable publications. The mechanisms involved in the numerous diseases covered by each chapter are also included herein. Low-Level Laser Therapy: History, Mechanisms, and Clinical Uses captures the incredible dynamic usefulness of this simple technology while also listing the therapeutic settings that have been deemed the most effective for dozens of medical ailments. Whether you are a student of medicine or a clinical practitioner, this book will serve as a helpful guide on how LLLT could play a role in the care you or your team provides on a daily basis.
Article
Purpose: With very photophobic patients, the advantages of red or near infrared light to develop new ophthalmology imaging devices seem obvious: no or little glare, possibility of long signal integration, no phototoxicity, and lesser autofluorescence of ocular tissues. Nevertheless, in this range, the shortest possible wavelength facilitates signal detection. The aim of this study was, thus, to determine the maximal irradiance tolerated with 6 wavelengths: 2 red, 2 far red, and 1 near infrared lights to determine the shortest wavelength well tolerated by patients, in comparison with the standard cobalt blue light of ophthalmology slitlamp. Methods: An interventional, monocentric, single-group assignment study was conducted on 30 eyes of 30 patients with infectious keratitis. Thanks to a customized machine, the photophobic eye was exposed to the 6 lights with increasing intensity. The patients switched off the light when the discomfort was too elevated. The maximal cumulative irradiance possible at 482, 650, 675, 700, 750, and 800 nm were 171, 689, 759, 862, 920, and 889 mW/cm, respectively. Results: The maximal cumulative irradiance tolerated by patients increased significantly with wavelength (P < 0.001), but the difference was not significant between each increment: red at 675 nm gave a significantly higher cumulative irradiance than blue at 482 nm; red at 700 nm did not provide significant gain compared with 675 nm; and far red at 750 nm still provided additional gain compared with 700 nm, but no significant gain was observed between 750 and 800 nm. The shortest wavelengths were stopped more quickly, and more than 50% of patients reached the maximum irradiance delivered by the source at 750 and 800 nm. Conclusions: We demonstrate that a light source at 750 and 800 nm can be used for ophthalmic imaging with good tolerance in photophobic patients. Clinical trial registration: NCT03586505.
Article
Positive behavioral improvement has been observed following transcranial near-infrared light therapy in humans with chronic traumatic brain injury and acute stroke. We first examined the effect of 808 nm laser diode irradiation on regional cerebral blood flow (rCBF) in mice. An 808 nm CW diode laser was applied to the hemisphere transcranially. Transcranial near-infrared laser irradiation increased rCBF by 30% compared to control value in mice. Near-infrared laser irradiation also provoked a significant increase in cerebral nitric oxide concentration. In the clinical setting, transcranial near-infrared lightemitting diode irradiation to the forehead in a patient with persistent vegetative state following head injury was done. rCBF showed focal increase of 20%, compared to the pre-treatment value. The patient showed some improvement in his neurological condition after light-emitting diode therapy. Transcranial near-infrared irradiation might increase rCBF with some improvement of neurological condition in patients. Further study is warranted.
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This chapter explains the theory and methods for the mapping of cytochrome oxidase activity in the brain using quantitative histochemistry. Cytochrome oxidase catalyzes the electron transfer from cytochrome c to oxygen in all higher forms of living organisms. cytochrome oxidase activity can be measured histochemically using diaminobenzidine as the electron donor to reduce cytochrome c. This histochemical reaction is performed in fresh-frozen brains under conditions of linearity, using internal activity standards and quantitative densitometry, to allow quantification of enzymatic activity units. During cellular respiration, this reaction is necessary for ATP synthesis because of its coupling with oxidative phosphorylation. Cytochrome oxidase is critically important to neurons because they depend on oxidative metabolism for energy production. This chapter also reviews the regional brain effects of cytochrome oxidase inhibition. Enhanced vulnerability to cytochrome oxidase inhibition is found in brain regions most often engaged in associative memory functions. It is proposed that this vulnerability may depend on the sustained neuronal metabolic demands that long-term learning and memory imposes on these regions.
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Continuous (CW) and pulsed light were used for the noninvasive measurement of hemoglobin oxygenation in tissues. A dual wavelength method of continuous illumination spectroscopy used 760 nm (deoxyhemoglobin peak) and 800 nm (an oxyhemoglobin-deoxyhemoglobin isosbestic point) to measure the kinetics and extent of oxyhemoglobin deoxygenation in brains during mild ischemia/hypoxia. Absorption and scattering were modeled in an artificial milk/yeast blood system, which gave an exponential relationship between absorption and optical path length to a depth of 7 cm. Time-resolved spectroscopy (10-ps resolution) afforded a display of the times and distances of arrival of photons emitted by the cat brain in response to a 10-ps input pulse. The emitted photons rose to a peak in a fraction of a nanosecond and declined exponentially over a few nanoseconds. The half-time of exponential decay corresponds to photon migration over a distance of 4 cm. Exponential light emission continued for several more nanoseconds when the brain was encased by the skull, which plays a key role in prolonging light emission. The exponential decline of light intensity has a value [exp(-microL)], where L is the path length determined from the time/distance scale and mu is the characteristic of the migration of light in the brain. The factor mu is increased by increasing absorption, and mu' = epsilon C where epsilon and C are the Beer-Lambert parameters of extinction coefficient (epsilon) and concentration (C). Thus, deoxyhemoglobin can be quantified in brain tissues.
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In order to gain some insight into the mechanism of interaction between Helium-Neon (He-Ne) laser light and mitochondrial cytochromes, the sensitivity of cytochrome electron transfer activity to He-Ne laser was tested. Irradiation of solutions containing either purified cytochromes or dissolved rat liver mitochondria was carried out (wavelength 632.8 nm, fluence rate 10 mW cm(-2), fluence 2 J cm(-2)); the irradiation conditions were the ones able to affect cytochrome c oxidase (COX) activity in mitochondria (Pastore et al., 1994). Cytochrome c oxidation catalysed by COX was affected by He-Ne laser irradiation of the purified enzyme. This result was obtained from measurements of the pseudo-first-order kinetic constant and from determinations of the turnover number of the enzyme, performed at different cytochrome c/COX ratios. Consistently, the kinetic parameters of COX changed. On the contrary, no alteration in the rate of electron transfer catalysed by either cytochrome c or bc1 complex was found. This study shows that purified COX is a specific target of He-Ne laser light; therefore, COX may be considered to be a mitochondrial photo-acceptor.
Article
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The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.
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Leber's hereditary optic neuropathy (LHON) is characterized by maternally transmitted, bilateral, central vision loss in young adults. It is caused by mutations in the mitochondrial DNA (mtDNA) encoded genes that contribute polypeptides to NADH dehydrogenase or complex I. Four mtDNA variants, the nucleotide pair (np) 3460A, 11778A, 14484C, and 14459A mutations, are known as "primary" LHON mutations and are found in most, but not all, of the LHON families reported to date. Here, we report the extensive genetic and biochemical analysis of five Russian families from the Novosibirsk region of Siberia manifesting maternally transmitted optic atrophy consistent with LHON. Three of the five families harbor known LHON primary mutations. Complete sequence analysis of proband mtDNA in the other two families has revealed novel complex I mutations at nps 3635A and 4640C, respectively. These mutations are homoplasmic and have not been reported in the literature. Biochemical analysis of complex I in patient lymphoblasts and transmitochondrial cybrids demonstrated a respiration defect with complex-I-linked substrates, although the specific activity of complex I was not reduced. Overall, our data suggests that the spectrum of mtDNA mutations associated with LHON in Russia is similar to that in Europe and North America and that the np 3635A and 4640C mutations may be additional mtDNA complex I mutations contributing to LHON expression.
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The purpose of this study was to assess and to formulate physically an irreducible set of irradiation parameters that could be relevant in the achieving reproducible light-induced effects in biological systems, both in vitro and in vivo. Light-tissue interaction studies focusing on the evaluation of irradiation thresholds are basic for the extensively growing applications for medical lasers and related light-emitting systems. These thresholds are of central interest in the rejuvenation of collagens, photorefractive keratectomy, and wound healing. There is ample evidence that the action of light in biological systems depends at least on two threshold parameters: the energy density and the intensity. Depending on the particular light delivery system coupled to an irradiation source, the mean energy density and the local intensity have to be determined separately using adequate experimental methods. From the observations of different research groups and our own observations, we conclude that the threshold parameters energy density and intensity are biologically independent from each other. This independence is of practical importance, at least for the medical application of photobiological effects achieved at low-energy density levels, accounting for the success and the failure in most of the cold laser uses since Mester's pioneering work.
Article
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Light close to and in the near-infrared range has documented benefits for promoting wound healing in human and animals. However, mechanisms of its action on cells are poorly understood. We hypothesized that light treatment with a light-emitting diode array at 670 nm (LED) is therapeutic in stimulating cellular events involving increases in cytochrome oxidase activity. LED was administered to cultured primary neurons whose voltage-dependent sodium channels were blocked by tetrodotoxin. The down-regulation of cytochrome oxidase activity by TTX was reverted to control levels by LED. LED alone also up-regulated enzyme activity. Thus, the results are consistent with our hypothesis that LED has a stimulating effect on cytochrome oxidase in neurons, even when they have been functionally silenced by TTX.
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Low energy laser irradiation (LELI) has been shown to promote skeletal muscle cell activation and proliferation in primary cultures of satellite cells as well as in myogenic cell lines. Here, we have extended these studies to isolated myofibers. These constitute the minimum viable functional unit of the skeletal muscle, thus providing a close model of in vivo regeneration of muscle tissue. We show that LELI stimulates cell cycle entry and the accumulation of satellite cells around isolated single fibers grown under serum-free conditions and that these effects act synergistically with the addition of serum. Moreover, for the first time we show that LELI promotes the survival of fibers and their adjacent cells, as well as cultured myogenic cells, under serum-free conditions that normally lead to apoptosis. In both systems, expression of the anti-apoptotic protein Bcl-2 was markedly increased, whereas expression of the pro-apoptotic protein BAX was reduced. In culture, these changes were accompanied by a reduction in the expression of p53 and the cyclin-dependent kinase inhibitor p21, reflecting the small decrease in viable cells 24 hours after irradiation. These findings implicate regulation of these factors as part of the protective role of LELI against apoptosis. Taken together, our findings are of critical importance in attempts to improve muscle regeneration following injury.
Article
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The purpose of this study was to determine the effects of prophylactic near-infrared light therapy from light-emitting diodes (LEDs) in pediatric bone marrow transplant (BMT) recipients. Oral mucositis (OM) is a frequent side effect of chemotherapy that leads to increased morbidity. Near-infrared light has been shown to produce biostimulatory effects in tissues, and previous results using near-infrared lasers have shown improvement in OM indices. However, LEDs may hold greater potential for clinical applications. We recruited 32 consecutive pediatric patients undergoing myeloablative therapy in preparation for BMT. Patients were examined by two of three pediatric dentists trained in assessing the Schubert oral mucositis index (OMI) for left and right buccal and lateral tongue mucosal surfaces, while the patients were asked to rate their current left and right mouth pain, left and right xerostomia, and throat pain. LED therapy consisted of daily treatment at a fluence of 4 J/cm(2) using a 670-nm LED array held to the left extraoral epithelium starting on the day of transplant, with a concurrent sham treatment on the right. Patients were assessed before BMT and every 2-3 days through posttransplant day 14. Outcomes included the percentage of patients with ulcerative oral mucositis (UOM) compared to historical epidemiological controls, the comparison of left and right buccal pain to throat pain, and the comparison between sides of the buccal and lateral tongue OMI and buccal pain. The incidence of UOM was 53%, compared to an expected rate of 70-90%. There was also a 48% and 39% reduction of treated left and right buccal pain, respectively, compared to untreated throat pain at about posttransplant day 7 (p < 0.05). There were no significant differences between sides in OMI or pain. Although more studies are needed, LED therapy appears useful in the prevention of OM in pediatric BMT patients.
Article
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Methanol intoxication produces toxic injury to the retina and optic nerve, resulting in blindness. The toxic metabolite in methanol intoxication is formic acid, a mitochondrial toxin known to inhibit the essential mitochondrial enzyme, cytochrome oxidase. Photobiomodulation by red to near-IR radiation has been demonstrated to enhance mitochondrial activity and promote cell survival in vitro by stimulation of cytochrome oxidase activity. The present studies were undertaken to test the hypothesis that exposure to monochromatic red radiation from light-emitting diode (LED) arrays would protect the retina against the toxic actions of methanol-derived formic acid in a rodent model of methanol toxicity. Using the electroretinogram as a sensitive indicator of retinal function, we demonstrated that three brief (2 min, 24 s) 670-nm LED treatments (4 J/cm(2)), delivered at 5, 25, and 50 h of methanol intoxication, attenuated the retinotoxic effects of methanol-derived formate. Our studies document a significant recovery of rod- and cone-mediated function in LED-treated, methanol-intoxicated rats. We further show that LED treatment protected the retina from the histopathologic changes induced by methanol-derived formate. These findings provide a link between the actions of monochromatic red to near-IR light on mitochondrial oxidative metabolism in vitro and retinoprotection in vivo. They also suggest that photobiomodulation may enhance recovery from retinal injury and other ocular diseases in which mitochondrial dysfunction is postulated to play a role.
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Parkinson's disease (PD), a common neurodegenerative disorder affects approximately 1% of the population over 65. PD is a late-onset progressive motor disease characterized by tremor, rigidity (stiffness), and bradykinesia (slowness of movement). The hallmark of PD is the selective death of dopamine-containing neurons in the substantia nigra pars compacta which send their projections to the striatum and the presence of cytoplasmic aggregates called Lewy bodies. Most cases of PD are sporadic but rare cases are familial, with earlier onset. The underlying mechanisms and causes of PD still remain unclear.
Article
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Far red and near infrared (NIR) light promotes wound healing, but the mechanism is poorly understood. Our previous studies using 670 nm light-emitting diode (LED) arrays suggest that cytochrome c oxidase, a photoacceptor in the NIR range, plays an important role in therapeutic photobiomodulation. If this is true, then an irreversible inhibitor of cytochrome c oxidase, potassium cyanide (KCN), should compete with LED and reduce its beneficial effects. This hypothesis was tested on primary cultured neurons. LED treatment partially restored enzyme activity blocked by 10–100 μm KCN. It significantly reduced neuronal cell death induced by 300 μm KCN from 83.6 to 43.5%. However, at 1–100 mm KCN, the protective effects of LED decreased, and neuronal deaths increased. LED significantly restored neuronal ATP content only at 10 μm KCN but not at higher concentrations of KCN tested. Pretreatment with LED enhanced efficacy of LED during exposure to 10 or 100 μm KCN but did not restore enzyme activity to control levels. In contrast, LED was able to completely reverse the detrimental effect of tetrodotoxin, which only indirectly down-regulated enzyme levels. Among the wavelengths tested (670, 728, 770, 830, and 880 nm), the most effective ones (830 nm, 670 nm) paralleled the NIR absorption spectrum of oxidized cytochrome c oxidase, whereas the least effective wavelength, 728 nm, did not. The results are consistent with our hypothesis that the mechanism of photobiomodulation involves the up-regulation of cytochrome c oxidase, leading to increased energy metabolism in neurons functionally inactivated by toxins.
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Photobiomodulation (PBM) has been proposed as a potential therapy for spinal cord injury (SCI). We aimed to demonstrate that 810 nm light can penetrate deep into the body and promote neuronal regeneration and functional recovery. Adult rats underwent a T9 dorsal hemisection, followed by treatment with an 810 nm, 150 mW diode laser (dosage = 1,589 J/cm2). Axonal regeneration and functional recovery were assessed using single and double label tract tracing and various locomotor tasks. The immune response within the spinal cord was also assessed. PBM, with 6% power penetration to the spinal cord depth, significantly increased axonal number and distance of regrowth (P < 0.001). PBM also returned aspects of function to baseline levels and significantly suppressed immune cell activation and cytokine/chemokine expression. Our results demonstrate that light, delivered transcutaneously, improves recovery after injury and suggests that light will be a useful treatment for human SCI.
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Photobiomodulation by light in the red to near infrared range (630-1000 nm) using low energy lasers or light-emitting diode (LED) arrays has been shown to accelerate wound healing, improve recovery from ischemic injury in the heart and attenuate degeneration in the injured optic nerve. Recent evidence indicates that the therapeutic effects of red to near infrared light result, in part, from intracellular signaling mechanisms triggered by the interaction of NIR light with the mitochondrial photoacceptor molecule cytochrome c oxidase. We have demonstrated that NIR-LED photo-irradiation increases the production of cytochrome oxidase in cultured primary neurons and reverses the reduction of cytochrome oxidase activity produced by metabolic inhibitors. We have also shown that NIR-LED treatment prevents the development of oral mucositis in pediatric bone marrow transplant patients. Photobiomodulation improves wound healing in genetically diabetic mice by upregulating genes important in the promotion of wound healing. More recent studies have provided evidence for the therapeutic benefit of NIR-LED treatment in the survival and functional recovery of the retina and optic nerve in vivo after acute injury by the mitochondrial toxin, formic acid generated in the course of methanol intoxication. Gene discovery studies conducted using microarray technology documented a significant upregulation of gene expression in pathways involved in mitochondrial energy production and antioxidant cellular protection. These findings provide a link between the actions of red to near infrared light on mitochondrial oxidative metabolism in vitro and cell injury in vivo. Based on these findings and the strong evidence that mitochondrial dysfunction is involved in the pathogenesis of numerous diseases processes, we propose that NIR-LED photobiomodulation represents an innovative and non-invasive therapeutic approach for the treatment of tissue injury and disease processes in which mitochondrial dysfunction is postulated to play a role including diabetic retinopathy, age-related macular degeneration, Leber's hereditary optic neuropathy and Parkinson's disease.
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Low energy laser irradiation (LELI) has been shown to promote skeletal muscle cell activation and proliferation in primary cultures of satellite cells as well as in myogenic cell lines. Here, we have extended these studies to isolated myofibers. These constitute the minimum viable functional unit of the skeletal muscle, thus providing a close model of in vivo regeneration of muscle tissue. We show that LELI stimulates cell cycle entry and the accumulation of satellite cells around isolated single fibers grown under serum-free conditions and that these effects act synergistically with the addition of serum. Moreover, for the first time we show that LELI promotes the survival of fibers and their adjacent cells, as well as cultured myogenic cells, under serum-free conditions that normally lead to apoptosis. In both systems, expression of the anti-apoptotic protein Bcl-2 was markedly increased, whereas expression of the pro-apoptotic protein BAX was reduced. In culture, these changes were accompanied by a reduction in the expression of p53 and the cyclin-dependent kinase inhibitor p21, reflecting the small decrease in viable cells 24 hours after irradiation. These findings implicate regulation of these factors as part of the protective role of LELI against apoptosis. Taken together, our findings are of critical importance in attempts to improve muscle regeneration following injury.
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This paper reviews studies on the basic principles of biostimulation of wound healing by various low-energy lasers. It looks at the mechanism of action of biostimulation as well as the lasers effect on cell proliferation, collagen synthesis, and would healing.
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Background and Objectives Both photobiomodulation (PBM) and olfactory ensheathing cells (OECs) transplantation improve recovery following spinal cord injury. However, neither the combination of these two therapies nor the effect of light on OECs has been reported. The purpose of this study was to determine the effect of light on OEC activity in vitro.Materials and MethodsOECs were purified from adult rat olfactory bulbs and exposed to 810 nm light (150 mW; 0, 0.2, or 68 J/cm2). After 7–21 days in vitro, cells underwent immunocytochemistry or RNA extraction and RT-PCR.ResultsAnalysis of immunolabeling revealed a significant decrease in fibronectin expression in the cultures receiving 68 J/cm2. Analysis of gene expression revealed a significant (P < 0.05) increase in brain derived neurotrophic factor (BDNF), glial derived neurotrophic factor (GDNF), and collagen expression in the 0.2 J/cm2 group in comparison to the non-irradiated and 68 J/cm2 groups. OEC proliferation was also found to significantly increase in both light treated groups in comparison to the control group (P < 0.001).Conclusions These results demonstrate that low and high dosages of PBM alter OEC activity, including upregulation of a number of neurotrophic growth factors and extracellular matrix proteins known to support neurite outgrowth. Therefore, the application of PBM in conjunction with OEC transplantation warrants consideration as a potential combination therapy for spinal cord injury. Lasers Surg. Med. © 2005 Wiley-Liss, Inc.
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Low power laser irradiation has been reported to cause biological effects due to the photochemical and/or photophysical action of the radiation. This study determined quantitatively if transcutaneous low power laser irradiation can affect the regeneration of the rat facial nerve. The facial nerve was crushed unilaterally in anesthetized rats and transcutaneously irradiated daily with a laser beam directed at the area of the crush injury. Laser treatment began on the day of the crush injury and was continued daily for 7, 8, or 9 days. Preliminary experiments determined the most effective wavelength, laser power, length of irradiation, and treatment schedule. The wavelengths examined were 361, 457, 514, 633, 720, and 1064. The laser powers and lengths of irradiation examined ranged from 8.5 to 40mW and 13 to 120min. Irradiation treatment was done daily, on alternating days and on the first 4 days postcrush. The most effective laser parameters for the low power treatment included daily irradiation with a helium-neon (HeNe) or argon pumped tunable dye laser a wavelength of 633nm, with a power of 8.5mW for 90 minutes (45.9J, 162.4J/cm2). The number of horseradish peroxidase (HRP) labeled neurons in the facial motor nucleus was used as an assay of the degree of regeneration. In rats in which the facial nerve was crushed but not irradiated, the average number of HRP labeled neurons in the facial nucleus was 22 on day 7 postcrush, 54 on day 8, 116 on day 9, and 1,149 on day 10. After HeNe or argon pumped tunable dye laser irradiation, the average number of HRP labeled neurons increased to 34 on day 7 postcrush, 148 on day 8, and 1,725 on day 9. There was a statistically significant difference between the control and irradiated rats on day 9 postcrush (P<0.01). These data indicate that transcutaneous low power irradiation with the lasers and parameters involved in this study increased the rate of regeneration of rat facial nerve following crush injury.
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Background and Objectives Photobiomodulation (PBM) has been proposed as a potential therapy for spinal cord injury (SCI). We aimed to demonstrate that 810 nm light can penetrate deep into the body and promote neuronal regeneration and functional recovery.Study Design/Materials and Methods Adult rats underwent a T9 dorsal hemisection, followed by treatment with an 810 nm, 150 mW diode laser (dosage = 1,589 J/cm2). Axonal regeneration and functional recovery were assessed using single and double label tract tracing and various locomotor tasks. The immune response within the spinal cord was also assessed.ResultsPBM, with 6% power penetration to the spinal cord depth, significantly increased axonal number and distance of regrowth (P < 0.001). PBM also returned aspects of function to baseline levels and significantly suppressed immune cell activation and cytokine/chemokine expression.Conclusion Our results demonstrate that light, delivered transcutaneously, improves recovery after injury and suggests that light will be a useful treatment for human SCI. © 2005 Wiley-Liss, Inc.
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The structure and function of mitochondrial respiratory-chain enzyme proteins were studied postmortem in the substantia nigra of nine patients with Parkinson's disease and nine matched controls. Total protein and mitochondrial mass were similar in the two groups. NADH-ubiquinone reductase (Complex I) and NADH cytochrome c reductase activities were significantly reduced, whereas succinate cytochrome c reductase activity was normal. These results indicated a specific defect of Complex I activity in the substantia nigra of patients with Parkinson's disease. This biochemical defect is the same as that produced in animal models of parkinsonism by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and adds further support to the proposition that Parkinson's disease may be due to an environmental toxin with action(s) similar to those of MPTP.
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The authors describe the changes occurring in the spinal cord of rats subjected to crush injury of the sciatic nerve followed by low-power laser irradiation of the injured nerve. Such laser treatment of the crushed peripheral nerve has been found to mitigate the degenerative changes in the corresponding neurons of the spinal cord and induce proliferation of neuroglia both in astrocytes and oligodendrocytes. This suggests a higher metabolism in neurons and a better ability for myelin production under the influence of laser treatment.
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The brain is composed of a heterogeneous population of neurons whose physiological characteristics often elude morphological identification. The tight coupling between neuronal activity and oxidative energy metabolism forms the basis for the use of cytochrome oxidase as an endogenous metabolic marker for neurons. In the past decade, cytochrome oxidase histo- and cytochemistry have provided a window to view the regional, cellular and subcellular functional diversity among neurons. These methods have shown that the entire neuron is often not metabolically homogeneous; most of the oxidative activity is usually found in dendrites. They have also revealed the dynamic metabolic responses of developing and mature neurons to altered functional demands.