Photobiostimulation in Neurodegenerative Diseases: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 3 by Jason Zhu.

Photobiomodulation (PBM), also known as Low-level Laser Therapy (LLLT), involves the use of light from a laser or light-emitting diode (LED) in the treatment of various disorders and it has recently gained increasing interest. Progressive neuronal loss with attendant consequences such as cognitive and/or motor decline characterize neurodegenerative diseases. The available therapeutic drugs have only been able to provide symptomatic relief and may also present with some side effects, thus precluding their use in treatment. There has been an exponential increase in interest and attention in the use of PBM as a therapy in various neurodegenerative diseases in animal studies. Because of the financial and social burden of neurodegenerative diseases on the sufferers and the need for the discovery of potential therapeutic inventions in their management, it is pertinent to examine the beneficial effects of PBM and the various cellular mechanisms by which it modulates neural activity.

 

  • photobiomodulation
  • low laser light therapy
  • light-emitting diode (LED)

1. Alzheimer’s Disease (AD)

Alzheimer’s disease is a progressive neurodegenerative condition and the most common form of dementia clinically characterized by cognitive and memory dysfunction [1]. and is associated with tau hyperphosphorylation and beta-amyloid protein aggregation. The treatments that are currently available for patients who suffer from Alzheimer’s disease are not very effective and come with constraints. In reality, these medications are ineffective for the vast majority of patients and are linked to a wide variety of adverse effects [2][3].
In the study by Michalikova et al. [4], a pretreatment with a daily 6 min exposure to near-infrared 1072 for 10 days resulted in significant behavioral effects in middle-aged female CD-1 mice (12 months) tested in a 3D-maze. Near-infrared treatment in middle-aged mice reversed the significant working memory deficits.
Transcranial Laser Therapy (TLT) has been hypothesized to maintain neuronal function by boosting ATP production, mitochondrial activity, and cellular respiration. To this end, a study was conducted to investigate how TLT influenced a transgenic mouse model of amyloid-protein precursor. TLT (808 nm, 0.5 W/cm2, 2.8 W/cm2 and 5.6 W/cm2, 675 J/cm2, 336 J/cm2, and 672 J/cm2 for 6 months) was administered three times weekly, beginning at the age of three months, with varying doses compared to a control group (no laser treatment) with treatments lasting 6 months. Amyloid load, inflammatory markers, brain and plasma beta-amyloid levels, cerebrospinal fluid beta-amyloid level, soluble amyloid precursor protein (sAPP) levels, and behavioral changes were assessed in the rats following the experimental period. The amyloid plaque accumulation in the brain was significantly decreased following TLT administration, and this effect was dose-dependent. Based on these findings, TLT showed promise in AD treatment [5].
Likewise, a narrow waveband of infrared light of 1072 nm that was administered on female TASTPM mice (2 months) for 6 min sessions for two consecutive days, biweekly for 5 months, showed significant results in decreasing amyloid plaques and upregulating heat-shock protein expression [6].
Purushothuman et al. [7] had also earlier reported that in two mouse models of AD (the K3 mice and APP/PS1 mice), photobiostimulation caused a significant reduction in Alzheimer’s disease markers and oxidative stress markers in both the cortex, hippocampus, and cerebellum [8].
The study by da Luz Eltchechem et al. [9] examined the impact of photobiomodulation (LED 627 nm) treatment for 21 days on spatial memory and behavioral state in rats with Alzheimer’s disease (AD) induced by intracerebral injection of Aβ25–35 toxins in the hippocampus. In their study, the PBM was placed in the frontal region of the rat and the irradiation was performed daily for 100 s at a dose of 7 J/cm2 with a potency of 70 mW. The result obtained from their study demonstrated that there was a significant reduction in beta-amyloid plaques as evaluated histologically following PBM treatment on days 7, 14, and 21. Spatial learning and memory assessment by the Morris water maze task and open field test conducted to assess several behaviors (locomotion, exploration, and anxiety) showed significant improvements following the 21 days.
An in vitro study by Sommer et al. [10] had earlier reported a reduction in beta-amyloid plaques following their incorporation into the human neuroblastoma cells (SH-EP cells) and treatment with light irradiation (600 nm).
Heo et al. [11] used a hippocampal cell line (HT-22) and mouse organotypic hippocampal tissues to examine the role of antioxidants, the BDNF expression, and antioxidant enzymes, as well as the activation of cAMP response element binding (CREB) and extracellular signal-regulated kinase (ERK) signal transduction pathways, to evaluate the effect of PBM on hippocampal oxidative stress. Photobiomodulation induced an increase in BDNF production by activating the ERK and CREB signaling pathways, protecting HT-22 cells from apoptosis. Additionally, the levels of phosphorylated ERK and CREB, which had dropped due to oxidative stress, and the expression of the antioxidant enzyme superoxide dismutase were all boosted by PBMT in hippocampal organotypic slices. This further substantiates the antioxidant role of photobiomodulation in counteracting oxidative stress and the likely beneficial role of photobiostimulation on hippocampal-dependent functions.
A study by Meng et al. [12] supported the beneficial role of photobiostimulation with evidence that PBM stimulates synaptogenesis and restoration of damaged synapses in chronic neurodegenerative disease, and acute or chronic traumatic brain injury occurs via upregulation of brain-derived neurotrophic factor (BDNF). In their study, they utilized the SH-SY5Y cell line and primary hippocampal neuronal cultures to be able to ascertain the effect of low-laser light treatment (LLLT) on beta amyloid-induced neuronal death and dendritic atrophy. They found that LLLT was able to attenuate beta amyloid-induced toxicity and neurodegeneration. Upregulation of BDNF was, however, ERK/CREB pathway-dependent which has also been documented earlier [13][14][15].
The role of glycogen synthase kinase beta (GSK-3β) in the hyperphosphorylation of the microtubule-associated protein (tau) and production of neurofibrillary tangles, one of the pathological hallmarks of AD, cannot be overemphasized [16]. Glycogen synthase 3 beta (GSK-3β) has also been known to have both apoptotic and anti-apoptotic functions [17][18][19]. In the same manner, the central nervous system development is dependent on Wnt/β-Catenin signaling, while β-Catenin can also be phosphorylated by GSK3β [16][20]. These pieces of evidence have demonstrated the roles of these pathways in the development and likewise as a potential target in the treatment of AD. To this end, the study by Liang et al. [16] found that low-power laser irradiation was able to inhibit the activity of GSK3β vis-à-vis activation of Akt which in turn inhibited beta amyloid-induced programmed cell death. This has elucidated the role that photobiomodulation has in the Akt/GSK3β/β-catenin pathway.
Inflammation, which is the response of living vascularized tissues to injury, is a major component of most neurodegenerative diseases. Glial cells (astrocytes and microglia) have been known to be activated during the inflammatory process in neurodegenerative diseases and also in the release of inflammatory molecules. Song et al. [21] sought to examine the role of LLLT on microgliosis and the downstream signaling events. In their study, microglial activation was modeled by lipopolysaccharide (LPS) treatment on microglia BV2 cells. They found that 20 J/cm2 LLLT diminished Toll-Like Receptors’ (TLR) inflammatory actions, evidenced by reduced expressions of cytokine and NO. It was concluded that Src/Syk/PI3K/Akt is involved in this perceived effect.
Sirtuins are a group of NAD+-dependent protein deacetylases that help fight age-related diseases such as cancer, diabetes, heart disease, and neurological diseases. The SIR2 ortholog Sirtuin1 (SIRT1) is one of the seven mammalian sirtuins and plays a crucial role in reducing the severity of neurodegenerative illnesses by modulating neuron survival, neurite outgrowth, synaptic plasticity, cognitive function, and neurogenesis [22][23]. SIRT1 has been reported to have neuroprotective functions in Alzheimer’s disease [23][24]. Because of the high expression of SIRT1 in the hippocampus, an important area for memory consolidation and also vulnerable to AD pathology, Zhang et al. [25] researched the role of photobiomodulation therapy in AD. They reported that photobiomodulation offered protection in AD pathology by facilitating a shift in the amyloid precursor protein to the non-amyloidogenic pathway through the activation of the AMP/PKA/SIRT1 pathway.

2. Parkinson’s Disease (PD)

After Alzheimer’s disease, the most common form of neurodegeneration is the movement disorder known as Parkinson’s disease (PD) [26]. About 7,000,000 people around the world suffer from this illness [27]. There are estimates that 4% of people over the age of 80 will develop this age-related condition. Currently, 1–2% of people over the age of 60 suffer from it [28]. Over 17,000 people are diagnosed with Parkinson’s disease each year [29]. It is more common in men and can appear as early as age 20 [30][31]. The primary cause of this disorder is the dopaminergic neuronal loss in the substantia nigra’s striatal-projecting pars compacta (SNc) [32]. Intracytoplasmic inclusions of proteins such as alpha-synuclein characterize these neurodegenerative changes that worsen over time. Lewy bodies, which are intracytoplasmic inclusions of the protein alpha-synuclein, and Lewy neurites are extracellular inclusions of the protein [33] are the neuropathological hallmarks of Parkinson’s disease.
Dopamine is a neurotransmitter that modulates a variety of brain functions and is involved in several pathways. The nigrostriatal pathway is a neuronal circuit that helps regulate movement [30]. Sixty percent to eighty percent of dopaminergic neurons are lost in PD, leading to motor symptoms. Resting tremors, bradykinesia, rigidity, or postural instability are all symptoms that help doctors make a diagnosis. Mood disorders such as anxiety and depression, sleep disturbances, fatigue, gastrointestinal disturbances, cognitive decline, and olfactory impairment are all examples of non-motor symptoms of Parkinson’s disease (PD). Parkinson’s disease can impact one’s QoL and ability to perform daily tasks in both motor and non-motor ways [34][35].
The beneficial effect of PBM (670 nm, 0.16 mW, 10 mW) on tyrosine hydroxylase-expressing neurons and Glial-Derived Neurotrophic Factors (GDNF) following 6-hydroxydopamine (6-OHDA) and MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) lesioned striatal area in monkeys was evaluated in the study by El Massri et al. [36]. The study concluded that PBM demonstrated neuroprotective effects by restoring the loss of tyrosine hydroxylase-expressing neurons and increasing GDNF expression as compared to the control. In the same manner, it was reported that PBM (670 nm) treatment also influenced astrogliosis marker (GFAP) in MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) [37] and also synaptogenesis and brain-derived neurotrophic factor expression (BDNF) [38]. Despite the substantial evidence of the role PBM plays in the restoration of dopaminergic neuronal cell loss [36][37][39][40], little is known of its role in a lipopolysaccharide (LPS) model of dopaminergic cell loss; hence, the study by O’Brien and O’Brien and Austin [41] through the use of transcranial near-infrared photobiomodulation following supra nigral injections of 10 µg and 20 µg LPS in Sprague Dawley rats showed attenuation of inflammatory changes which was, however, dependent on the dose of the LPS administered.
Alim-Louis Benabid and his team in Grenoble have developed an implantable light-emitting device that has been tested in mouse, rat, and monkey models of PD by embedding the light-emitting device close to the midbrain. Intracranial PBM prevented the death of dopaminergic cells caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine, and it decreased the level of severity of the resulting functional deficit, in animal models [42].
Remote photobiostimulation, a procedure that involves irradiation to a specific tissue and the surrounding non-irradiated tissue also being protected has also been established [43]. Following the discovery of remote photobiostimulation, Johnstone et al. [44] found that irradiating the dorsum of mice with 670 nm light and protecting the head with aluminum foil reduced substantia nigra dopaminergic neuronal cell loss in the MPTP mouse model of PD. This was further established in another study using a different mouse strain [45].
Recent transcriptomic results from Ganeshan et al. [46] lend credence to the idea that remote PBM activates signaling systems within the brain that recruit stem cells, bolstering the case for more targeted future studies to directly examine whether remote PBM stimulates the peripheral mobilization of stem cells and their recruitment to injured regions of the brain.

3. Traumatic Brain Injury (TBI)

Treatment options for traumatic brain injury (TBI) remain a challenge to date. Alterations in cerebral blood flow (CBF) are also linked to traumatic brain injury, with a decrease in blood flow following unresponsive vasodilation likely caused by nitric oxide release in the tissue [47]. Likewise, acute TBI models in several animal studies have been used to recapitulate the human form of TBI because of the impossibility of modeling chronic TBI in animals [48]. After recovering from a moderate or severe head injury, it is quite common for people to experience a wide range of persistent symptoms, some of which include depression, headaches, sleep disturbances, and cognitive impairment (such as poor memory, impaired executive function, and difficulties concentrating) [48].
The potential benefit of photobiomodulation on traumatic brain injury [49][50] was earlier documented in the literature. The study sought to examine the role of the application of red or near-infrared (NIR) on the scalp with the hope that it would be able to improve the cognitive deterioration experienced by mild and traumatic brain-injury patients. In their study, patients with chronic and mild traumatic brain injuries resulting from either motor vehicle accidents, home accidents, or sports injuries were recruited into the study following which a light emitting diode (LED) (5.35 cm diameter, 500 mW, 22.2 mW/cm2) was administered on the head for 10 min for 6 weeks (18 sessions; 3 times weekly). Before and after the LED administration period, several neurophysiological tests were conducted to ascertain the pre- and post-effect of the application of the LED treatments. It was concluded from the study that there were significant improvements in cognitive deterioration following treatments.
Because of the involvement of the mitochondrial complex IV electron transport chain enzyme (cytochrome C oxidase) [51][52] in the photobiomodulation process and also its role as a photoacceptor following biostimulation, with the knowledge that the mitochondria are compromised during traumatic brain injury [53][54], interventions towards the enhancement of mitochondrial functions are necessary. According to Naeser et al. [50], the putative mechanism by which photobiostimulation may lead to significant improvements in traumatic brain injury is via the increase in mitochondrial ATP production which could enhance cellular respiration, oxygenation, and function. It is known that in cells whose mitochondria are compromised, nitric oxide inhibits cytochrome c oxidase. Therefore in response to red/NIR photons, nitric oxide is released and diffuses outside the cell wall, leading to local vasodilation and increased blood flow [50]. Additionally, transcranial photobiomodulation demonstrated anti-inflammatory effects in different brain pathologies brought about by inflammation [55].
It is plausible that the mechanism by which PBM improves cerebral blood flow [56][57] and delivery of oxygen to the brain parenchyma is through enhancement of nitric oxide production [58][59].

4. Stroke

A stroke is classified as a cerebrovascular accident (CVA) and presents a significant socioeconomic burden on the sufferers of this condition. Naeser et al. [60] had earlier reported the significant benefit of transcranial photobiomodulation in stroke. In a recent case study by Stephan et al. [61], laser photobiomodulation was proven to show significant improvements in stroke and aphasia.
In rat stroke models caused by either permanent middle cerebral artery occlusion (MCAO) via craniotomy or by insertion of a filament, LLLT has been demonstrated to improve neurological deficits [62][63].

5. Epilepsy

Recurrent unprovoked epileptic seizures are the hallmark of epilepsy, which is produced by aberrant discharges of electrical activity in brain cells and can result in abnormal behavioral patterns [64][65][66]. Epilepsy affects both sexes equally at the rate of about 1% of the global population [67]. The majority of people with epilepsy have temporal lobe epilepsy (TLE) [68]. Studies are now beginning to explore the role of phototherapy in this condition. An evaluation of the effects of infrared lasers of varying powers on key neurotransmitters in the cortex and hippocampus (glutamate, aspartate, glycine, GABA, and taurine) uncovered that daily laser irradiation at 90 mW produced the most pronounced inhibitory effect in the cortex after 7 days [69]. Additionally, following pilocarpine administration in a rat model of epilepsy, it has been reported that laser therapy lowered the major neurotransmitters involved in epilepsy [70].
Excitotoxicity-mediated cellular death is an integral phenomenon in epilepsy. Low-level laser light therapy has proven to possess beneficial effects on primary neuronal cultures treated with excitatory amino acid neurotransmitters. Increases in ATP, mitochondrial membrane potential, intracellular calcium concentrations, oxidative stress, and nitric oxide levels were all significantly improved by low-level laser therapy (LLLT; 3 J/cm2 delivered at 25 mW/cm2 over 2 min) [71].

6. Major Depressive Disorders (MDD)

Major depressive disorder, also known as MDD, is widely regarded as being among the most urgent issues pertaining to mental health. Over the past 30 years, there has been an almost 50% increase in the number of incident cases across the globe, and there are currently more than 264 million people of all ages who are affected [72][73][74]. Notably, the present pharmacological interventions for depression present with side effects [75], likewise some types of depression are pharmaco-resistant [76]. It is therefore imperative to identify effective therapeutic interventions free from side effects, safe, economical, and non-invasive.
Several reports highlighting the role of photobiomodulation on animal models of depression have been documented. The reserpine model of depression was studied with the use of transcranial low laser irradiation by Mohammed [77]. In the study, transcranial laser irradiation of rats with different doses of (80, 200, and 400 mW), wavelength (804 nm) one week post reserpine (0.2 mg/kg) administration was sufficient to ameliorate the depressant effect following reserpine administration.
Furthermore, in a study by Xu et al. [78], LLLT was used to stimulate shaved scalp in a mice model of depression. The power output density and wavelength used in the study were 23 mW/cm2 and 808 nm, respectively, and laser irradiation was performed for a total of 28 days singly, for 30 min each day. LLLT at 808 nm resulted in reduced immobility and increased motor activity while at the same time mitigating depression-like behaviors. Several other studies have also reported the beneficial roles of photobiostimulation in depression [79][80][81][82].

7. Involvement of Remote (Systemic) Photobiostimulation

It is plausible that the delivery of light photons remotely could also provide some beneficial effects to the brain, perhaps by downregulating pro-inflammatory and upregulating anti-inflammatory cytokines [83][84]. Remote biostimulation (peripheral stimulation) may possess some beneficial effects for the central nervous system. The indirect application of near-infrared light in an MPTP-mouse model of Parkinson’s disease had some neuroprotective effects [44]. In their experiment, mice were treated with either direct NIR delivery to the head or the body. Few studies have examined such an indirect action, even though there is still accumulating evidence in this regard. These few studies have found remote, often bilateral, effects on tissues after local irradiation of skin wounds, gliomas (implanted on the dorsum of mice and irradiating abdomen), skin abrasions, and oral mucosa lesions [85][86][87][88]. Remote ischemic preconditioning also protects the brain, heart, and lungs from stress [89][90].

8. Effect of Polarization in Photobiomodulation

It is known that different properties or parameters may influence the effect of photobiomodulation in biological tissues, for example, polarization [91]. According to Mester et al. [92][93], parameters such as the fluence, the wavelength, the irradiance, the numbers and times of exposure, etc., may influence the effect that photobiomodulation possesses on tissues. More recently, Huang et al. [94] and Hadis et al. [95] also reported in their study on certain parameters (about 10) to be put into consideration for a much more effective photobiomodulatory action. These parameters include fluence, wavelength, irradiation time, energy, parameters of the pulses, beam area, power, number, the interval between the treatments, and the location of the tissue.
Polarization, which is the property that confers on light the ability to travel in a single plane is now the focus of recent studies [96]. The process of converting unpolarized light (light wave traveling in more than a single plane) to polarized (light wave traveling in a single plane) is known as polarization. Examples of unpolarized light sources include light from the sun, light from lamps, and tube light. In unpolarized light, there is a constancy in the direction of light propagation but with differing planes of change in amplitude. Light polarization is made possible through the use of a polarizer which blocks all other vibrations or propagation making light waves (photons) pass through a single plane. This may give a much more direct effect on biological tissues.
Photobiomodulation with polarized light was able to improve chronic lesions in patients [96]. The evidence that polarization of light may have a better advantage than non-polarization has been documented [91].
Linear, circular, and elliptical types of light polarization have been discussed depending on the orientation of the electric field [91][97]. The linear and circular types of light polarization have demonstrated significant effects at the cellular level when compared with unpolarized light. In the study by Ando et al. [98], they investigated the role of light polarization (800 nm LLLT) on spinal cord injury (SCI) in rat models. They found that treatment efficacy significantly improved with parallel polarization (based on the direction in which light was applied) as compared with perpendicular polarization.
In the study by Tada et al. [99], they sought to investigate the effect of light-emitting diode treatment on wound healing using polarized light on wound healing. They found that treatments with polarized light (linear and circular polarization) increased the wound healing process compared to unpolarized light. Hamblin [100] and Tripodi et al. [101] have also reported the role of polarization in photobiomodulation in a recently published work.

9. PBM in Other Degenerative Diseases

Despite several reports on the beneficial role of photobiostimulation on certain neurodegenerative diseases, there is a paucity of information on the role of photobiostimulation on frontotemporal lobe degeneration, Amyotrophic Lateral Sclerosis, Huntington’s disease, and several other neurodegenerative diseases. Because of the socioeconomic burden and the reduction in the Quality of Life (QoL) of the sufferers of these conditions, more pre-clinical and clinical studies are needed to ascertain the role of PBM in their management, and likewise considering the different properties that may influence light stimulation of biological tissues.

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