Alzheimer's and Parkinson's disease are the two most common neurodegenerative disorders. They develop after a progressive death of many neurons in the brain. Although therapies are available to treat the signs and symptoms of both diseases, the progression of neuronal death remains relentless, and it has proved difficult to slow or stop. Hence, there is a need to develop neuroprotective or disease-modifying treatments that stabilize this degeneration. Red to infrared light therapy (λ = 600–1070 nm), and in particular light in the near infrared (NIr) range, is emerging as a safe and effective therapy that is capable of arresting neuronal death. Previous studies have used NIr to treat tissue stressed by hypoxia, toxic insult, genetic mutation and mitochondrial dysfunction with much success. Here we propose NIr therapy as a neuroprotective or disease-modifying treatment for Alzheimer's and Parkinson's patients.

Introduction

Several recent studies in animal models of Alzheimer's and Parkinson's disease have reported that low-level near infrared light (NIr) therapy not only mitigates the behavioral deficits associated with these conditions but also has neuroprotective effects, slowing the underlying death of neurons. Current clinical therapies for both diseases do not achieve a comparable slowing of degeneration and neuroprotection, though they do relieve motor signs in Parkinson's disease and, to a lesser extent, the cognitive, and memory deficits in Alzheimer's disease. In this review, we consider the evidence for neuroprotection by NIr in animal models of these diseases, the putative mechanisms by which NIr may work to protect cells against insult, the safety of NIr therapy and finally, the potential effective use of NIr therapy in patients. First, we provide an overview of Alzheimer's and Parkinson's disease and current treatment options for these conditions.

Overview

Neurodegeneration refers to a progressive death of neurons, by either genetic environmental or currently unknown factors. It includes a range of disorders, with the two most common being Alzheimer's and Parkinson's disease. Over time, as more and more neurons die, the signs and symptoms associated with each disorder worsen, making many routine day-day activities increasingly more difficult for patients (Tierney et al., 2013; Schapira et al., 2014; Brettschneider et al., 2015; Coppedè and Migliore, 2015; Goedert, 2015; Herrup, 2015; Nelson and Tabet, 2015).

The neuropathology and patterns of neurodegeneration across the brain in Alzheimer's and Parkinson's disease are very different, hence resulting in very different signs and symptoms. However, there are similarities in the proposed mechanisms of neuronal death in each disease. The current treatments for patients of both diseases offer at best symptomatic relief (particularly in Parkinson's disease) but do not provide neuroprotection or are not disease-modifying, at least in humans.

From the Bench to the Clinic: The Evidence for Neuroprotection by Near Infrared Light (NIr) Treatment in Alzheimer's and Parkinson's Disease

Low-level laser or LED (light emitting diode) therapy using red to infrared light (λ = 600–1070 nm), conflated here to the term “near infrared light” (NIr), is an emerging, putative neuroprotective treatment that is showing promise in several pre-clinical models of disease. For example, NIr has been reported beneficial in animal models of retinal disease (Eells et al., 2004; Natoli et al., 2010, 2013; Albarracin et al., 2013; Begum et al., 2013; Gkotsi et al., 2014), traumatic brain (Ando et al., 2011; Oron et al., 2012; Quirk et al., 2012a; Xuan et al., 2013, 2014, 2015) and optic nerve (Fitzgerald et al., 2010) injury, experimentally-induced stroke (Lapchak et al., 2004; DeTaboada et al., 2006; Oron et al., 2006), familial amyotrophic lateral sclerosis (Moges et al., 2009), multiple sclerosis (Muili et al., 2012), Parkinson's disease (Liang et al., 2008; Whelan et al., 2008; Ying et al., 2008; Shaw et al., 2010; Peoples et al., 2012; Moro et al., 2013, 2014; Purushothuman et al., 2013; Vos et al., 2013; Johnstone et al., 2014a,b; Darlot et al., 2015; El Massri et al., 2015; Reinhart et al., 2015a,b) and Alzheimer's disease (Michalikova et al., 2008; DeTaboada et al., 2011; Grillo et al., 2013; Purushothuman et al., 2014, 2015). In humans, NIr therapy has been reported to improve executive, cognitive, and emotional functions (Barrett and Gonzalez-Lima, 2013; Blanco et al., 2015), together with performance in a range of clinical tests after ischaemic stroke (Lampl et al., 2007; Lapchak, 2010), brain trauma (Naeser et al., 2011, 2014), depression (Schiffer et al., 2009) and in age-related macular degeneration (Merry et al., 2012). The fact that NIr therapy has been reported to be effective in so many different models of disease and in a range of neural systems suggests that it is not a targeted therapy, but instead, acts to mitigate ubiquitous processes relating to cell damage and death. Recent work indicates that NIr is effective in reducing neuronal death induced by apoptosis, but not necrosis (Quirk et al., 2012a). The pathway to apoptosis is likely to involve a critical decline in cellular energy production (Galluzzi et al., 2012), that NIr may help to restore (Hamblin and Demidova, 2006; Liang et al., 2008; Ying et al., 2008; Desmet et al., 2009; Rojas and Gonzalez-Lima, 2011; Chung et al., 2012; Begum et al., 2013; Gkotsi et al., 2014). This mechanism is presumably common to all the above mentioned conditions and is perhaps why NIr therapy has such broad potential applications. In the context of Alzheimer's and Parkinson's disease, although they have distinct initiating causes, both diseases converge on common pathways of inflammation and oxidative stress, mitochondrial dysfunction and neuronal death, indicating that NIr may be beneficial to both through the same protective mechanisms.

NIr for Alzheimer's Disease and Parkinson's Disease

A number of experimental studies have demonstrated that NIr therapy improves motor behavior and provides neuroprotection in various rodent models of both Alzheimer's and Parkinson's disease; for Parkinson's disease, these benefits have been reported in a non-human primate model as well. However, the evidence for therapeutic benefit at the clinical level is far sparser, prompting the need for systematic, large-scale clinical trials of NIr therapy in Alzheimer's and Parkinson's patients.

How Does NIr Work to Neuroprotect?

The mechanisms that underpin NIr-induced neuroprotection are not entirely clear, although they appear to operate in at least two different biological levels. First, NIr acts at a cellular level, activating intracellular cascades that ultimately contribute to the survival of the target, and possibly neighboring, cells and/or stimulating neurogenesis. Second, NIr appears capable of triggering systemic protective mechanisms; this presumably involves as yet unidentified circulating cellular or humoral factors that can transduce protective effects to the brain.

Direct Stimulation of Cells

There is a large body of work reporting that a number of molecular and cellular systems are influenced by NIr. At a cellular level, NIr displays a biphasic dose-response curve, suggesting that NIr is a low-level stressor of cells and that the activation of endogenous cellular stress response systems is likely to be central to its efficacy (Hamblin and Demidova, 2006; Desmet et al., 2009; Rojas and Gonzalez-Lima, 2011; Chung et al., 2012). The main direct target of NIr appears to be cytochrome c oxidase, a key enzyme of the mitochondrial respiratory chain (Figure 2A). This enzyme is a photoacceptor of light in the NIr range; NIr exposure produces a redox change in cytochrome c oxidase which causes a transient change in mitochondrial membrane potential, leading to increase ATP production and a burst in low levels of reactive oxygen species (Hamblin and Demidova, 2006; Desmet et al., 2009; Rojas and Gonzalez-Lima, 2011; Chung et al., 2012). This, in turns, triggers a cascade of secondary downstream signaling pathways that collectively stimulate endogenous cell protection and repair mechanisms (Hamblin and Demidova, 2006; Desmet et al., 2009; Chung et al., 2012; Rojas and Gonzalez-Lima, 2011). This modulation of multiple molecular systems appears capable of both conditioning neurons to resist future damage and accelerating repair of neurons damaged by a previous or continuing insult (e.g., Liang et al., 2008; Ying et al., 2008).

In addition to protecting and repairing damaged or dysfunctional neurons, there is emerging evidence from mouse models of traumatic brain injury that NIr also stimulates neurogenesis and synaptogenesis (Figure 2A). In a series of studies using a mouse model of traumatic brain injury, Xuan and colleagues found that a NIr treatment regime that improved neurological performance (Xuan et al., 2013), also increased markers of neuroprogenitor proliferation in the hippocampal region (i.e., dentate gyrus) and subventricular zone (Xuan et al., 2014), brain regions known to harbor neural stems cells. Other early responses in these regions included up-regulation of brain-derived neurotrophic factor, which was associated with subsequent up-regulation of synaptogenesis markers in the lesion site (Xuan et al., 2013). Similar observations of NIr-induced increases in neuroprogenitor cell proliferation in the subventricular zone have been made in a rat model of stroke (Oron et al., 2006).

It should be noted that these studies have focussed on the effect of NIr on neurons; similar NIr-induced cellular mechanisms may also be at play within brain capillary endothelial cells (Figure 2A). Mitochondrial dysfunction of these cells has been related to various vascular conditions, including atherosclerosis and hypertension (Tang et al., 2014). In the context of neurodegeneration, both Alzheimer's and Parkinson's disease have been implicated as vascular disorders, with suggestions that the neurodegenerative process begins with the breakdown of the integrity of small cerebral vessels and the blood-brain barrier (see above). This “breakdown” may begin with mitochondrial dysfunction (Grammas et al., 2011). Following, we propose that NIr-induced neuroprotection in Alzheimer's and Parkinson's disease might involve repair of the damaged mitochondria in local endothelial cells, leading subsequently to a restoration of the integrity of the endothelial network and blood-brain barrier in the region, resulting ultimately in improved neuronal survival (Figure 2A).

Indirect Stimulation of Systemic Factors

In addition to direct beneficial actions on damaged cells, there is increasing evidence that NIr treatment might also activate a more global, systemic response (Figure 2B). This evidence arises from the observation that local application of NIr to a particular body part can induce beneficial effects in distant body tissues (Braverman et al., 1989; Stone et al., 2013; Johnstone et al., 2014a,b, 2015). For example, neuroprotection of the mouse brain against MPTP insult has been demonstrated following the “remote” application of NIr to the dorsum of the animal, with no direct application to the head (Stone et al., 2013; Johnstone et al., 2014a,b, 2015). While the mechanism remains unknown, it presumably involves the stimulation of one or more circulating molecules or cell types. One possibility is the stimulation of immune cells, for example mast cells and macrophages, that could help neuroprotect cells in the brain (Byrnes et al., 2005; Chung et al., 2012; Muili et al., 2012). There may also be effects on inflammatory mediators, as NIr is associated with down-regulation of pro-inflammatory cytokines and up-regulation of anti-inflammatory cytokines (Muili et al., 2012). In addition, bone marrow-derived stem cells may also be involved; a series of studies has demonstrated that NIr exposure increases proliferation of c-kit-positive cells in the bone marrow and that, following myocardial infarction in rats, these cells are mobilized and recruited specifically to the site of damage where they are associated with a reduction in myocardial infarct size and ventricular dilatation (Tuby et al., 2011). These cells, together with immune cells, may release trophic factors (e.g., nerve growth factor, brain-derived neurotrophic factor) that improve the function of dying cells and help their survival (Hou et al., 2008).

Another possibility is for a signaling system between mitochondria in different body tissues. Mitochondria in distress in one body tissue have been suggested to produce an unidentified extracellular signal (mitokine) that is then transmitted to cells in remote body tissues and as a consequence induces a mitochondrial stress response (Durieux et al., 2011; Taylor et al., 2014). In relation to NIr and Alzheimer's and Parkinson's disease, NIr applied to remote tissue may prompt a signal system between mitochondria of peripheral tissues and brain, inducing repair mechanisms in the damaged cells in the brain (Johnstone et al., 2014a,b, 2015). Taken all together, the systemic mechanisms underlying remote NIr-induced neuroprotection may share similarities with other remote tissue protection phenomena—these include remote ischaemic conditioning, where induction of brief ischaemic episodes in one organ provides protection of other distant organs (Hausenloy and Yellon, 2008; Yetgin et al., 2012), and the so-called “abscopal” effect sometimes observed in radiation treatment of metastatic cancer, where treatment targeted at a tumor leads to not only a shrinking of the local tumor but also a shrinking of tumors far from the treated area (Postow et al., 2012).

More research is required to understand the interplay between direct cellular and indirect systemic mechanisms of NIr-induced protection. Both appear capable of acting independently—the findings of numerous in vitro cell culture studies reporting that NIr is neuroprotective, indicate clearly that the indirect systemic effect is not necessary for NIr-induced neuroprotection and repair of damaged neurons (Hamblin and Demidova, 2006; Desmet et al., 2009; Rojas and Gonzalez-Lima, 2011; Chung et al., 2012), while accumulating evidence from mouse models suggest remote NIr application provides neuroprotection in the absence of direct NIr stimulation (Johnstone et al., 2014b, 2015; Farfara et al., 2015). The phenomenon of indirect NIr-induced neuroprotection is likely to involve the same mechanisms, at a cellular level, as those that provide neuroprotection to damaged cells with direct NIr stimulation (i.e., stimulation of mitochondrial function; Figure 2A). Although the concept of indirect, remote NIr therapy holds promise for future applications, it is not yet as fully understood and developed as direct NIr therapy, thus our subsequent discussion will focus primarily on direct NIr stimulation. Further, some early results in an animal model of Parkinson's disease suggest that, although remote NIr provides neuroprotection, this protection was not as robust as when NIr was applied directly to the head (Stone et al., 2013; Johnstone et al., 2014b; presumably stimulating local neurons and/or endothelial cells). In other words, neuroprotection was achieved with both local and remote NIr treatment, but the local treatment was the more effective. As a working hypothesis, we suggest that direct stimulation of the mitochondria and reparative mechanisms, either in the neurons themselves or in the local endothelial cells (and/or stimulation of neurogenesis), forms the primary mechanism of NIr-induced neuroprotection. A more systemic (indirect) stimulation of immune and/or stem cells may form a secondary and complementary mechanism. We suggest that stimulation of both direct and indirect mechanisms would generate maximum NIr-induced neuroprotection.

Is NIr Therapy Safe?

To date, there are no reports of major safety issues nor side-effects after NIr treatment. The commercial LED panels for NIr therapy have already received non-significant risk status by the Food and Drug Administration and previous studies have indicated no adverse impact on brain tissue structure and function after NIr treatment (power range from ~1 to 700 mW/cm2; Desmet et al., 2006; Hamblin and Demidova, 2006; Ilic et al., 2006; Zivin et al., 2009; McCarthy et al., 2010; Naeser et al., 2011, 2014; Rojas and Gonzalez-Lima, 2011; Chung et al., 2012; Tata and Waynant, 2012; Quirk et al., 2012a,b; Moro et al., 2014). There is one sole account of some neuronal damage and negative behavioral outcomes in mice, but this was evident after an exceptionally high power intensity (750 mW/cm2; Ilic et al., 2006), approximately one hundred times higher than the dose required to elicit a therapeutic response (e.g., < 10 mW/cm2). Hence, when taken together, these data indicate that when NIr was applied at therapeutic doses (and even well above these doses), its impact on body tissue was overwhelmingly positive, and had a very large safety margin of application (Desmet et al., 2006; Hamblin and Demidova, 2006; Ilic et al., 2006; Zivin et al., 2009; McCarthy et al., 2010; Naeser et al., 2011, 2014; Rojas and Gonzalez-Lima, 2011; Chung et al., 2012; Tata and Waynant, 2012; Quirk et al., 2012a,b; Moro et al., 2014). Further, there appears to be no longer-term side effects associated with NIr application; in a long-term study in rats, no adverse effects were noted after daily treatment for 12 months (McCarthy et al., 2010).

NIr Therapy in Alzheimer's and Parkinson's Disease Patients: Can It Work?

The key question that still remains is whether NIr therapy can be neuroprotective in humans. In order for maximum effect, the primary goal would be for sufficient NIr signal to reach the main zones of pathology, to elicit a protective, or reparative effect within damaged cells (and perhaps also neurogenesis); a secondary goal would be for the NIr signal to also trigger systemic neuroprotective factors, for example circulating cells or molecules (see above).

In summary, there are clear indications that NIr can be an effective neuroprotective treatment for both neurodegenerative diseases, although the modes of delivery would be different; while extracranial NIr therapy would suffice for Alzheimer's disease, intracranial NIr therapy would be required for Parkinson's disease (Figure 3).

What Would be the Advantages of Using NIr Therapy?

There would be several key advantages for the use of NIr therapy over current treatments for both Alzheimer's and Parkinson's disease. First and foremost, NIr has the potential to be neuroprotective. A growing body of pre-clinical evidence indicates that NIr therapy slows or stops disease pathology (Liang et al., 2008; Ying et al., 2008; Shaw et al., 2010; Peoples et al., 2012; Moro et al., 2013; Purushothuman et al., 2013, 2014, 2015; Johnstone et al., 2014b; El Massri et al., 2015; Reinhart et al., 2015a,b). This is something that the current mainstay of treatments for both diseases—drug therapy—does not do. Second, it is safe, with no reported side effects (see above). Third, treatment would be simple. For potential neuroprotection in Alzheimer's disease, patients would apply the NIr extracranially, perhaps in the form of a helmet or a hand held device, over the entire cranium; in Parkinson's disease, patients would require a minimally invasive surgical stereotactic procedure for the insertion of a NIr optical device within the brain; in some cases, this procedure might be undertaken at the same time as stereotactic surgery for deep brain stimulation (see below). This device would be linked to a battery source and pacemaker device (as with patients receiving deep brain stimulation; Benabid et al., 2009) applying the NIr to the brainstem when required. The procedural risks would be comparable to those of single electrode deep brain stimulation.

Conclusions and Implications of Future Therapy

Although in its infancy, with the bulk of results still at the pre-clinical “proof of concept” stage, NIr therapy has the potential to develop into a safe and effective neuroprotective treatment for patients with Alzheimer's and Parkinson's disease (and presumably other neurodegenerative diseases such multiple sclerosis and amyotrophic lateral sclerosis). If NIr was applied at early stages of the disease process, for example at first diagnosis, it could potentially slow further progression by protecting neurons from death. Consequently, over time, the greater neuronal survival would lessen the clinical signs and symptoms. Further, NIr therapy—because of its lack of side-effects and neuroprotective potential—is amenable to use in conjunction with other treatments. For example, patients may have NIr therapy with a reduced dosage of drugs as a first line treatment; the potential neuroprotective effect of NIr could prolong the efficacy of the drug therapy. Further, in Parkinson's patients selected for deep brain stimulation, they may also have an NIr optical fiber implanted surgically at the same time, thereby potentially offering neuroprotection of the remaining dopaminergic cells. There is much to do in further developing this treatment, but the therapeutic possibilities are many and the potential outcomes very exciting. We await the outcomes of major clinical trials using NIr therapy on these patients with much anticipation.

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Frontiers | Turning On Lights to Stop Neurodegeneration: The Potential of Near Infrared Light Therapy in Alzheimer's and Parkinson's Disease | Neuroscience

Front. Neurosci., 11 January 2016 | https://doi.org/10.3389/fnins.2015.00500