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The helmet experiment in Parkinson's disease: An observation of the mechanism of neuroprotection by near infra-red light

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A puzzling feature of reports of near infrared light (NIr) treatment of soft tissue wounds is the lack of laterality in the tissue response - it is typically bilateral after a unilateral exposure. This has led to the idea that NIr has an ‘indirect’ effect on non-irradiated tissues, mediated by circulating ‘factors’. We have recently reported that NIr protects midbrain dopaminergic cells of mice from parkinsonian insult. In those studies, NIr was directed to the head, on the assumption that it would penetrate the skull and brain to reach the midbrain; in practice the whole dorsum of the mouse was irradiated. In this study, we applied NIr to the body only, preventing the radiation reaching the head with a ‘helmet’ of aluminium foil. NIr radiation of the body only was effective in protecting these cells, although less protective than radiation of both body and head. The results suggest that the neuroprotective effect of NIr may be mediated at least partially by a systemic or indirect effect. The possibility of immune system involvement will be discussed.
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Proceedings of the 9th WALT Congress (September 28-30, 2012, QT Gold Coast, Surfers Paradise, Australia)
The helmet experiment in Parkinson’s disease: an observation
of the mechanism of neuroprotection by near infra-red light
Stone J.1, Johnstone D.1, Mitrofanis J.2
1Discipline of Physiology, 2Anatomy & Histology, 1,2Bosch Institute, University of Sydney, Australia
Summary
A puzzling feature of reports of near infrared light (NIr) treatment of soft tissue wounds is the lack of
laterality in the tissue response - it is typically bilateral after a unilateral exposure. This has led to the idea that
NIr has an ‘indirect’ effect on non-irradiated tissues, mediated by circulating ‘factors’. We have recently
reported that NIr protects midbrain dopaminergic cells of mice from parkinsonian insult. In those studies, NIr
was directed to the head, on the assumption that it would penetrate the skull and brain to reach the midbrain; in
practice the whole dorsum of the mouse was irradiated. In this study, we applied NIr to the body only,
preventing the radiation reaching the head with a ‘helmet’ of aluminium foil. NIr radiation of the body only was
effective in protecting these cells, although less protective than radiation of both body and head. The results
suggest that the neuroprotective effect of NIr may be mediated at least partially by a systemic or indirect effect.
The possibility of immune system involvement will be discussed.
Introduction
The mechanism by which near infrared light (NIr), from either lasers (low level laser therapy, LLLT) or
from light emitting diodes (LED) (i.e., photobiomodulation, PBM) induces wound healing in damaged soft
tissue and protects central nervous structures against degeneration remains elusive: although many groups have
tested for, and identified, possible pathways. The idea that NIr acts directly is supported by evidence that a key
enzyme in the oxidative phosphorylation pathways of the mitochondrion, cytochrome c oxidase, absorbs NIr.
This understanding is encouraged by the ability of NIr wavelengths to penetrate deeply into tissue1.
This present study reports a test of an alternative idea: that NIr acts indirectly, by activating factors that
circulate around the body and can act at any site of tissue damage or stress. The evidence for this indirect action
is limited, because only a few studies have tested for or considered the possibility. In essence, these few studies
have noted remote, often bilateral, effects on tissues, after local exposure on skin wounds2, gliomas (implanted
on the dorsum of mice, and irradiating abdomen)3, skin abrasions4 and oral mucosa lesions5. Further, recent
studies have reported that critical-to-life tissues such as brain, heart and lung are protected from stress by remote
ischaemic preconditioning6, 7. The stress involved in these conditioning regimes seems to elicit a protective
response, and when the stress is limited to part of the body (say a limb), it becomes clear that remote organs are
protected, supporting the idea of circulating factors2.
As a first step to test whether the neuroprotective mechanism of NIr involves activation of a more
global system, we undertook a series of experiments in which the NIr treatment of MPTP(1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine)-treated mice was limited to the body. Our earlier studies8, 9 achieved protection of
midbrain dopaminergic cells in MPTP-treated mice by radiation directed at the head, but in fact reaching all of
dorsum of the animal. We assumed in this work that NIr acted by directly impacting the mitochondria of
protected cells, having penetrated the cranium and brain parenchyma. We have since wondered if we would
achieve protection of midbrain dopaminergic cells if we applied NIr to just the body.
Materials & Methods
Male BALB/c (n=40) mice were housed on a 12hr light/dark cycle with unlimited access to food and
water. Animal Ethics Committee of University of Sydney approved all experiments.
This study comprised two series of NIr treatment experiments, where NIr was applied to either the (i)
head and body or (ii) body (“helmet”). There were four experimental groups, each of five mice, within each
series. Mice received intraperitoneal injections of either MPTP or saline, combined with NIr treatment or not.
The different groups were (1) Saline: saline injections with no NIr (2) Saline-NIr: saline injections with NIr (3)
MPTP: MPTP injections with no NIr (4) MPTP-NIr: MPTP injections with NIr.
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Proceedings of the 9th WALT Congress (September 28-30, 2012, QT Gold Coast, Surfers Paradise, Australia)
Following previous work8, 9, we used an acute MPTP mouse model. We made two MPTP (total of
50mg/kg per mouse) or saline injections over a 30-hour period. Following each injection, mice in the MPTP-NIr
and Saline-NIr groups were given NIr (670nm) treatment from a light-emitting device (LED; Quantum WARP
10, Quantum Devices, Inc, Barneveld, WI, USA), equating to ~0.5 Joule/cm2 to the brain 9. About 6 hours after
each injection and first NIr treatment, mice in these groups received a second NIr treatment, but no MPTP or
saline injection. For each NIr treatment, the LED was held 1-2 cm directly above either the head9, 10 or the body
of the mouse. In the latter cases, the head region was protected by the aluminium foil helmet, which did not
permit any penetration of NIr (after measurements using a calibrated sensor). For the Saline and MPTP groups,
mice were held under the LED as described above, but the device was not turned on 8-11. After the last treatment,
mice were allowed to survive for six days.
Following the survival period, mice were anaesthetised with an intraperitoneal injection of sodium
pentobarbital (60mg/ml) and perfused transcardially with 4% buffered paraformaldehyde. The brains were
processed for routine tyrosine hydroxylase (TH) immunocytochemistry as described previously9. Briefly,
midbrain sections were incubated in anti-TH (Sigma-Aldrich), followed by biotinylated anti-rabbit IgG and
streptavidin-peroxidase complex (Bioscientific Pty Ltd) and then reacted in a 3,3’- diaminobenzidine
tetrahydrochloride (Sigma).
Following previous studies8-10, TH+ cell number within the substantia nigra pars compacta (SNc) was
estimated using the optical fractionator method (StereoInvestigator, MBF Science). For comparisons between
groups, a one-way ANOVA test was performed, in conjunction with a Tukey-Kramer multiple comparison test.
Results
Fig 1 shows the estimated TH+ cell number in the SNc of the four groups in the head and body (Fig 1A)
and body only (Fig 1B) series. For the Saline and Saline-NIr groups of both series, TH+ cell number was similar;
no significant differences were evident between these groups (p>0.05). For the MPTP groups in both series, TH+
cell number was significantly less than in the saline control groups (35-40%; p<0.001). In the MPTP-NIr groups,
TH+ cell number was higher than in the MPTP group of the head and body series (~30%) and also, but to a lesser
extent, in the body only series (~20%). These differences reached significance for both the head and body
(p<0.001) and body only (p<0.05) series. Although TH+ cell number in the MPTP-NIr group was significantly
higher than in the MPTP groups, it was slightly lower than the saline groups for both the head and body (~10%)
and body only (~15%) series. This difference was not significant for the head and body series (p>0.05), but was
significant for the body only (p<0.05) series.
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Proceedings of the 9th WALT Congress (September 28-30, 2012, QT Gold Coast, Surfers Paradise, Australia)
Fig 2 shows TH+ cells in the SNc in each of the groups studied for the body only series, namely Saline
(Fig 2A), Saline-NIr (Fig 2B), MPTP (Fig 2C) and MPTP-NIr (Fig 2D) groups. There were clearly fewer TH+
cells in the SNc of the MPTP group compared to the other groups. These trends are illustrated further in the
schematics of this figure (Fig 2A1,B1,C1,D1), that show the distribution of the TH+ cells along the rostrocaudal
axis of the SNc in the different groups. Note the lesser number of TH+ cells across the SNc in the MPTP group
compared to the others.
Conclusions
Our working hypothesis in recent studies8-11 has been that NIr acts to protect midbrain dopaminergic
cells by penetrating the cranium and the parenchyma of the brain, to reach the midbrain, there to be absorbed by
photoacceptors in the mitochondria of the dopaminergic cells, upregulating protective pathways in stressed cells.
Present results direct attention to an additional, perhaps alternative, idea, one that suggests that absorption of NIr
by the skin or perhaps by lymph nodes near the skin upregulates a still-unknown response, which can circulate
through the body, either as activated cells, or as cytokines released into the blood. It is possible that NIr exerts
neuroprotective actions by both direct and indirect actions.
Much work will be needed to test, confirm and elaborate this indirect response. The work of Schwartz
and colleagues12, 13 may provide a guide. Their studies adduce evidence of neuroprotection mediated by
circulating monocytes and lymphocytes. Although Schwartz et al did not study wound healing, which is the most
common focus of studies of LLLT or PBM, nor did they use LLLT or PBM, the concept of a cohort of protective
immune-system cells is relevant in the present context.
Qualitatively, body-only and whole-body NIr produced the same effect on MPTP-stressed SNc cells –
protection or rescue. Quantitatively, the lesser effect of body only radiation could reflect the loss of a direct,
transcranial action or the reduction in skin area irradiated. This question – whether NIr acts both directly and
indirectly – will be addressed in many future studies.
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Proceedings of the 9th WALT Congress (September 28-30, 2012, QT Gold Coast, Surfers Paradise, Australia)
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... Mounting evidence suggests that remote photobiomodulation-induced protection extends to the brain (Fig. 1). In the MPTP-treated mouse model, irradiating the dorsum of the animals with 670 nm following MPTP injection, while simultaneously shielding the head with aluminum foil, yielded substantial neuroprotection; MPTP-treated mice with photobiomodulation of the body had more dopaminergic neurons than sham-treated MPTP mice [53,66,74]. In addition to mitigating damage following an insult, a subsequent study demonstrated that remote photobiomodulation provided neuroprotection when administered as a pre-conditioning intervention. ...
... Photobiomodulation applied to cells in culture, which relies solely on direct stimulation, has been shown to be neuroprotective, indicating that indirect stimulation is not essential for neuroprotection [46][47][48][49]. On the other hand, photobiomodulation applied remotely, to a distant body part (e.g., dorsum of the animal) relying solely on indirect systemic stimulation, offers neuroprotection also, indicating that direct stimulation is not fundamental to the process [53,66,[71][72][73][74]. ...
... So, does one type of stimulation work better than the other? From results in animal models, it has been shown that direct stimulation is more effective than the remote indirect systemic stimulation, that direct stimulation offers the better chance for distressed neurons to protect and repair themselves [53,74] (Fig. 1). The direct stimulation may form the primary mechanism of neuroprotection, while the indirect systemic stimulation forms a secondary and complementary mechanism [35,36]. ...
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... The red-light-helmet for treating PD is under investigation [156][157][158], which uses a helmet lined with light-emitting diodes (LEDs) of wavelengths across the red to near-infrared range (i.e., 670, 810, and 850 nm) with or without an intranasal LED device (660 nm). Preliminary results are promising regarding improved symptoms of the tested PwP [156][157][158]. ...
... The red-light-helmet for treating PD is under investigation [156][157][158], which uses a helmet lined with light-emitting diodes (LEDs) of wavelengths across the red to near-infrared range (i.e., 670, 810, and 850 nm) with or without an intranasal LED device (660 nm). Preliminary results are promising regarding improved symptoms of the tested PwP [156][157][158]. ...
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... In addition to direct stimulation, photobiomodulation has been shown -quite remarkably -to be beneficial to neuronal survival even when it is applied to a distant or remote location; that is, when it is not applied directly to the neurones (Figure 2). The evidence for this indirect stimulation has been accumulated from many previous studies in a range of animal models of disease -from diabetes to Alzheimer's and Parkinson's disease -showing that photobiomodulation applied to one body part can induce neuroprotective effects in another, more distant body part (Braverman et al., 1989;Tuby et al., 2011;Stone et al., 2013;Johnstone et al., 2014Johnstone et al., , 2016Liebert et al., 2014;Farfara et al., 2015;Saliba et al., 2015;Oron and Oron, 2016;Mitrofanis, 2017;Blivet et al., 2018;Kim et al., 2019). For this effect, photobiomodulation is thought to activate circulating immune (Byrnes et al., 2005;Chung et al., 2012;Muili et al., 2012Muili et al., , 2013Saliba et al., 2015) and/or stem (Tuby et al., 2011;Arany et al., 2014;Farfara et al., 2015;Khan and Arany, 2015;Oron and Oron, 2016) cells, or even freefloating mitochondria (Al Amir Dache et al., 2020), within the cardiovascular or lymphatic systems that then leads to an increase in overall mitochondrial activity -in a similar fashion to the direct stimulation described above -in the distressed neurones located in the brain. ...
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... 13,14 Treatment of areas remote from the site of injury can be an effective strategy in animal models, 20 including models of PD and Alzheimer's disease 18,[21][22][23][24] even when the head of the animal is shielded from irradiation. 25 The mechanism of this systemic effect may be stimulation of stem cells, 20,26 immunomodulation, 27 stimulation of circulating cell-free mitochondria, 28 modulating circulating chemical messengers, 21 or a combination of these. Another potential mechanism of action is via the microbiome. ...
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... PBM has been shown to precondition and protect animals (including non-human primates) from a toxin (MPTP)-induced PD model, both in the signs of the induced PD and protection of the neurons in the substantia nigra [20][21][22]. This preconditioning effect was also observed when PBM was delivered to areas remote from the brain [15,[23][24][25], including when the head was shielded from light [26]. Several small trials and case studies are currently being undertaken with transcranial PBM [27][28][29]. ...
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... PBM has been shown to precondition and protect animals (including non-human primates) from a toxin (MPTP)-induced PD model, both in the signs of the induced PD and protection of the neurons in the substantia nigra (20)(21)(22). This preconditioning effect was also observed when PBM was delivered to areas remote from the brain (15,(23)(24)(25), including when the head was shielded from light (26). Several small trials and case studies are currently being undertaken with transcranial PBM (27)(28)(29). ...
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... In a series of experiments on Parkinson's disease, Stone, Johnstone, Mitrofanis and colleagues have shown that neuroprotection against Parkinsonian MPTP insult (in mice) can be achieved with PBM delivered to areas of the body remote from the brain. 36,[171][172][173][174] This abscopal effect of PBM is postulated to be due to immune cells, stem cells, or a circulating (unidentified) mediator. The possibility exists that this mediator is linked to changes in the microbiome. ...
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Objective: The objective of this narrative review was to investigate the history of light therapy in hospital settings, with reference to physiotherapy and particularly in an Australian context.Types of articles and search method:a review of available literature was conducted on PubMed, Medline and Google Scholar using keywords light therapy, photobiomodulation, physiotherapy, low-level laser, heliotherapy. Physiotherapy textbooks from Sydney University Library were searched. Historical records were accessed from the San Hospital library. Interviews were conducted with the San Hospital Chief Librarian and a retired former Head Physiotherapist from Royal Prince Alfred Hospital.Summary: Historically, light treatment has been used in both medical and physiotherapy practice. From its roots in ancient Egypt, India, and Greece, through to medieval times, the modern renaissance in ‘light as therapy ’ was begun by Florence Nightingale who, in the 1850s, advocated the use of clean air and an abundance of sunlight to restore health. Modern light therapy (phototherapy) had a marked uptake in use in medicine in Scandinavia, America, and Australia from 1903, following the pioneering work of Niels Finsen in the late 19th century, which culminated in Dr Finsen receiving the Nobel Prize for Medicine for the treatment of tuberculosis scarring with ultraviolet (UV) light, and treatment of smallpox scarring with red light. Treatment with light, especially UVB light, has been widely applied by physiotherapists in hospitals for dermatological conditions since the 1950s, particularly in Australia, Scandinavia, USA, England and Canada. In parallel, light treatment in hospitals for hyperbilirubinemia was used for neonatal jaundice. Since the 1980s light was also used in the medical specialties of ophthalmology, dermatology, and cardiology. In more recent years in physiotherapy, light was mostly used as an adjunct to the management of orthopedic/rheumatological conditions. Since the 1990s, there has been global use of light, in the form of photobiomodulation for the management of lymphedema, including in supportive cancer care. Photobiomodulation in the form of low-level laser has been used by physiotherapists and pain doctors since the 1990s in the management of chronic pain. The use of light as therapy is exemplified by its use in the San Hospital in Sydney, where light therapy was introduced in 1903 (after Dr. John Harvey Kellogg visited Niels Finsen in Denmark) and is practiced by nurses, physiotherapists and doctors until the present day. The use of light has expanded into new and exciting practices including supportive cancer care, and treatment of depression, oral mucositis, retinopathy of prematurity, and cardiac surgery complications. Light is also being used in the treatment of neurological diseases, such as Parkinson‘s disease, traumatic brain injury, and multiple sclerosis. The innovative uses of light in physiotherapy treatment would not be possible without the previous experience of successful application of light treatment.Conclusion: Light therapy has had a long tradition in medicine and physiotherapy. Although it has fallen somewhat out of favour over the past decades, there has been a renewed interest using modern techniques in recent times. There has been continuous use of light as a therapy in hospitals in Australia, most particularly the San Hospital in Sydney where it has been in use for almost 120 years.
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The tissue-protective properties of photobiomodulation (PBM) (low-intensity red to near-infrared light therapy) have been demonstrated for a number of diseases and injuries, including those of the central nervous system. By modifying mitochondrial function and stimulating a mild adaptive stress response, PBM appears to enhance cellular and tissue resilience against existing or subsequent insults, providing significant neuroprotection to vulnerable neurons. There is considerable evidence that transcranial PBM mitigates the loss of dopaminergic cells and functional deficits in small animal models of Parkinson's disease (PD). However, the absorption of light by the scalp, skull, and cerebral cortex makes the translation of this therapy to human patients difficult. Creative approaches to irradiating the deep brain stem structures affected in PD, by delivering light intracranially or intranasally, have been trialed to overcome this barrier to clinical translation. Perhaps most remarkable and promising are demonstrations that the beneficial effects of PBM are not confined to the tissue irradiated; and that irradiation of a peripheral, easily accessed tissue can induce resilience in all tissues of the body, including the PD-critical midbrain. This chapter reviews the evidence of PBM-induced neuroprotection in the context of PD and the challenges that remain in translating PBM into a viable intervention for PD patients.
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We have shown previously that photobiomodulation or near-infrared light (NIr) treatment protects dopaminergic cells of the substantia nigra pars compacta (SNc) in an acute MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease (PD). In this study, we tested the protective and rescue action of NIr treatment in a chronic MPTP model, developed to resemble more closely the slow progressive degeneration in PD patients. We examined three regions of dopaminergic cells, the SNc, periaqueductal grey matter (PaG) and zona incerta-hypothalamus (ZI-Hyp). BALB/c mice had MPTP or saline injections over five weeks, followed by a three-week survival. NIr treatment was applied either at the same time as (simultaneous series) or after (post-treatment series) the MPTP insult. There were four groups within each series; Saline, Saline-NIr, MPTP and MPTP-NIr. Brains were processed for tyrosine hydroxylase (TH) immunochemistry and cell number was analysed using the optical fractionator method. In the SNc, there was a significant reduction (≈ 45%) in TH(+) cell number in the MPTP groups compared to the saline controls of both series. In the MPTP-NIr groups of both series, TH(+) cell number was significantly higher (≈ 25%) than in the MPTP groups, but lower than in the saline controls (≈ 20%). By contrast in the PaG and ZI-Hyp, there were no significant differences in TH(+) cell number between the MPTP an MPTP-NIr groups of either series. In summary, exposure to NIr either at the same time or well after chronic MPTP insult saved many SNc dopaminergic cells from degeneration.
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This study explores whether near-infrared (NIr) light treatment neuroprotects dopaminergic cells in the substantia nigra pars compacta (SNc) and the zona incerta-hypothalamus (ZI-Hyp) from degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. BALB/c albino mice were divided into four groups: 1) Saline, 2) Saline-NIr, 3) MPTP, 4) MPTP-NIr. The injections were intraperitoneal and they were followed immediately by NIr light treatment (or not). Two doses of MPTP, mild (50 mg/kg) and strong (100 mg/kg), were used. Mice were perfused transcardially with aldehyde fixative 6 days after their MPTP treatment. Brains were processed for tyrosine hydroxylase (TH) immunochemistry. The number of TH(+) cells was estimated using the optical fractionator method. Our major finding was that in the SNc there were significantly more dopaminergic cells in the MPTP-NIr compared to the MPTP group (35%-45%). By contrast, in the ZI-Hyp there was no significant difference in the numbers of cells in these two groups. In addition, our results indicated that survival in the two regions after MPTP insult was dose-dependent. In the stronger MPTP regime, the magnitude of loss was similar in the two regions ( approximately 60%), while in the milder regime cell loss was greater in the SNc (45%) than ZI-Hyp ( approximately 30%). In summary, our results indicate that NIr light treatment offers neuroprotection against MPTP toxicity for dopaminergic cells in the SNc, but not in the ZI-Hyp.
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