[Show abstract][Hide abstract] ABSTRACT: ABSTRACT We have used the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model to explore whether (i) the neuroprotective effect of near infrared light (NIr) treatment in the SNc is dose-dependent and (ii) the relationship between tyrosine hydroxylase (TH)+ terminal density and glial cells in the caudate-putamen complex (CPu). Mice received MPTP injections (50 mg/kg) and 2 J/cm2 NIr dose with either 2 d or 7 d survival period. In another series, with a longer 14 d survival period, mice had a stronger MPTP regime (100 mg/kg) and either 2 J/cm2 or 4 J/cm2 NIr dose. Brains were processed for routine immunohistochemistry and cell counts were made using stereology. Our findings were that in the 2 d series, no change in SNc TH+ cell number was evident after any treatment. In the 7 d series however, MPTP insult resulted in ∼45% reduction in TH+ cell number; after NIr (2 J/cm2) treatment, many cells were protected from the toxic insult. In the 14 d series, MPTP induced a similar reduction in TH+ cell number. NIr mitigated the loss of TH+ cells, but only at the higher dose of 4 J/cm2; the lower dose of 2 J/cm2 had no neuroprotective effect in this series. The higher dose of NIr, unlike the lower dose, also mitigated the MPTP- induced increase in CPu astrocytes after 14 d; these changes were independent of TH+ terminal density, of which, did not vary across the different experimental groups. In summary, we showed that neuroprotection by NIr irradiation in MPTP-treated mice was dose-dependent; with increasing MPTP toxicity, higher doses of NIr were required to protect cells and reduce astrogliosis.
International Journal of Neuroscience 12/2014; DOI:10.3109/00207454.2014.994063 · 1.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This review traces evidence that age-related dementia (Alzheimer's disease) results from the destructive impact of the pulse on cerebral vasculature. Evidence is reviewed that the neuropathology of the dementia is caused by the breakdown of small cerebral vessels (silent microbleeds), that the microbleeds result from pulse-induced damage to the cerebral vessels, and that pulse becomes increasingly destructive with age, because of the age-related stiffening of the aorta and great arteries, which causes an increase in the intensity of the pressure pulse. Implications for therapy are discussed, and evidence is reviewed that pulse-induced destruction of the brain, and of another highly vascular organ, the kidney, are becoming the default forms of death, the way we die if we survive the infections, cardiovascular disease, and malignancies, which still, for a decreasing minority, inflict the tragedy of early death.
[Show abstract][Hide abstract] ABSTRACT: The central nervous system undergoing degeneration can be stabilized, and in some models can be restored to function, by neuroprotective treatments. Photobiomodulation (PBM) and dietary saffron are distinctive as neuroprotectants in that they upregulate protective mechanisms, without causing measurable tissue damage. This study reports a first attempt to combine the actions of PBM and saffron. Our working hypothesis was that the actions of PBM and saffron in protecting retinal photoreceptors, in a rat light damage model, would be additive. Results confirmed the neuroprotective potential of each used separately, but gave no evidence that their effects are additive. Detailed analysis suggests that there is actually a negative interaction between PBM and saffron when given simultaneously, with a consequent reduction of the neuroprotection. Specific testing will be required to understand the mechanisms involved and to establish whether there is clinical potential in combining neuroprotectants, to improve the quality of life of people affected by retinal pathology, such as age-related macular degeneration, the major cause of blindness and visual impairment in older adults.
PLoS ONE 06/2014; 9(6):e100389. DOI:10.1371/journal.pone.0100389 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have previously shown near infrared light (NIr), directed transcranially, mitigates loss of dopaminergic cells in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mice, a model of parkinsonism. These findings complement others suggesting NIr treatment protects against damage from various insults. However one puzzling feature of NIr treatment is that unilateral exposure can lead to a bilateral healing response, suggesting NIr may have 'indirect' protective effects. We investigated whether remote NIr treatment is neuroprotective by administering different MPTP doses (50, 75, 100 mg/kg) to mice and treating with 670 nm light directed specifically at either the head or body. Our results show that, despite no direct irradiation of the damaged tissue, remote NIr treatment produces a significant rescue of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta at the milder MPTP dose of 50 mg/kg (∼30% increase vs sham-treated MPTP mice, p<0.05). However this protection did not appear as robust as that achieved by direct irradiation of the head (∼50% increase vs sham-treated MPTP mice, p<0.001). There was no quantifiable protective effect of NIr at higher MPTP doses, irrespective of the delivery mode. Astrocyte and microglia cell numbers in substantia nigra pars compacta were not influenced by either mode of NIr treatment. In summary, the findings suggest that treatment of a remote tissue with NIr is sufficient to induce protection of the brain, reminiscent of the 'abscopal effect' sometimes observed in radiation treatment of metastatic cancer. This discovery has implications for the clinical translation of light-based therapies, providing an improved mode of delivery over transcranial irradiation.
[Show abstract][Hide abstract] ABSTRACT: Parkinson’s disease is a movement disorder with cardinal signs of resting tremor, akinesia, and rigidity. These manifest after a progressive death of many dopaminergic neurons of the midbrain. Unfortunately, the progression of this neuronal death has proved difficult to slow and impossible to reverse despite an intense search for the specific causes and for treatments that address the causes. There is a corresponding need to develop approaches that regulate the self-repair mechanisms of neurons, independent of the specific causes of the damage that leads to their death. Red to infrared light therapy (λ=600–1,070 nm) is emerging as an effective, repair-oriented therapy that is capable of stabilizing dying neurons. Initially a space-age anecdote, light therapy has become a treatment for tissue stressed by the known causes of age-related diseases: hypoxia, toxic environments, and mitochondrial dysfunction. Here we focus on several issues relating to the use of light therapy for Parkinson’s disease: 1) What is the evidence that it is neuroprotective? We consider the basic science and clinical evidence; 2) What are the mechanisms of neuroprotection? We suggest a primary mechanism acting directly on the neuron’s mitochondria (direct effect) as well as a secondary, supportive mechanism acting indirectly through systemic systems (indirect effect); 3) Could this be effective in humans? We discuss the pros and cons of this treatment in humans, including the development of a new surgical method of delivery; and 4) What are the advantages of using light therapy? We explore the features that make this therapy a promising potential treatment. In summary, early evidence indicates that light regulates specific neuronal functions and is neuroprotective in animal models of Parkinson’s disease. The stage is set for detailed and rigorous explorations into its use on Parkinson’s disease patients, in particular, whether light slows the disease progression rather than simply mitigating signs.
[Show abstract][Hide abstract] ABSTRACT: Previous work has demonstrated the efficacy of irradiating tissue with red to infrared light in mitigating cerebral pathology and degeneration in animal models of stroke, traumatic brain injury, parkinsonism and Alzheimer's disease (AD). Using mouse models, we explored the neuroprotective effect of near infrared light (NIr) treatment, delivered at an age when substantial pathology is already present in the cerebral cortex.
We studied two mouse models with AD-related pathologies: the K369I tau transgenic model (K3), engineered to develop neurofibrillary tangles, and the APPswe/PSEN1dE9 transgenic model (APP/PS1), engineered to develop amyloid plaques. Mice were treated with NIr 20 times over a four-week period and histochemistry was used to quantify AD-related pathological hallmarks and other markers of cell damage in the neocortex and hippocampus.
In the K3 mice, NIr treatment was associated with a reduction in hyperphosphorylated tau, neurofibrillary tangles and oxidative stress markers (4-hydroxynonenal and 8-hydroxy-2[prime]-deoxyguanosine) to near wildtype levels in the neocortex and hippocampus, and with a restoration of expression of the mitochondrial marker cytochrome c oxidase in surviving neurons. In the APP/PS1 mice, NIr treatment was associated with a reduction in the size and number of amyloid-beta plaques in the neocortex and hippocampus.
Our results, in two transgenic mouse models, suggest that NIr may have potential as an effective, minimally-invasive intervention for mitigating, and even reversing, progressive cerebral degenerations.
Alzheimer's Research and Therapy 01/2014; 6(1):2. DOI:10.1186/alzrt232 · 3.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Object:
Previous experimental studies have documented the neuroprotection of damaged or diseased cells after applying, from outside the brain, near-infrared light (NIr) to the brain by using external light-emitting diodes (LEDs) or laser devices. In the present study, the authors describe an effective and reliable surgical method of applying to the brain, from inside the brain, NIr to the brain. They developed a novel internal surgical device that delivers the NIr to brain regions very close to target damaged or diseased cells. They suggest that this device will be useful in applying NIr within the large human brain, particularly if the target cells have a very deep location.
An optical fiber linked to an LED or laser device was surgically implanted into the lateral ventricle of BALB/c mice or Sprague-Dawley rats. The authors explored the feasibility of the internal device, measured the NIr signal through living tissue, looked for evidence of toxicity at doses higher than those required for neuroprotection, and confirmed the neuroprotective effect of NIr on dopaminergic cells in the substantia nigra pars compacta (SNc) in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson disease in mice.
The device was stable in freely moving animals, and the NIr filled the cranial cavity. Measurements showed that the NIr intensity declined as distance from the source increased across the brain (65% per mm) but was detectable up to 10 mm away. At neuroprotective (0.16 mW) and much higher (67 mW) intensities, the NIr caused no observable behavioral deficits, nor was there evidence of tissue necrosis at the fiber tip, where radiation was most intense. Finally, the intracranially delivered NIr protected SNc cells against MPTP insult; there were consistently more dopaminergic cells in MPTP-treated mice irradiated with NIr than in those that were not irradiated.
In summary, the authors showed that NIr can be applied intracranially, does not have toxic side effects, and is neuroprotective.
Journal of Neurosurgery 10/2013; 120(3). DOI:10.3171/2013.9.JNS13423 · 3.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dietary saffron and photobiomodulation (low-level infrared radiation, PBM) are emerging as therapeutically promising protectants for neurodegenerative conditions, such as the retinal dystrophies. In animal models, saffron and PBM, given in limited daily doses, protect retina and brain from toxin- or light-induced stress. This study addresses the rate at which saffron and PBM, given in daily doses, induce neuroprotection, using a light damage model of photoreceptor degeneration in Sprague Dawley (SD) rats.
Rats were raised in dim cyclic (12 h 5 lux, 12 h dark) illumination, treated with saffron or PBM for 2-10 d, and then exposed to bright damaging light (1,000 lux for 24 h). After 1 week survival, the retina was assessed for photoreceptor death (using the TUNEL reaction), for surviving photoreceptor damage (thickness of the outer nuclear layer) and for the expression of a stress-related protein GFAP, using immunohistochemistry. Preconditioning the retina with saffron or PBM reduced photoreceptor death, preserved the population of surviving photoreceptors and reduced the upregulation of GFAP in Müller cells. At the daily dose of saffron used (1 mg/kg), protection was detectable at 2 d, increasing to 10 d. At the daily dose of PBM used (5 J/cm(2) at 670 nm) protection was detectable at 5 d, increasing to 7-10 d.
The results provide time parameters for exploration of the mechanisms and durability of the protection provided by saffron and PBM.
American Journal of Neurodegenerative Diseases 10/2013; 2(3):208-220.
[Show abstract][Hide abstract] ABSTRACT: We have examined whether near-infrared light (NIr) treatment mitigates oxidative stress and increased expression of hyperphosphorylated tau in a tau transgenic mouse strain (K3) that has a progressive degeneration of dopaminergic cells in the substantia nigra pars compacta (SNc). The brains of wild-type (WT), untreated K3 and NIr-treated K3 mice, aged five months (thus after the onset of parkinsonian signs and neuropathology), were labelled immunohistochemically for the oxidative stress markers 4-hydroxynonenal (4-HNE) and 8-hydroxy-2'-deoxyguanosine (8-OHDG), hyperphosphorylated tau (using the AT8 antibody) and tyrosine hydroxylase (TH). The average intensity and area of 4-HNE, 8-OHDG and AT8 immunoreactivity were measured using the MetaMorph software and TH(+) cell number was estimated using stereology. Our results showed immunoreactivity for 4-HNE, 8-OHDG and AT8 within the SNc was increased in K3 mice compared to WT, and that this increase was mitigated by NIr. Results further showed that TH(+) cell number was lower in K3 mice than in WT, and that this loss was mitigated by NIr. In summary, NIr treatment reduced the oxidative stress caused by the tau transgene in the SNc of K3 mice and saved SNc cells from degeneration. Our results, when taken together with those in other models, strengthen the notion that NIr treatment saves dopaminergic cells in the parkinsonian condition.
Brain research 08/2013; 1535. DOI:10.1016/j.brainres.2013.08.047 · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
We have shown previously that near-infrared light (NIr) treatment or photobiomodulation neuroprotects dopaminergic cells in substantia nigra pars compacta (SNc) from degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Balb/c albino mice, a well-known model for Parkinson’s disease. The present study explores whether NIr treatment offers neuroprotection to these cells in C57BL/6 pigmented mice. In addition, we examine whether NIr influences behavioural activity in both strains after MPTP treatment. We tested for various locomotive parameters in an open-field test, namely velocity, high mobility and immobility.
Balb/c (albino) and C57BL/6 (pigmented) mice received injections of MPTP (total of 50 mg/kg) or saline and NIr treatments (or not) over 48 hours. After each injection and/or NIr treatment, the locomotor activity of the mice was tested. After six days survival, brains were processed for TH (tyrosine hydroxylase) immunochemistry and the number of TH+ cells in the substantia nigra pars compacta (SNc) was estimated using stereology. Results showed higher numbers of TH+ cells in the MPTP-NIr groups of both strains, compared to the MPTP groups, with the protection greater in the Balb/c mice (30% vs 20%). The behavioural tests revealed strain differences also. For Balb/c mice, the MPTP-NIr group showed greater preservation of locomotor activity than the MPTP group. Behavioural preservation was less evident in the C57BL/6 strain however, with little effect of NIr being recorded in the MPTP-treated cases of this strain. Finally, there were differences between the two strains in terms of NIr penetration across the skin and fur. Our measurements indicated that NIr penetration was considerably less in the pigmented C57BL/6, compared to the albino Balb/c mice.
In summary, our results revealed the neuroprotective benefits of NIr treatment after parkinsonian insult at both cellular and behavioural levels and suggest that Balb/c strain, due to greater penetration of NIr through skin and fur, provides a clearer model of protection than the C57BL/6 strain.
[Show abstract][Hide abstract] ABSTRACT: Understanding the response of the brain to haemorrhagic damage is important in haemorrhagic stroke and increasingly in the understanding the cerebral degeneration and dementia that follow head trauma and head-impact sports. In addition, there is growing evidence that haemorrhage from small cerebral vessels is important in the pathogenesis of age-related dementia (Alzheimer's disease). In a penetration injury model of rat cerebral cortex, we have examined the neuropathology induced by a needlestick injury, with emphasis on features prominent in the ageing and dementing human brain, particularly plaque-like depositions and the expression of related proteins. Needlestick lesions were made in neo- and hippocampal cortex in Sprague Dawley rats aged 3-5 months. Brains were examined after 1-30 d survival, for haemorrhage, for the expression of hyperphosphorylated tau, Aβ, amyloid precursor protein (APP), for gliosis and for neuronal death. Temporal cortex from humans diagnosed with Alzheimer's disease was examined with the same techniques. Needlestick injury induced long-lasting changes-haem deposition, cell death, plaque-like deposits and glial invasion-along the needle track. Around the track, the lesion induced more transient changes, particularly upregulation of Aβ, APP and hyperphosporylated tau in neurons and astrocytes. Reactions were similar in hippocampus and neocortex, except that neuronal death was more widespread in the hippocampus. In summary, experimental haemorrhagic injury to rat cerebral cortex induced both permanent and transient changes. The more permanent changes reproduced features of human senile plaques, including the formation of extracellular deposits in which haem and Aβ-related proteins co-localised, neuronal loss and gliosis. The transient changes, observed in tissue around the direct lesion, included the upregulation of Aβ, APP and hyperphosphorylated tau, not associated with cell death. The findings support the possibility that haemorrhagic damage to the brain can lead to plaque-like pathology.
PLoS ONE 03/2013; 8(3):e59740. DOI:10.1371/journal.pone.0059740 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: There is growing evidence that the spice saffron, which contains powerful anti-oxidants, offers protection against neurodegenerative disorders, including age-related macular degeneration and Alzheimer's disease. Objective: We examined whether saffron pre-treatment protects dopaminergic cells of the substantia nigra pars compacta (SNc) and retina in an acute MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease. Methods: BALB/c mice received MPTP or saline injections over a 30 hour period, followed by six days survival. For five days prior to injections, the drinking water of the saffron groups was supplemented with saffron (0.01% w/v), while non-saffron groups received normal tap water. After the survival period was complete, brains were processed for tyrosine hydroxylase (TH) immunochemistry and the number of TH+ cells was analysed using the optical fractionator method. Results: In both the SNc and retina, non-conditioned MPTP-injected mice had a reduced number of TH+ cells (30–35%) compared to the saline-injected controls. Saffron pre-conditioning mitigated the reduction, with pre-conditioned MPTP-injected mice having SNc and retinal TH+ cell numbers close to control levels, significantly (25–35%) higher than in non-conditioned MPTP-injected mice. Conclusions: Our results indicated that saffron pre-treatment of mice saved many dopaminergic cells of the SNc and retina from parkinsonian (MPTP) insult.
[Show abstract][Hide abstract] ABSTRACT: 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.
9th World Association for Laser Therapy Congress; 01/2013
[Show abstract][Hide abstract] ABSTRACT: We examined whether near-infrared light (NIr) treatment (photobiomodulation) saves dopaminergic amacrine cells of the retina in an acute and a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson disease. For the acute model, BALB/c mice had MPTP (100 mg/kg) or saline injections over 30 hours, followed by a six-day-survival period. For the chronic model, mice had MPTP (200 mg/kg) or saline injections over five weeks, followed by a three-week-survival period. NIr treatment was applied either at the same time (simultaneous series) or well after (posttreatment series) the MPTP insult. There were four groups within each series: Saline, Saline-NIr, MPTP, and MPTP-NIr. Retinae were processed for tyrosine hydroxylase (TH) immunochemistry, and cell number was analysed. In the MPTP groups, there was a significant reduction in TH(+) cell number compared to the saline controls; this reduction was greater in the acute (~50%) compared to the chronic (~30%) cases. In the MPTP-NIr groups, there were significantly more TH(+) cells than in the MPTP groups of both series (~30%). In summary, we showed that NIr treatment was able to both protect (simultaneous series) and rescue (posttreatment series) TH(+) cells of the retina from parkinsonian insult.
[Show abstract][Hide abstract] ABSTRACT: We have shown previously that near-infrared light (NIr) treatment or photobiomodulation neuroprotects dopaminergic cells in substantia nigra pars compacta (SNc) from degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. The present study explores whether NIr treatment changes the patterns of Fos expression in the subthalamic region, namely, the subthalamic nucleus (STN) and zona incerta (ZI); both cell groups have abnormally overactive cells in parkinsonian cases. BALB/c mice were treated with MPTP (100-250 mg/kg) or saline either over 30 hours followed by either a two-hour or six-day survival period (acute model) or over five weeks followed by a three-week survival period (chronic model). NIr and MPTP were applied simultaneously. Brains were processed for Fos immunochemistry, and cell number was estimated using stereology. Our major finding was that NIr treatment reduced (30-45%) the increase in Fos(+) cell number evident in the STN and ZI after MPTP insult. This reduction was concurrent with the neuroprotection of dopaminergic SNc cells shown previously and was evident in both MPTP models (except for the 2 hours survival period which showed no changes in cell number). In summary, our results indicated that NIr had long lasting effects on the activity of cells located deep in the brain and had repaired partially the abnormal activity generated by the parkinsonian toxin.