[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. · 4.39 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. Methods 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. Results 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. Conclusions 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; · 3.15 Impact Factor
[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.
[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.
Journal of Parkinson's Disease. 03/2013; 3(1):77-83.
[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: 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 01/2013; 8(3):e59740. · 3.73 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 disease. 01/2013; 2(3):208-220.
[show abstract][hide abstract] ABSTRACT: This study examined the impact of prolonged (up to 35 day) exposure to hyperoxia on the morphology and function of the retina, in the C57BL/6J mouse, as a basis for interpretation of gene expression changes. Mice of the C57BL/6J strain were raised from birth in dim cyclic illumination (12 h 5 lux, 12 h dark). Adult animals (90-110 days) were exposed to continuous hyperoxia (75% oxygen) for up to 35 d. Retinas were examined after 0 d (controls), 3 d, 7 d, 14 d and 35 d. Spatial and temporal patterns of photoreceptor death were mapped, using the TUNEL technique. Immunohistochemistry and a specific assay were used to assess the expression of a stress-related protein (GFAP) and the activity of key antioxidant enzymes (SOD). The dark-adapted flash electroretinogram was used to assess the function of rods and cones. RNA hybridized to Affymetrix Genechips was used to assess gene expression during the first 3 d of exposure. Photoreceptors were stable during the first 7 d exposure to hyperoxia, but thereafter showed progressive damage and degeneration, which began in a 'hot-spot' 0.5 mm inferior to the optic disc, then spread into surrounding retina. SOD activity was upregulated at 14 d, but not at earlier time points. GFAP expression was upregulated in Müller cells from 3 d. Rod and cone components of the ERG were supernormal at 3 d and 7 d, but then fell below control levels. Gene expression changes suggested possible mechanisms for this early supernormality of function. At 14 d exposure, damage to and death of photoreceptors were prominent and spreading, and function was correspondingly degraded. However at 3 d exposure, hyperoxia-induced supernormal functional responses in rods, while leaving their structure apparently undamaged. Variations in early (3 days) gene expression provide a partial insight into the mechanisms involved in this.
Experimental Eye Research 01/2011; 92(4):306-14. · 3.03 Impact Factor
[show abstract][hide abstract] ABSTRACT: Environmental stress (bright light, hypoxia) can "condition" retinal photoreceptors, increasing their resistance to subsequent stress. The present study tests whether another photoreceptor-lethal stress, hyperoxia, can induce similar resistance.
Vulnerability to hyperoxia was tested in young adult C57BL/6J mice exposed to 1000 lux cyclic light for 1 week or to 50% O2 for 1 week and then to 75% O2 for 2 weeks. Vulnerability to light was tested in Balb/cJ mice exposed to 300 lux cyclic light for 2 days or to 75% O2 for 2 weeks and then to 1000 lux cyclic light for 1 week. Retinas were analyzed for photoreceptor death, levels of stress-related proteins (GFAP, FGF-2, MnSOD, acrolein), and the regulation of candidate neuroprotective genes (HSP70.1, Ledgf, FGF-13, Timp2).
Light preconditioning did not cause measurable death of photoreceptors but reduced photoreceptor death induced by subsequent hyperoxic or light stress, reduced levels of stress-related proteins, and maintained the length and organization of photoreceptor outer segments. Hyperoxic preconditioning caused measurable cell death but provided no protection against subsequent hyperoxic or light stress. Of the four candidate neuroprotective proteins examined, the regulation of only one (Timp2) seemed associated with the neuroprotection observed.
Light preconditioning, causing only minimal damage to photoreceptors, induced protection against subsequent stress from both hyperoxia and light. By contrast, hyperoxic preconditioning caused measurable photoreceptor damage but induced no protection against light or hyperoxia. These data suggest a separation between stress-induced damage to photoreceptors and the upregulation of protective mechanisms, encouraging the search for ways to protect the retina without damaging it.
[show abstract][hide abstract] ABSTRACT: In the C57BL/6J mouse retina, hyperoxia-induced degeneration of photoreceptors shows strong regional variation, beginning at a locus ~0.5 mm inferior to the optic disc. To identify gene expression differences that might underlie this variability in vulnerability, we have used microarray techniques to describe regional (superior-inferior) variations in gene expression in the retina.
Young adult C57BL/6J mice raised in dim cyclic illumination (12 h at 5 lx and 12 h in darkness) were exposed to hyperoxia (75% oxygen for two weeks). Retinas were collected from hyperoxia-exposed and control animals without fixation and divided into superior and inferior halves. RNA was extracted from each sample, purified, and hybridized to Mouse Gene 1.0 ST arrays (Affymetrix). The consistency of the microarray results was assessed using quantitative PCR for selected genes. Expression data were analyzed to identify genes and ncRNAs whose differential expression between the superior and inferior retina could be associated with relative vulnerability to hyperoxia.
In control retinas, only two genes showed a fold difference in expression >2 between the superior and inferior retina; another 25 showed a fold difference of 1.5-2.0. Of these 27, the functions of six genes, including ventral anterior homeobox containing gene 2 (Vax2) and T-box 5 (Tbox5), are related to parameters of anatomic development and the functions of five are related to sensory perception. Among the latter, short-wave-sensitive cone opsin (Opn1sw) was more strongly expressed in the inferior retina and medium-wave-sensitive cone opsin (Opn1mw) in the superior retina. This is consistent with known differences in S- and M-cone distribution, confirming our separation of retinal regions. The highest fold difference was reported for membrane metalloendopeptidase (Mme), a member from the metallothionein group of cytoprotective proteins. To identify genes whose regulation by hyperoxia was significantly different between the inferior and superior retina, we calculated the "fold margin" (FM, the difference between hyperoxia-induced regulation in the inferior and superior retina) for each gene, and identified genes for which abs(FM) > 0.5. Genes thus identified numbered 112, and included many immune-, cell defense-, and inflammation- related genes.
Gene expression analysis revealed relatively subtle differences between inferior and superior regions of control C57BL/6J retinas, with only 27 genes showing an expression difference >1.5 fold. Among these, genes related to cytoprotection and apoptosis were included, along with genes related to central projections and cone-type differences. After hyperoxia-induced photoreceptor degeneration had begun, the number of genes that showed significant expression differences between the inferior and superior retina more than quadrupled, with genes related to immune processes, defense processes, and inflammation being numerically dominant.
[show abstract][hide abstract] ABSTRACT: To identify the genes and noncoding RNAs (ncRNAs) involved in the neuroprotective actions of a dietary antioxidant (saffron) and of photobiomodulation (PBM).
We used a previously published assay of photoreceptor damage, in which albino Sprague Dawley rats raised in dim cyclic illumination (12 h 5 lux, 12 h darkness) were challenged by 24 h exposure to bright (1,000 lux) light. Experimental groups were protected against light damage by pretreatment with dietary saffron (1 mg/kg/day for 21 days) or PBM (9 J/cm(2) at the eye, daily for 5 days). RNA from one eye of four animals in each of the six experimental groups (control, light damage [LD], saffron, PBM, saffronLD, and PBMLD) was hybridized to Affymetrix rat genome ST arrays. Quantitative real-time PCR analysis of 14 selected genes was used to validate the microarray results.
LD caused the regulation of 175 entities (genes and ncRNAs) beyond criterion levels (p<0.05 in comparison with controls, fold-change >2). PBM pretreatment reduced the expression of 126 of these 175 LD-regulated entities below criterion; saffron pretreatment reduced the expression of 53 entities (50 in common with PBM). In addition, PBM pretreatment regulated the expression of 67 entities not regulated by LD, while saffron pretreatment regulated 122 entities not regulated by LD (48 in common with PBM). PBM and saffron, given without LD, regulated genes and ncRNAs beyond criterion levels, but in lesser numbers than during their protective action. A high proportion of the entities regulated by LD (>90%) were known genes. By contrast, ncRNAs were prominent among the entities regulated by PBM and saffron in their neuroprotective roles (73% and 62%, respectively).
Given alone, saffron and (more prominently) PBM both regulated significant numbers of genes and ncRNAs. Given before retinal exposure to damaging light, thus while exerting their neuroprotective action, they regulated much larger numbers of entities, among which ncRNAs were prominent. Further, the downregulation of known genes and of ncRNAs was prominent in the protective actions of both neuroprotectants. These comparisons provide an overview of gene expression induced by two neuroprotectants and provide a basis for the more focused study of their mechanisms.
[show abstract][hide abstract] ABSTRACT: To examine the susceptibility of photoreceptors to hyperoxic stress in two rat strains, the pigmented Long Evans (LE) and the albino Sprague-Dawley (SD).
Adult LE and SD rats were exposed to hyperoxia (75% oxygen) for 14 days. Retinas were assessed for electroretinogram (ERG) responses, cell death, and expression of a retinal stress factor.
In the LE strain, exposure to hyperoxia significantly reduced amplitudes of rod a-wave, rod b-wave and cone b-wave components of the ERG, and caused a 55-fold increase in photoreceptor cell death rates, and an upregulation of GFAP expression. In the SD strain, hyperoxic exposure had no measurable effect on the ERG response of rods or cones, and resulted in a modest (5-fold) increase in the rate of photoreceptor cell death.
In LE and SD strains, hyperoxia induces cell death specific to photoreceptors. The effect is an order of magnitude more severe in the pigmented LE strain suggesting a strong genetic component to oxygen sensitivity, as reported previously between the albino Balb/C and pigmented C57BL/6 strains of mice.
Advances in experimental medicine and biology 01/2010; 664:473-9. · 1.83 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hyperoxia-induced photoreceptor degeneration occurs preferentially in the inferior retina of C57BL/6 J mice. This study investigates differential gene expression in the inferior and superior retina of C57BL/6 J mouse, before and after hyperoxic stress.
At the age of P (postnatal day) 83-90, mice were placed in constant normoxia or hyperoxia (75% O(2)) for 2 weeks. Retinas from control and exposed mice were removed and RNA was extracted from superior and inferior regions. The RNA from 2 animals (1 male and 1 female) at each condition was extracted, purified and hybridized to an Affymetrix MouseGene 1.0 ST Array to elucidate gene expression. Experiments were run in triplicate and analysis of the expression patterns was performed using GeneSpring and Partek Genomics Suite softwares.
Over 400 genes showed significant differential expression by location and treatment using 2-way ANOVA analysis. In the control material, no genes showed a differential expression greater than twofold between inferior and superior retina. After hyperoxic stress, 154 genes in the inferior and 30 genes in the superior retina showed a greater than twofold change in expression. Among those, genes such as Edn2, GFAP, Bcl3 and C1qb showed expression differences of greater than three fold between inferior and superior retina. Real time PCR was used to verify gene expression of control genes as well as genes of interest.
These microarray data may provide clues for identifying previously unknown factors and pathways responsible for the vulnerability of inferior retina to hyperoxic stress and for the eventual identification of therapeutic targets.
Advances in experimental medicine and biology 01/2010; 664:217-22. · 1.83 Impact Factor
[show abstract][hide abstract] ABSTRACT: This study tests the potential of light restriction to optimise retinal structure and function in adulthood, using the P23H-3 rhodopsin-mutant transgenic rat as a model. P23H-3 rats were reared in scotopic (5 lux) or mesopic (40-60 lux) cyclic (12 h/12 h light/dark) light. A further 2 groups were reared in one of these light conditions to P(postnatal day)30, and then were transferred to the other condition. Retinae were examined at P30-365. Rod and cone function were assessed by the dark-adapted flash electroretinogram. The rate of photoreceptor death was assessed with the TUNEL technique, and photoreceptor survival by the thickness of the outer nuclear layer (ONL). Photoreceptor structural changes were assessed by immunohistochemistry. Mesopic rearing severely reduced the number, function and outer segment (OS) length of photoreceptors. Light restriction in the adult (achieved by moving mesopic-reared animals to scotopic conditions at P30) slowed photoreceptor death, induced recovery of the ERG and of OS length in survivors, resulting in an adult retina that matched the scotopic-reared in function, photoreceptor survival (stability) and structure. Conversely, light exposure in the adult (achieved by moving scotopic-reared animals to mesopic conditions at P30) accelerated photoreceptor death, shortened OSs and reduced the ERG, resulting in a retina that was as damaged and dysfunctional as a mesopic-reared retina, and showed greater photoreceptor instability. Present observations suggest, that the stability and function of adult photoreceptors are determined by both early and adult ambient light experience. Light restriction in the adult was effective in inducing the self-repair of photoreceptors, and the recovery of their function and stability. Light restriction in the juvenile (before P30) improved early photoreceptor survival but made adult photoreceptors vulnerable to brighter light experienced in adulthood. For comparable human dystrophies, these results suggest that light restriction begun after retinal maturation may be effective in optimising the structure, function and stability of the adult retina.
Experimental Eye Research 10/2009; 89(6):1003-11. · 3.03 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess the effect of accelerated rod damage on the integrity of cones in the rat retina.
Rhodopsin-mutant P23H-3 and Sprague-Dawley (SD) rats were raised in scotopic ambient conditions (12 hours dark, 12 hours 5 lux) and then exposed to photopic conditions (12 hours dark, 12 hours 300 lux). Rods and cones were assessed for cell death, outer segment (OS) morphology, and electroretinogram (ERG) responses.
Cones in the P23H-retina were affected rapidly by photopic exposure. Exposure for 2 days caused 50% reductions in LM- and S-cone OS length and cone ERG responses, associated with and preceded by reductions in rod OS length and ERG responses. Although 2 days' exposure increased the rate of rod death, outer nuclear layer thinning was minimal, and no evidence of cone death was detected. In the SD retina, the same photopic exposure had no measurable effects on death rates, OS length, or ERG responses in either rods or cones. Longer (7 days) photopic exposure reduced cone and rod OS length and ERG responses in SD, as well as P23H-3 retinas, but less severely than in the P23H-3 strain.
Cones are damaged rapidly in the P23H-3 retina when rod damage is accelerated by raised ambient illumination. This close dependence of cone integrity on rod integrity contrasts with the life-long persistence of cone function in the scotopic reared P23H-3 rat. In humans suffering comparable photoreceptor dystrophies, the maintenance of steady, low ambient light may, by minimizing acute rod damage, optimize the function of surviving cones.
[show abstract][hide abstract] ABSTRACT: To follow the status of cones over the life of the P23H-3 transgenic rat, while the rod population is depleted.
P23H-3 heterozygous and Sprague-Dawley (SD) control rats were raised in dim, cyclic light from postnatal day (P)10 to P540. Retinas were examined for cone density, cone outer segment (OS) length, cone axon and soma morphology, and the amplitude of rod and cone components of the electroretinogram (ERG) were determined.
In the P23H-3 retina, cone density followed a developmental pattern, increasing from P10 until P20, declining during early adult life (to P150), then steadying at levels found in the SD retina until P540. Cone OSs elongated to P30 and then slowly shortened during late adulthood; at P350 and P540, cone OSs were significantly shorter than in the background SD strain. Cone axons shortened slowly throughout adult life as the outer nuclear layer thinned. The rod a-wave declined steadily in the P23H-3 retina from P10, falling below amplitudes seen in the SD strain from early life. By contrast, the cone b-wave maintained amplitude at SD levels, until P380.
Despite the ongoing loss of rod function and numbers, cone numbers in the P23H-3 retina were maintained at levels found in the SD rat to the oldest age examined, and cone function and OS morphology were maintained for approximately 1 year, indicating a long period of cone independence. The long period of cone survival creates an opportunity to induce self-repair, if the stress causing their dysfunction can be reduced.
[show abstract][hide abstract] ABSTRACT: Although the key pathologies of the demented brain have been known for over a century, and the senile plaque is the focus of intense research, the mechanisms that cause plaques to form are not established. This paper proposes that the formation of each plaque is initiated by bleeding from a cerebral capillary, which creates the conditions for formation of an amyloid-rich plaque. Specifically, it is argued that ischaemia caused by the haemorrhage upregulates the expression of beta-amyloid by local neural cells, and that haemoglobin released into the neuropil binds to the beta-amyloid and promotes its oligomerisation. The premise that the event that initiates plaque formation is vascular explains why the risk factors for ALDs and cardiovascular diseases overlap; why drugs and lifestyle changes with vaso-protective effects protect against dementia; and why oxidative stress is prominent early in the genesis of Alzheimer-like dementias. The vascular premise also suggests that the anatomical substrate for the spread of plaque formation is the capillary bed of the cerebral cortex, and provides an explanation of why plaque formation is age-related, occurring as the capillary bed becomes fragile with age. The more specific premise, that haemorrhage creates the conditions for plaque formation, explains many of the features of plaques: their small and relatively uniform size, each being the site of a capillary bleed; why plaques form around capillaries; why haem is found in every plaque; why an inflammatory response is prominent where plaques form; why plaque formation and haemorrhagic stroke commonly co-occur in both sporadic and familial dementias; why plaques form around vessels in mouse models of plaque formation induced by transgenes that mimic the mutations that cause familial disease; why the acute petechial bleeding caused by brain trauma can lead to the formation of plaques. The hypothesis also suggests an explanation of how ALD's can occur without plaque formation, as when the cerebral capillaries become blocked or constricted in flow, without haemorrhage. Advances in the prevention of dementia will be gained, it is argued, from understanding of why the cerebral capillary bed becomes unstable with age, and how that instability can be prevented, delayed or slowed. Advances in the treatment of dementia will be gained from techniques that minimise the neural damage caused by a multitude of tiny strokes.
Medical Hypotheses 09/2008; 71(3):347-59. · 1.05 Impact Factor
[show abstract][hide abstract] ABSTRACT: To examine the response of mouse retina to sustained hyperoxia. Hyperoxia is toxic to photoreceptors after sustained exposure (7-14 days in the C57BL/6J mouse) but has been reported to enhance photoreceptor function after short-term exposure.
Retinas from the hyperoxia-vulnerable C57BL/6J mouse and from the hyperoxia-resistant BALB/cJ mouse were examined after 0, 3, 7, 14, and 35 days' exposure to 75% oxygen. Quantitative PCR, TUNEL, and immunohistochemical techniques were used to trace the regulation and site of expression of the early-response, potentially protective gene Oxr1.
In the C57BL/6J retina, Oxr1 was upregulated at 3 days of exposure, matching the early period of resistance to hyperoxia in this strain, and fell below control levels at 14 days, when photoreceptor degeneration had begun. By contrast, the stress-related gene GFAP was upregulated only at 7 to 14 days. Immunohistochemistry showed a concentration of Oxr1 in the inner part of photoreceptor outer segments, but, as photoreceptors underwent apoptosis, Oxr1 concentrated in the nucleus, confirming earlier reports that photoreceptors were resistant to hyperoxia until 14 days in the BALB/cJ mouse and, correspondingly, that the upregulation of Oxr1 in outer segments was sustained until 14 days.
The patterns of Oxr1 expression observed suggest that the gene is associated with resistance to hyperoxic challenge and that it acts at the level of the outer segment. The retinal response to hyperoxia may constitute acute and chronic phases in which photoreceptors are first resistant, and then vulnerable, to oxidative damage. Understanding this biphasic response may be important in understanding the role of oxygen in the progress of retinal dystrophy.