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1.  Animal Models of Diabetic Retinopathy: Summary and Comparison 
Journal of Diabetes Research  2013;2013:106594.
Diabetic retinopathy (DR) is a microvascular complication associated with chronic exposure to hyperglycemia and is a major cause of blindness worldwide. Although clinical assessment and retinal autopsy of diabetic patients provide information on the features and progression of DR, its underlying pathophysiological mechanism cannot be deduced. In order to have a better understanding of the development of DR at the molecular and cellular levels, a variety of animal models have been developed. They include pharmacological induction of hyperglycemia and spontaneous diabetic rodents as well as models of angiogenesis without diabetes (to compensate for the absence of proliferative DR symptoms). In this review, we summarize the existing protocols to induce diabetes using STZ. We also describe and compare the pathological presentations, in both morphological and functional aspects, of the currently available DR animal models. The advantages and disadvantages of using different animals, ranging from zebrafish, rodents to other higher-order mammals, are also discussed. Until now, there is no single model that displays all the clinical features of DR as seen in human. Yet, with the understanding of the pathological findings in these animal models, researchers can select the most suitable models for mechanistic studies or drug screening.
doi:10.1155/2013/106594
PMCID: PMC3826427  PMID: 24286086
2.  Carriers in Cell-Based Therapies for Neurological Disorders 
There is a pressing need for long-term neuroprotective and neuroregenerative therapies to promote full function recovery of injuries in the human nervous system resulting from trauma, stroke or degenerative diseases. Although cell-based therapies are promising in supporting repair and regeneration, direct introduction to the injury site is plagued by problems such as low transplanted cell survival rate, limited graft integration, immunorejection, and tumor formation. Neural tissue engineering offers an integrative and multifaceted approach to tackle these complex neurological disorders. Synergistic therapeutic effects can be obtained from combining customized biomaterial scaffolds with cell-based therapies. Current scaffold-facilitated cell transplantation strategies aim to achieve structural and functional rescue via offering a three-dimensional permissive and instructive environment for sustainable neuroactive factor production for prolonged periods and/or cell replacement at the target site. In this review, we intend to highlight important considerations in biomaterial selection and to review major biodegradable or non-biodegradable scaffolds used for cell transplantation to the central and peripheral nervous system in preclinical and clinical trials. Expanded knowledge in biomaterial properties and their prolonged interaction with transplanted and host cells have greatly expanded the possibilities for designing suitable carrier systems and the potential of cell therapies in the nervous system.
doi:10.3390/ijms150610669
PMCID: PMC4100175  PMID: 24933636
age-related neurodegeneration; drug delivery and drug-likeness; blood-brain barrier; biomaterials; cell encapsulation; microcarriers; central nervous system injury; peripheral nervous system
3.  Hypoxia-Induced Oxidative Stress in Ischemic Retinopathy 
Oxidative stress plays a crucial role in the pathogenesis of retinal ischemia/hypoxia, a complication of ocular diseases such as diabetic retinopathy (DR) and retinopathy of prematurity (ROP). Oxidative stress refers to the imbalance between the production of reactive oxygen species (ROS) and the ability to scavenge these ROS by endogenous antioxidative systems. Free radicals and ROS are implicated in the irreversible damage to cell membrane, DNA, and other cellular structures by oxidizing lipids, proteins, and nucleic acids. Anti-oxidants that can inhibit the oxidative processes can protect retinal cells from ischemic/hypoxic insults. In particular, treatment using anti-oxidants such as vitamin E and lutein, inhibition of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) or related signaling pathways, and administration of catalase and superoxide dismutase (SOD) are possible therapeutic regimens for DR, ROP, and other retinal ischemic diseases. The role of oxidative stress in the pathogenesis of DR and ROP as well as the underlying mechanisms involved in the hypoxia/ischemia-induced oxidative damage is discussed. The information provided will be beneficial in understanding the underlying mechanisms involved in the pathogenesis of the diseases as well as in developing effective therapeutic interventions to treat oxidative stress-induced damages.
doi:10.1155/2012/426769
PMCID: PMC3483772  PMID: 23125893
4.  Neuroprotective effects of lutein in a rat model of retinal detachment 
Background
Retinal detachment (RD) is a leading cause of blindness, and although final surgical re-attachment rate has greatly improved, visual outcome in many macula-off detachments is disappointing, mainly because of photoreceptor cell death. We previously showed that lutein is anti-apoptotic in rodent models of ischemia/reperfusion injury. The objective of this study is to investigate lutein as a possible pharmacological adjunct to surgery.
Methods
Subretinal injections of 1.4 % sodium hyaluronate were used to induce RD in Sprague–Dawley rats until their retinae were approximately 70 % detached. Daily injections of corn oil (control group) or 0.5 mg/kg lutein in corn oil (treatment group) were given intraperitoneally starting 4 h after RD induction. Animals were euthanized 3 days and 30 days after RD and their retinae were analyzed for photoreceptor apoptosis and cell survival at the outer nuclear layer (ONL) using TUNEL staining and cell counting on retinal sections. Glial fibrillary acidic protein (GFAP) and rhodopsin (RHO) expression were evaluated with immunohistochemistry. Western blotting was done with antibodies against cleaved caspase-3, cleaved caspase-8 and cleaved caspase-9 to delineate lutein’s mechanism of action in the apoptotic cascade. To seek a possible therapeutic time window, the same set of experiments was repeated with treatment commencing 36 h after RD.
Results
When lutein was given 4 h after RD, there were significantly fewer TUNEL-positive cells in ONL 3 days after RD when compared with the vehicle group. Cell counting showed that there were significantly more nuclei in ONL in lutein-treated retinae by day 30. Treatment groups also showed significantly reduced GFAP immunoreactivity and preserved RHO expression. At day 3 after RD, Western blotting showed reduced expression of cleaved caspase-3 and cleaved caspase-8 in the treatment group. No difference was found for cleaved caspase-9. When lutein was given 36 h after RD similar results were observed.
Conclusions
Our results suggest that lutein is a potent neuroprotective agent that can salvage photoreceptors in rats with RD, with a therapeutic window of at least 36 h. The use of lutein in patients with RD may serve as an adjunct to surgery to improve visual outcomes.
doi:10.1007/s00417-012-2128-z
PMCID: PMC3536954  PMID: 22899456
Apoptosis; Xanthophyll; Healon; Retinal neuron; Retinal detachment; Lutein; Neuroprotection
5.  Lycium barbarum Extracts Protect the Brain from Blood-Brain Barrier Disruption and Cerebral Edema in Experimental Stroke 
PLoS ONE  2012;7(3):e33596.
Background and Purpose
Ischemic stroke is a destructive cerebrovascular disease and a leading cause of death. Yet, no ideal neuroprotective agents are available, leaving prevention an attractive alternative. The extracts from the fruits of Lycium barbarum (LBP), a Chinese anti-aging medicine and food supplement, showed neuroprotective function in the retina when given prophylactically. We aim to evaluate the protective effects of LBP pre-treatment in an experimental stroke model.
Methods
C57BL/6N male mice were first fed with either vehicle (PBS) or LBP (1 or 10 mg/kg) daily for 7 days. Mice were then subjected to 2-hour transient middle cerebral artery occlusion (MCAO) by the intraluminal method followed by 22-hour reperfusion upon filament removal. Mice were evaluated for neurological deficits just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, immunohistochemical analysis, and Western blot experiments. Evans blue (EB) extravasation was determined to assess blood-brain barrier (BBB) disruption after MCAO.
Results
LBP pre-treatment significantly improved neurological deficits as well as decreased infarct size, hemispheric swelling, and water content. Fewer apoptotic cells were identified in LBP-treated brains by TUNEL assay. Reduced EB extravasation, fewer IgG-leaky vessels, and up-regulation of occludin expression were also observed in LBP-treated brains. Moreover, immunoreactivity for aquaporin-4 and glial fibrillary acidic protein were significantly decreased in LBP-treated brains.
Conclusions
Seven-day oral LBP pre-treatment effectively improved neurological deficits, decreased infarct size and cerebral edema as well as protected the brain from BBB disruption, aquaporin-4 up-regulation, and glial activation. The present study suggests that LBP may be used as a prophylactic neuroprotectant in patients at high risk for ischemic stroke.
doi:10.1371/journal.pone.0033596
PMCID: PMC3306421  PMID: 22438957
6.  Selective Over-Expression of Endothelin-1 in Endothelial Cells Exacerbates Inner Retinal Edema and Neuronal Death in Ischemic Retina 
PLoS ONE  2011;6(10):e26184.
The level of endothelin-1 (ET-1), a potent vasoconstrictor, was associated with retinopathy under ischemia. The effects of endothelial endothelin-1 (ET-1) over-expression in a transgenic mouse model using Tie-1 promoter (TET-1 mice) on pathophysiological changes of retinal ischemia were investigated by intraluminal insertion of a microfilament up to middle cerebral artery (MCA) to transiently block the ophthalmic artery. Two-hour occlusion and twenty-two-hour reperfusion were performed in homozygous (Hm) TET-1 mice and their non-transgenic (NTg) littermates. Presence of pyknotic nuclei in ganglion cell layer (GCL) was investigated in paraffin sections of ipsilateral (ischemic) and contralateral (non-ischemic) retinae, followed by measurement of the thickness of inner retinal layer. Moreover, immunocytochemistry of glial fibrillary acidic protein (GFAP), glutamine synthetase (GS) and aquaporin-4 (AQP4) peptides on retinal sections were performed to study glial cell reactivity, glutamate metabolism and water accumulation, respectively after retinal ischemia. Similar morphology was observed in the contralateral retinae of NTg and Hm TET-1 mice, whereas ipsilateral retina of NTg mice showed slight structural and cellular changes compared with the corresponding contralateral retina. Ipsilateral retinae of Hm TET-1 mice showed more significant changes when compared with ipsilateral retina of NTg mice, including more prominent cell death in GCL characterized by the presence of pyknotic nuclei, elevated GS immunoreactivity in Müller cell bodies and processes, increased AQP-4 immunoreactivity in Müller cell processes, and increased inner retinal thickness. Thus, over-expression of endothelial ET-1 in TET-1 mice may contribute to increased glutamate-induced neurotoxicity on neuronal cells and water accumulation in inner retina leading to edema.
doi:10.1371/journal.pone.0026184
PMCID: PMC3203861  PMID: 22053184
7.  Lycium Barbarum Polysaccharides Reduce Neuronal Damage, Blood-Retinal Barrier Disruption and Oxidative Stress in Retinal Ischemia/Reperfusion Injury 
PLoS ONE  2011;6(1):e16380.
Neuronal cell death, glial cell activation, retinal swelling and oxidative injury are complications in retinal ischemia/reperfusion (I/R) injuries. Lycium barbarum polysaccharides (LBP), extracts from the wolfberries, are good for “eye health” according to Chinese medicine. The aim of our present study is to explore the use of LBP in retinal I/R injury. Retinal I/R injury was induced by surgical occlusion of the internal carotid artery. Prior to induction of ischemia, mice were treated orally with either vehicle (PBS) or LBP (1 mg/kg) once a day for 1 week. Paraffin-embedded retinal sections were prepared. Viable cells were counted; apoptosis was assessed using TUNEL assay. Expression levels of glial fibrillary acidic protein (GFAP), aquaporin-4 (AQP4), poly(ADP-ribose) (PAR) and nitrotyrosine (NT) were investigated by immunohistochemistry. The integrity of blood-retinal barrier (BRB) was examined by IgG extravasations. Apoptosis and decreased viable cell count were found in the ganglion cell layer (GCL) and the inner nuclear layer (INL) of the vehicle-treated I/R retina. Additionally, increased retinal thickness, GFAP activation, AQP4 up-regulation, IgG extravasations and PAR expression levels were observed in the vehicle-treated I/R retina. Many of these changes were diminished or abolished in the LBP-treated I/R retina. Pre-treatment with LBP for 1 week effectively protected the retina from neuronal death, apoptosis, glial cell activation, aquaporin water channel up-regulation, disruption of BRB and oxidative stress. The present study suggests that LBP may have a neuroprotective role to play in ocular diseases for which I/R is a feature.
doi:10.1371/journal.pone.0016380
PMCID: PMC3027646  PMID: 21298100
8.  Lutein Protects RGC-5 Cells Against Hypoxia and Oxidative Stress 
Retinal ischemia and oxidative stress lead to neuronal death in many ocular pathologies. Recently, we found that lutein, an oxy-carotenoid, protected the inner retina from ischemia/reperfusion injury. However, it is uncertain whether lutein directly protects retinal ganglion cells (RGCs). Here, an in vitro model of hypoxia and oxidative stress was used to further investigate the neuroprotective role of lutein in RGCs. Cobalt chloride (CoCl2) and hydrogen peroxide (H2O2) were added to a transformed RGC cell line, RGC-5, to induce chemical hypoxia and oxidative stress, respectively. Either lutein or vehicle was added to cultured cells. A higher cell count was observed in the lutein-treated cells compared with the vehicle-treated cells. Our data from this in vitro model revealed that lutein might protect RGC-5 cells from damage when exposed to either CoCl2-induced chemical hypoxia or H2O2-induced oxidative stress. These results suggest that lutein may play a role as a neuroprotectant.
doi:10.3390/ijms11052109
PMCID: PMC2885097  PMID: 20559505
antioxidants; carotenoids; cobalt chloride; hydrogen peroxide; ischemia; RGC-5

Results 1-8 (8)