Gillipsie Minhas

Preclinical Models to Investigate Retinal Ischemia: Advances and Drawbacks

Retinal ischemia is a major cause of blindness worldwide. It is associated with various disorders such as diabetic retinopathy, glaucoma, optic neuropathies, stroke, and other retinopathies. Retinal ischemia is a clinical condition that occurs due to lack of appropriate supply of blood to the retina. As the retina has a higher metabolic demand, any hindrance in the blood supply to it can lead to decreased supply of oxygen, thus causing retinal ischemia. The pathology of retinal ischemia is still not clearly known. To get a better insight into the pathophysiology of retinal ischemia, the role of animal models is indispensable. The standard treatment care for retinal ischemia has limited potential. Transplantation of stem cells provide neuroprotection and to replenish damaged cells is an emerging therapeutic approach to treat retinal ischemia. In this review we provide an overview of major animal models of retinal ischemia along with the current and preclinical treatments in use.

Pathophysiology of stroke and stroke-induced retinal ischemia: emerging role of stem cells.

The current review focuses on pathophysiology, animal models and molecular analysis of stroke and retinal ischemia, and the role of stem cells in recovery of these disease conditions. Research findings associated with ischemic stroke and retinal ischemia have been discussed, and efforts towards prevention and limiting the recurrence of ischemic diseases, as well as emerging treatment possibilities with endothelial progenitor cells (EPCs) in ischemic diseases, are presented. Although most neurological diseases are still not completely understood and reliable treatment is lacking, animal models provide a major step in validating novel therapies. Stem cell approaches constitute an emerging form of cell‐based therapy to treat ischemic diseases since it is an attractive source for regenerative therapy in the ischemic diseases. In this review, we highlight the advantages and limitations of this approach with a focus on key observations from preclinical animal studies and clinical trials. Further research, especially on treatment with EPCs is warranted. J. Cell. Physiol. 227: 1269–1279, 2012.

Role of iron in ischemia-induced neurodegeneration: mechanisms and insights.

Iron is an important micronutrient for neuronal function and survival. It plays an essential role in DNA and protein synthesis, neurotransmission and electron transport chain due to its dual redox states. On the contrary, iron also catalyses the production of free radicals and hence, causes oxidative stress. Therefore, maintenance of iron homeostasis is very crucial and it involves a number of proteins in iron metabolism and transport that maintain the balance. In ischemic conditions large amount of iron is released and this free iron catalyzes production of more free radicals and hence, causing more damage. In this review we have focused on the iron transport and maintenance of iron homeostasis at large and also the effect of imbalance in iron homeostasis on retinal and brain tissue under ischemic conditions. The understanding of the proteins involved in the homeostasis imbalance will help in developing therapeutic strategies for cerebral as well retinal ischemia.

Animal Models of Retinal Ischemia

Retinal ischemia is a frequent source of irreparable visual impairment and even loss of sight, affecting over a hundred million individuals in the world. It is associated with a wide range of clinical retinal disorders, like ischemic optic neuropathies, obstructive retinopathies, carotid occlusive disorders, diabetic retinopathy and glaucoma. Retinal ischemia occurs when the blood supply to retina is inadequate to meet the metabolic requirements of the retina. If treatment is not given to fix this imbalance, the outcome is irreversible, ischemic and apoptotic cascades resulting in cell death. Appropriate study models, particularly animal models, are necessary for further understanding the etiology, pathology, and evolution of retinal ischemia and also in order to help in the evaluation, development, and improvement of therapeutic strategies. Accordingly, quite a few in-vivo and ex-vivo mammalian models have been developed to study this syndrome. The rat models of retinal ischemia are frequently used, because the distribution of retinal and choroidal blood supply is quite similar to that in humans. The retina has been extensively used for the study of pathophysiology of ischemia and mechanism of damage triggered by ischemia and excitotoxicity. Compared to all the other tissues, retina has a higher metabolic rate; any disturbance in blood supply can have an effect on the supply of oxygen and the substrates leading to retinal ischemia. The retina has a dual blood supply. The photoreceptors and most of the outer plexiform layer (OPL) are nourished by choriocapillaries, while the inner retinal layers are nourished by the central retinal artery. The actual effects of retinal ischemia vary, depending on the position of the occlusion. It is clear that occlusion of the retinal artery leads to inner retinal ischemia only, but occlusion of ophthalmic artery leads to global retinal ischemia, as it supplies blood to the central retinal artery as well as choriocapillaries.

Modeling transient retinal ischemia in mouse by ligation of pterygopalatine artery

Background Retinal ischemia is a major cause of visual impairment and blindness worldwide. The available therapeutic strategies have limited potential. Purpose In order to understand the pathophysiology and validating therapies for retinal ischemia, establishment of reproducible animal models is necessary. Methods In the model discussed in this article, the pterygopalatine artery (PPA) is ligated along with the external carotid artery for 3.5 hours and thereafter allowed to reperfuse. Because PPA supplies the blood to the ophthalmic artery, the ligation of this artery causes retinal ischemia. Results This article describes the validation of retinal ischemia-reperfusion model in mouse through PPA ligation and its validation through fluorescein fundus angiography (FFA) and immunofluorescence staining for glial fibrillary acidic protein (GFAP), a glial injury marker. Conclusions In conclusion this article describes the creation of mouse model of retinal ischemia-reperfusion injury which can be reproduced in a shorter time duration resulting in reduced mortality.

Characterization of Lin-ve CD34 and CD117 cell population reveals an increased expression in bone marrow derived stem cells.

The purpose of the study was to evaluate the expression of CD45, CD34, Sca-1 and CD117 in mouse bone marrow, Lin-ve and Lin+ve population. Bone marrow cells were isolated from C57/BL6J mouse and mononuclear population was separated from rest of the cell population. With the help of Magnetic associated cell sorter (MACS), Linve and Lin+ve cells were separated from the bone marrow. The expression of CD45, CD34, Sca1 and CD117 was evaluated in bone marrow, Lin-ve and Lin+ve population by flow cytometry. We found a significant increase in the expression of CD34 and CD117 in Lin-ve as compared to the bone marrow and Lin+ve population. These findings suggest that Lin-ve population has higher expression of stem cell progenitor markers and could be useful for tissue repair and regeneration.

Hypoxia in CNS Pathologies: Emerging Role of miRNA-Based Neurotherapeutics and Yoga Based Alternative Therapies

Cellular respiration is a vital process for the existence of life. Any condition that results in deprivation of oxygen (also termed as hypoxia) may eventually lead to deleterious effects on the functioning of tissues. Brain being the highest consumer of oxygen is prone to increased risk of hypoxia-induced neurological insults. This in turn has been associated with many diseases of central nervous system (CNS) such as stroke, Alzheimers, encephalopathy etc. Although several studies have investigated the pathophysiological mechanisms underlying ischemic/hypoxic CNS diseases, the knowledge about protective therapeutic strategies to ameliorate the affected neuronal cells is meager. This has augmented the need to improve our understanding of the hypoxic and ischemic events occurring in the brain and identify novel and alternate treatment modalities for such insults. MicroRNA (miRNAs), small non-coding RNA molecules, have recently emerged as potential neuroprotective agents as well as targets, under hypoxic conditions. These 18–22 nucleotide long RNA molecules are profusely present in brain and other organs and function as gene regulators by cleaving and silencing the gene expression. In brain, these are known to be involved in neuronal differentiation and plasticity. Therefore, targeting miRNA expression represents a novel therapeutic approach to intercede against hypoxic and ischemic brain injury. In the first part of this review, we will discuss the neurophysiological changes caused as a result of hypoxia, followed by the contribution of hypoxia in the neurodegenerative diseases. Secondly, we will provide recent updates and insights into the roles of miRNA in the regulation of genes in oxygen and glucose deprived brain in association with circadian rhythms and how these can be targeted as neuroprotective agents for CNS injuries. Finally, we will emphasize on alternate breathing or yogic interventions to overcome the hypoxia associated anomalies that could ultimately lead to improvement in cerebral perfusion.

Role of Ionizing Radiation in Neurodegenerative Diseases

Ionizing radiation (IR) from terrestrial sources is continually an unprotected peril to human beings. However, the medical radiation and global radiation background are main contributors to human exposure and causes of radiation sickness. At high-dose exposures acute radiation sickness occurs, whereas chronic effects may persist for a number of years. Radiation can increase many circulatory, age related and neurodegenerative diseases. Neurodegenerative diseases occur a long time after exposure to radiation, as demonstrated in atomic bomb survivors, and are still controversial. This review discuss the role of IR in neurodegenerative diseases and proposes an association between neurodegenerative diseases and exposure to IR.