Exposure to the complement C5b-9 complex sensitizes 661W photoreceptor cells to both apoptosis and necroptosis.

The loss of photoreceptors is the defining characteristic of many retinal degenerative diseases, but the mechanisms that regulate photoreceptor cell death are not fully understood. Here we have used the 661W cone photoreceptor cell line to ask whether exposure to the terminal complement complex C5b-9 induces cell death and/or modulates the sensitivity of these cells to other cellular stressors. 661W cone photoreceptors were exposed to complete normal human serum following antibody blockade of CD59. Apoptosis induction was assessed morphologically, by flow cytometry, and on western blotting by probing for cleaved PARP and activated caspase-3. Necroptosis was assessed by flow cytometry and Sirtuin 2 inhibition using 2-cyano-3-[5-(2,5-dichlorophenyl)-2-furyl]-N-5-quinolinylacrylamide (AGK2). The sensitivity of 661W cells to ionomycin, staurosporine, peroxide and chelerythrine was also investigated, with or without prior formation of C5b-9. 661W cells underwent apoptotic cell death following exposure to C5b-9, as judged by poly(ADP-ribose) polymerase 1 cleavage and activation of caspase-3. We also observed apoptotic cell death in response to staurosporine, but 661W cells were resistant to both ionomycin and peroxide. Interestingly, C5b-9 significantly increased 661W sensitivity to staurosporine-induced apoptosis and necroptosis. These studies show that low levels of C5b-9 on 661W cells can induce apoptosis, and that C5b-9 specifically sensitizes 661W cells to certain apoptotic and necroptotic pathways. Our observations provide new insight into the potential role of the complement system in photoreceptor loss, with implications for the molecular aetiology of retinal disease

Ocular Manifestations of Alzheimer's Disease in Animal Models

Alzheimer's disease (AD) is the most common form of dementia, and the pathological changes of senile plaques (SPs) and neurofibrillary tangles (NFTs) in AD brains are well described. Clinically, a diagnosis remains a postmortem one, hampering both accurate and early diagnosis as well as research into potential new treatments. Visual deficits have long been noted in AD patients, and it is becoming increasingly apparent that histopathological changes already noted in the brain also occur in an extension of the brain; the retina. Due to the optically transparent nature of the eye, it is possible to image the retina at a cellular level noninvasively and thus potentially allow an earlier diagnosis as well as a way of monitoring progression and treatment effects. Transgenic animal models expressing amyloid precursor protein (APP) presenilin (PS) and tau mutations have been used successfully to recapitulate the pathological findings of AD in the brain. This paper will cover the ocular abnormalities that have been detected in these transgenic AD animal models

Microglia: Key Players in Retinal Ageing and Neurodegeneration

Microglia are the resident immune cells of the central nervous system (CNS) and play a key role in maintaining the normal function of the retina and brain. During early development, microglia migrate into the retina, transform into a highly ramified phenotype, and scan their environment constantly. Microglia can be activated by any homeostatic disturbance that may endanger neurons and threaten tissue integrity. Once activated, the young microglia exhibit a high diversity in their phenotypes as well as their functions, which relate to either beneficial or harmful consequences. Microglial activation is associated with the release of cytokines, chemokines, and growth factors that can determine pathological outcomes. As the professional phagocytes in the retina, microglia are responsible for the clearance of pathogens, dead cells, and protein aggregates. However, their phenotypic diversity and phagocytic capacity is compromised with ageing. This may result in the accumulation of protein aggregates and myelin debris leading to retinal neuroinflammation and neurodegeneration. In this review, we describe microglial phenotypes and functions in the context of the young and ageing retina, and the mechanisms underlying changes in ageing. Additionally, we review microglia-mediated retinal neuroinflammation and discuss the mechanisms of microglial involvement in retinal neurodegenerative diseases

How latanoprost changed glaucoma management

Glaucoma is currently considered one of the leading causes of severe visual impairment and blindness worldwide. Topical medical therapy represents the treatment of choice for many glaucoma patients. Introduction of latanoprost, 25 years ago, with an entirely new mechanism of action from that of the antiglaucoma drugs used up to that time was a very important milestone. Since then, due mainly to their efficacy, limited systemic side effects and once daily dosing, prostaglandin analogues (PGAs) have become as the first-choice treatment for primary open-angle glaucoma. PGAs are in general terms well tolerated, although they are associated with several mild to moderate ocular and periocular adverse events. Among them, conjunctival hyperemia, eyelash changes, eyelid pigmentation, iris pigmentation and hypertrichosis around the eyes are the most prevalent. The objective of this paper is to review the role of PGAs in the treatment of glaucoma over the 25 years since the launch of Latanoprost and their impact on clinical practice outcomes

Cyclodiode vs micropulse transscleral laser treatment

Background: Continuous-wave transscleral cyclophotocoagulation (CW-TSCP) is usually reserved for advanced/refractory glaucoma. Micropulse transscleral laser therapy (MPTLT) utilises short energy pulses separated by ‘off’-periods. MPTLT is postulated to have fewer complications, but its relative efficacy is not known. The National Institute for Health and Care Excellence (NICE) has deemed the evidence supporting MPTLT use of inadequate quality, limiting its use to research. This study aims to evaluate MPTLT efficacy and safety compared to CW-TSCP. / Methods: This 24-month follow-up retrospective audit included 85 CW-TSCP and 173 MPTLT eyes at a London tertiary referral centre. Primary outcome was success rate at the last follow-up; defined as at least 20% intraocular pressure (IOP) reduction with the same/fewer medications, and IOP between 6 and 18 mmHg. Secondary outcomes were acetazolamide use and success rates per glaucoma type. Safety outcomes were reported as complication rates. / Results: By 24-months, mean IOP reduced from 34.6[±1.4]mmHg to 19.0[± 3.0]mmHg post-CW-TSCP (p < 0.0001); and from 26.1[±0.8]mmHg to 19.1[±2.2]mmHg post-MPTLT (p < 0.0001). Average IOP decreased by 45.1% post-CW-TSCP, and 26.8% post-MPTLT. Both interventions reduced medication requirements (p ≤ 0.05). More CW-TSCP patients discontinued acetazolamide (p = 0.047). Overall success rate was 26.6% for CW-TSCP and 30.6% for MPTLT (p = 0.83). Only primary closed-angle glaucoma saw a significantly higher success rate following CW-TSCP (p = 0.014). CW-TSCP complication rate was significantly higher than MPTLT (p = 0.0048). / Conclusion: Both treatments significantly reduced IOP and medication load. CW-TSCP had a greater absolute/proportionate IOP-lowering effect, but it carried a significantly greater risk of sight-threatening complications. Further prospective studies are required to evaluate MPTLT compared to CW-TSCP

High-Resolution Ocular Imaging: Combining Advanced Optics and Microtechnology

Recent developments in imaging technologies offer great potential for the assessment of retinal ganglion cell disorders, with particular relevance to glaucoma. In particular, advances in this field have allowed unprecedented in vivo access to the retinal layers, using many different properties of light to differentiate cellular structures. This article is a summary of currently available and investigational advanced, high-resolution imaging technologies and their potential applications to glaucoma. It represents the topics of discussion at the annual Optic Nerve Rescue and Restoration Think Tank, sponsored by The Glaucoma Foundation, entitled “High Resolution Imaging of the Eye: Advanced Optics, Microtechnology and Nanotechnology” and held in New York, New York, September 28-29, 2007

Age-related retinal thickness in Down's syndrome: A high-risk population for dementia.

Introduction:People with Down's syndrome (DS) have a high prevalence of early-onset Alzheimer's disease. Early markers of Alzheimer's disease pathology identifiable before clinical change are needed for the evaluation of preventative treatments. The retina, an extension of the brain, may provide a noninvasive imaging site. Methods:Forty-nine adults with DS and 36 age-matched controls completed retinal nerve fibre layer (RNFL) assessments using optical coherence tomography. RNFL thickness was analyzed in relation to cognitive status and age and previously acquired cortical thickness and cerebral amyloid β binding data in a subgroup. Results:RNFL thickness was greater in the DS group and did not show age-related thinning. RNFL correlated positively with cognitive scores and cortical thickness and was reduced in participants with positive cerebral amyloid β binding. Discussion:Increased RNFL in adults with DS may represent early Alzheimer's disease-related changes. Thinning was present in those with cerebral amyloid β binding, independent of age

Simultaneous co-delivery of neuroprotective drugs from multiloaded PLGA microspheres for the treatment of glaucoma

Glaucoma is a multifactorial neurodegenerative disorder and one of the leading causes of irreversible blindness globally and for which intraocular pressure is the only modifiable risk factor. Although neuroprotective therapies have been suggested to have therapeutic potential, drug delivery for the treatment of ocular disorders such as glaucoma remains an unmet clinical need, further complicated by poor patient compliance with topically applied treatments. In the present study we describe the development of multi-loaded PLGA-microspheres (MSs) incorporating three recognised neuroprotective agents (dexamethasone (DX), melatonin (MEL) and coenzyme Q10 (CoQ10)) in a single formulation (DMQ-MSs) to create a novel sustained-release intraocular drug delivery system (IODDS) for the treatment of glaucoma. MSs were spherical, with a mean particle size of 29.04 ± 1.89 μm rendering them suitable for intravitreal injection using conventional 25G-32G needles. Greater than 62% incorporation efficiency was achieved for the three drug cargo and MSs were able to co-deliver the encapsulated active compounds in a sustained manner over 30-days with low burst release. In vitro studies showed DMQ-MSs to be neuroprotective in a glutamate-induced cytotoxicity model (IC50 10.00±0.94 mM versus 6.89±0.82 mM in absence of DMQ-MSs) in R28 cell line. In vivo efficacy studies were performed using a well-established rodent model of chronic ocular hypertension (OHT), comparing single intravitreal injections of microspheres of DMQ-MSs to their equivalent individual single drug loaded MSs mixture (MSsmix), empty MSs, no-treatment OHT only and naïve groups. Twenty one days after OHT induction, DMQ-MSs showed a significantly neuroprotective effect on RGCs compared to OHT only controls. No such protective effect was observed in empty MSs and single-drug MSs treated groups. This work suggests that multi-loaded PLGA MSs present a novel therapeutic approach in the management of retinal neurodegeneration conditions such as glaucoma

MicroShunt versus trabeculectomy for surgical management of glaucoma: a retrospective analysis

This case-control study aims to compare the efficacy, safety, and postoperative burden of MicroShunt versus trabeculectomy. The first consecutive cohort of MicroShunt procedures (n = 101) was matched to recent historical trabeculectomy procedures (n = 101) at two London hospital trusts. Primary endpoints included changes in intraocular pressure (IOP) and glaucoma medications. Secondary outcome measures included changes in retinal nerve fibre layer (RNFL) thickness, rates of complications, further theatre interventions, and the number of postoperative visits. From the baseline to Month-18, the median [interquartile range] IOP decreased from 22 [17–29] mmHg (on 4 [3–4] medications) to 15 [10–17] mmHg (on 0 [0–2] medications) and from 20 [16–28] mmHg (on 4 [3–4] medications) to 11 [10–13] mmHg (on 0 [0–0] medications) in the MicroShunt and trabeculectomy groups, respectively. IOP from Month-3 was significantly higher in the MicroShunt group (p = 0.006), with an increased number of medications from Month-12 (p = 0.024). There were greater RNFL thicknesses from Month-6 in the MicroShunt group (p = 0.005). The rates of complications were similar (p = 0.060) but with fewer interventions (p = 0.031) and postoperative visits (p = 0.001) in the MicroShunt group. Therefore, MicroShunt has inferior efficacy to trabeculectomy in lowering IOP and medications but provides a better safety profile and postoperative burden and may delay RNFL loss