Electroporation-mediated gene delivery of cleavage-resistant pro-nerve growth factor causes retinal neuro- and vascular degeneration.

Purpose: Neurotrophins, including nerve growth factor (NGF), are secreted by glia as a pro-form (proNGF) that is normally cleaved into the mature ligand. Increases of proNGF has been well documented in retinal neurodegenerative diseases. Since systemic overexpression of proNGF exhibits embryonic lethality, we aimed to establish a model that specifically and stably overexpresses a cleavage-resistant mutant of proNGF (proNGF123) plasmid in the retina using electroporation.

Diabetes exacerbates retinal oxidative stress, inflammation, and microvascular degeneration in spontaneously hypertensive rats.

Purpose: Hypertension and diabetes are known risk factors for retinal microvascular damage. However, the combined effects of diabetes with early and established stages of hypertension on retinal microvascular degeneration remain incompletely understood.

Methods: Male spontaneously hypertensive rats (SHR) were compared to SHR with streptozotocin-induced diabetes (SHR+D) for 6 or 10 weeks and Wistar rats as controls.

Acute treatment with candesartan reduces early injury after permanent middle cerebral artery occlusion.

We have shown that reduction of blood pressure (BP) immediately after the onset of reperfusion reduced neurovascular damage and improved functional outcome after experimental cerebral ischemia and candesartan is particularly effective in improving long-term functional outcome. In this study, we sought to determine if early BP lowering with candesartan, in the presence of an occluded cerebral artery, will reduce injury and improve outcome after experimental stroke. Male Wistar rats underwent 24 h or 7 days of middle cerebral artery occlusion (MCAO).

Thioredoxin interacting protein is a novel mediator of retinal inflammation and neurotoxicity.

Background And Purpose: Up-regulation of thioredoxin interacting protein (TXNIP), an endogenous inhibitor of thioredoxin (Trx), compromises cellular antioxidant and anti-apoptotic defences and stimulates pro-inflammatory cytokines expression, implying a role for TXNIP in apoptosis. Here we have examined the causal role of TXNIP expression in mediating retinal neurotoxicity and assessed the neuroprotective actions of verapamil, a calcium channel blocker and an inhibitor of TXNIP expression.

Experimental Approach: Retinal neurotoxicity was induced by intravitreal injection of NMDA in Sprague-Dawley rats, which received verapamil (10 mg·kg(-1), p.

Neurovascular protective effect of FeTPPs in N-methyl-D-aspartate model: similarities to diabetes.

We have previously shown a causal role of peroxynitrite in mediating retinal ganglion cell (RGC) death in diabetic and neurotoxicity models. In the present study, the role of peroxynitrite in altering the antioxidant and antiapoptotic thioredoxin (Trx) system will be investigated as well as the subsequent effects on glial activation and capillary degeneration. Excitotoxicity of the retina was induced by intravitreal injection of N-methyl-d-aspartate (NMDA) in rats, which also received the peroxynitrite decomposition catalyst FeTPPs.

Early intervention of tyrosine nitration prevents vaso-obliteration and neovascularization in ischemic retinopathy.

Diabetic retinopathy and retinopathy of prematurity are blinding disorders that follow a pathological pattern of ischemic retinopathy and affect premature infants and working-age adults. Yet, the treatment options are limited to laser photocoagulation. The goal of this study is to elucidate the molecular mechanism and examine the therapeutic effects of inhibiting tyrosine nitration on protecting early retinal vascular cell death and late neovascularization in the ischemic retinopathy model.

Peroxynitrite mediates retinal neurodegeneration by inhibiting nerve growth factor survival signaling in experimental and human diabetes.

Objective: Recently we have shown that diabetes-induced retinal neurodegeneration positively correlates with oxidative stress and peroxynitrite. Studies also show that peroxynitrite impairs nerve growth factor (NGF) survival signaling in sensory neurons. However, the causal role of peroxynitrite and the impact of tyrosine nitration on diabetes-induced retinal neurodegeneration and NGF survival signaling have not been elucidated.

Erythropoietin prevents haloperidol treatment-induced neuronal apoptosis through regulation of BDNF.

Functional alterations in the neurotrophin, brain-derived neurotrophic factor (BDNF) have recently been implicated in the pathophysiology of schizophrenia. Furthermore, animal studies have indicated that several antipsychotic drugs have time-dependent (and differential) effects on BDNF levels in the brain. For example, our previous studies in rats indicated that chronic treatment with the conventional antipsychotic, haloperidol, was associated with decreases in BDNF (and other neurotrophins) in the brain as well as deficits in cognitive function (an especially important consideration for the therapeutics of schizophrenia).