Transient phenotypic changes in endothelial cells and pericytes in neonatal mouse retina following short-term blockade of vascular endothelial growth factor receptors.

Background: A short-term interruption of vascular development causes structural abnormalities in retinal vasculature. However, the detailed changes in vascular components (endothelial cells, pericytes, and basement membranes) remain to be fully determined. The present study aimed to provide a detailed description of morphological changes in vascular components following a short-term interruption of retinal vascular development in mice.

Mammalian Target of Rapamycin (mTOR) as a Potential Therapeutic Target in Pathological Ocular Angiogenesis.

Pathological ocular angiogenesis is a causative factor of retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. Vascular endothelial growth factor (VEGF) plays an important role in pathological angiogenesis, and anti-VEGF agents have been used to treat the ocular diseases that are driven by pathological angiogenesis. However, adverse effects associated with the blockade of VEGF signaling, including impairments of normal retinal vascular growth and retinal function, were suggested.

Role of Glial Cells in μ-Opioid Receptor-Mediated Vasodilation in the Rat Retina.

Purpose: Our recent study demonstrated that herkinorin, a non-opioid μ-receptor agonist derived from salvinorin A, dilates retinal arterioles through stimulation of μ-opioid receptors in rats. Activation of neuronal nitric oxide (NO) synthase and the presence of ganglion cells in the retina appear to be crucial for inducing μ-opioid receptor-mediated retinal vasodilation. In the present study, we examined the role of the interaction between neurons and glia in the retinal vasodilator mechanism involving μ-opioid receptors in rats.

Activation inhibitors of nuclear factor kappa B protect neurons against the NMDA-induced damage in the rat retina.

We reported that high-mobility group Box-1 (HMGB1) was involved in excitoneurotoxicity in the retina. HMGB1 is known to activate nuclear factor kappa B (NF-κB). However, the role of NF-κB in excitotoxicity is still controversial.

Expression and Function of the Cholinergic System in Immune Cells.

T and B cells express most cholinergic system components-e.g., acetylcholine (ACh), choline acetyltransferase (ChAT), acetylcholinesterase, and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively).

Probucol prevents the attenuation of β-adrenoceptor-mediated vasodilation of retinal arterioles in diabetic rats.

Probucol is an antihyperlipidemic drug with potent antioxidant properties. Oxidative stress plays an important role in the pathogenesis of diabetic retinopathy. In this study, we aimed to investigate the protective effects of probucol against diabetes-induced retinal vascular dysfunction in a rat model of diabetes.

Opioid receptor activation is involved in neuroprotection induced by TRPV1 channel activation against excitotoxicity in the rat retina.

Recently, we reported that capsaicin, a transient receptor potential vanilloid type1 (TRPV1) agonist, protected against excitotoxicity induced by intravitreal N-methyl-D-aspartic acid (NMDA) in the rats in vivo. It has been reported that morphine, an opioid receptor agonist, ameliorated excitotoxicity induced by ischemia-reperfusion in the retina, and that capsaicin-induced neuroprotection was reduced by naloxone, an opioid receptor antagonist in the brain. The aim of the present study is to clarify whether activation of opioid receptors is involved in the capsaicin-induced neuroprotection in the retina.

MEK/ERK- and calcineurin/NFAT-mediated mechanism of cerebral hyperemia and brain injury following NMDA receptor activation.

N-methyl-d-aspartate (NMDA) receptor activation increases regional cerebral blood flow (rCBF) and induces neuronal injury, but similarities between these processes are poorly understood. In this study, by measuring rCBF in vivo, we identified a clear correlation between cerebral hyperemia and brain injury. NMDA receptor activation induced brain injury as a result of rCBF increase, which was attenuated by an inhibitor of mitogen-activated protein kinase or calcineurin.

Stimulation of μ-opioid receptors dilates retinal arterioles by neuronal nitric oxide synthase-derived nitric oxide in rats.

Opioids contribute to the regulation of cerebral vascular tone. The purpose of this study was to examine the effects of herkinorin, a non-opioid μ-opioid receptor agonist derived from salvinorin A, on blood vessels in the rat retina and to investigate the mechanism underlying the herkinorin-induced retinal vasodilatory response. Ocular fundus images were captured using an original high-resolution digital fundus camera in vivo.

l-Citrulline ameliorates cerebral blood flow during cortical spreading depression in rats: Involvement of nitric oxide- and prostanoids-mediated pathway.

l-Citrulline is a potent precursor of l-arginine, and exerts beneficial effect on cardiovascular system via nitric oxide (NO) production. Migraine is one of the most popular neurovascular disorder, and imbalance of cerebral blood flow (CBF) observed in cortical spreading depression (CSD) contributes to the mechanism of migraine aura. Here, we investigated the effect of l-citrulline on cardiovascular changes to KCl-induced CSD.

Stimulation of β- and β-adrenoceptors dilates retinal blood vessels in rats.

Our previous studies have demonstrated that adrenaline dilates rat retinal arterioles by stimulating propranolol-sensitive β-adrenoceptors and β-adrenoceptors, and selective stimulation of β- or β-adrenoceptors causes retinal vasodilator responses. In the present study, we compared the effects of β- and β-adrenoceptor stimulation on rat retinal arterioles in vivo. Rat ocular fundus images were captured using an original high-resolution digital fundus camera.

Anti-diabetic drug metformin dilates retinal blood vessels through activation of AMP-activated protein kinase in rats.

The aim of this study was to examine whether metformin, a biguanide anti-hyperglycemic drug, dilates retinal blood vessels in rats. Ocular fundus images were captured with an original high-resolution digital fundus camera in vivo and diameters of retinal blood vessels were measured. Both systemic blood pressure and heart rate were continuously recorded.

A delay in vascularization induces abnormal astrocyte proliferation and migration in the mouse retina.

Background: Astrocytes migrate into the retina through the optic nerve head by means of the axons of retinal ganglion cells, and spread radially toward the peripheral retina. Endothelial cells migrate along the astrocyte cellular network to form the retinal surface vasculature. Here, we examined the effects of a delay in retinal vascularization on the migration and proliferation status of astrocytes in mice.

Acetylcholine released from T cells regulates intracellular Ca, IL-2 secretion and T cell proliferation through nicotinic acetylcholine receptor.

Aims: T lymphocytes synthesize acetylcholine (ACh) and express muscarinic and nicotinic ACh receptors (mAChR and nAChR, respectively) responsible for increases in the intracellular Ca concentration ([Ca]). Our aim in the present study was to assess whether autocrine ACh released from T lymphocytes regulates their physiological functions.

Main Methods: MOLT-3 human leukemic cell line and murine splenocytes were loaded with fura-2 to monitor [Ca] changes in the absence or presence of several AChR antagonists, including mecamylamine, methyllycaconitine and scopolamine.

Exposure to high-concentration oxygen in the neonatal period induces abnormal retinal vascular patterning in mice.

The interruption of vascular development could cause structural and functional abnormalities in tissues. We have previously reported that short-term treatment of newborn mice with vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors induces abnormal retinal vascular growth and patterns. An exposure of neonatal mice to high-concentration oxygen disturbs normal retinal vascular development.

Apelin-36 is protective against N-methyl-D-aspartic-acid-induced retinal ganglion cell death in the mice.

Retinal ganglion cell death in glaucoma is caused at least in part by a large Ca influx through N-methyl-D-aspartic acid (NMDA) receptors. Apelin is a peptide originally found in the tissue extracts of bovine stomach. Recent studies have been shown that apelin protects against the ischemic-reperfused injury in the brain.

CRAC channels are required for [Ca(2+)]i oscillations and c-fos gene expression after muscarinic acetylcholine receptor activation in leukemic T cells.

Aims: T lymphocytes express muscarinic acetylcholine receptors (mAChRs) involved in regulating their proliferation, differentiation and cytokine release. Activation of M1, M3 or M5 mAChRs increases the intracellular Ca(2+) concentration ([Ca(2+)]i) through inositol-1,4,5-phosphate (IP3)-mediated Ca(2+) release from endoplasmic reticulum Ca(2+) stores. In addition, T lymphocytes express Ca(2+)-release activated Ca(2+) (CRAC) channels to induce Ca(2+) influx and to regulate diverse immune functions.

Protective effects of PF-4708671 against N-methyl-d-aspartic acid-induced retinal damage in rats.

We previously demonstrated that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), protects against N-methyl-d-aspartic acid (NMDA)-induced retinal damage in rats. Rapamycin inhibits mTOR activity, thereby preventing the phosphorylation of ribosomal protein S6, which is a downstream target of S6 kinase. Therefore, we aimed to determine whether PF-4708671, an inhibitor of S6 kinase, protects against NMDA-induced retinal injury.

Protective Effects of Everolimus against N-Methyl-D-aspartic Acid-Induced Retinal Damage in Rats.

We previously demonstrated that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), protects against N-methyl-D-aspartic acid (NMDA)-induced retinal neurotoxicity, but the mechanism underlying this protection is not fully understood. The present study aimed to examine the effects of everolimus, another inhibitor of mTOR, on neuronal cell loss and inflammation in a rat model of NMDA-induced retinal neurotoxicity, and to determine whether the extracellular signal-regulated kinase (ERK) pathway contributes to the protective effect of everolimus. Intravitreal injection of NMDA (200 nmol) resulted in (1) cell loss in the ganglion cell layer, (2) increase in the numbers of CD45-positive leukocytes and Iba1-positive microglia, and (3) phosphorylation of ribosomal protein S6 (pS6), a downstream indicator of mTOR activity.

Short-term treatment with VEGF receptor inhibitors induces retinopathy of prematurity-like abnormal vascular growth in neonatal rats.

Retinal arterial tortuosity and venous dilation are hallmarks of plus disease, which is a severe form of retinopathy of prematurity (ROP). In this study, we examined whether short-term interruption of vascular endothelial growth factor (VEGF) signals leads to the formation of severe ROP-like abnormal retinal blood vessels. Neonatal rats were treated subcutaneously with the VEGF receptor (VEGFR) tyrosine kinase inhibitors, KRN633 (1, 5, or 10 mg/kg) or axitinib (10 mg/kg), on postnatal day (P) 7 and P8.

Vasodilator Effects of Elcatonin, a Synthetic Eel Calcitonin, on Retinal Blood Vessels in Rats.

The aim of this study was to examine the effects of elcatonin, a synthetic derivative of eel calcitonin, on rat retinal blood vessels, and to determine how diabetes affects the retinal vascular responses. Ocular fundus images were captured with an original high-resolution digital fundus camera in vivo. The retinal vascular responses were evaluated by measuring the diameter of retinal blood vessels contained in the digital images.

Retinal region-dependent susceptibility of capillaries to high-concentration oxygen exposure and vascular endothelial growth factor receptor inhibition in neonatal mice.

Retinal blood flow insufficiency due to capillary loss induces hypoxia in the retina, leading to an abnormal angiogenesis, relating to ischemic retinopathy. To better understand the mechanism and process of retinal capillary regression, we examined the process of hyperoxia- and vascular endothelial growth factor receptor (VEGFR) inhibitor-induced retinal capillary regression in neonatal mice. We also investigated the effects of Ca(2+) channel blockers, amlodipine and nicardipine, on hyperoxia-induced capillary regression.

Involvement of prostaglandin I(2) in nitric oxide-induced vasodilation of retinal arterioles in rats.

The soluble guanylyl cyclase/cGMP system plays an important role in the vasodilator response to nitric oxide (NO) in various vascular beds. However, in rat retinal arterioles, the cyclooxygenase-1/cAMP-mediated pathway contributes to the vasodilator effects of NO, although the specific prostanoid involved remains to be elucidated. In the present study, we investigated the role of prostaglandin I2 and its receptor (prostanoid IP receptor) system in NO-induced vasodilation of rat retinal arterioles in vivo.

Deferiprone Protects against Photoreceptor Degeneration Induced by Tunicamycin in the Rat Retina.

Endoplasmic reticulum stress has been reported to be involved in the pathogenesis of retinitis pigmentosa, macular degeneration and diabetic retinopathy. In the present study, we examined the effects of deferiprone, an iron chelator, on photoreceptor degeneration induced by tunicamycin (300 nmol/eye), an endoplasmic reticulum stress inducer, in the rat retina. Scotopic electroretinogram measurement and morphometric evaluation were done 7 d after the injection of tunicamycin.

High-mobility group Box-1 is involved in NMDA-induced retinal injury the in rat retina.

High-mobility group Box-1 (HMGB1) is known to be released from injured cells and to induce an inflammatory response. Although HMGB1 was reported to mediate ischemia-reperfusion injury of the brain, its role in glutamate excitotoxicity of the retina remains controversial. Here, the authors demonstrated the evidence that HMGB1 is involved in the retinal damage induced by NMDA.