L-Citrulline dilates rat retinal arterioles via nitric oxide- and prostaglandin-dependent pathways in vivo.

L-Citrulline is an effective precursor of L-arginine produced by the L-citrulline/L-arginine cycle, and it exerts beneficial effects on the cardiovascular system by supporting enhanced nitric oxide (NO) production. NO dilates retinal blood vessels via the cyclooxygenase-mediated pathway. The purpose of this study was to examine the effects of L-citrulline on retinal circulation and to investigate the potential involvement of NO and prostaglandins in L-citrulline-induced responses in rats.

Non-neuronal cholinergic system in regulation of immune function with a focus on α7 nAChRs.

In 1929, Dale and Dudley described the first reported natural occurrence of acetylcholine (ACh) in an animal's body. They identified this ACh in the spleens of horses and oxen, which we now know suggests possible involvement of ACh in the regulation of lymphocyte activity and immune function. However, the source and function of splenic ACh were left unexplored for several decades.

P2X7 receptor antagonists protect against N-methyl-D-aspartic acid-induced neuronal injury in the rat retina.

Activation of N-methyl-d-aspartic acid (NMDA) receptors followed by a large Ca(2+) influx is thought to be a mechanism of glaucoma-induced neuronal cell death. It is possible that damage-associated molecular patterns leak from injured cells, such as adenosine triphosphate, causing retinal ganglion cell death in glaucoma. In the present study, we histologically investigated whether antagonists of the P2X7 receptor protected against NMDA-induced retinal injury in the rat in vivo.

Preventive effects of rapamycin on inflammation and capillary degeneration in a rat model of NMDA-induced retinal injury.

Inhibitors of the mammalian target of rapamycin (mTOR) have been shown to protect against neuronal injury, but the mechanisms underlying this effect are not fully understood. The present study aimed to examine the effects of rapamycin, an inhibitor of the mTOR pathway, on inflammation and capillary degeneration in a rat model of N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity. Inflammation and capillary degeneration were evaluated by counting the numbers of CD45-positive leukocytes and Iba1-positive microglia, and by measuring the length of empty basement membrane sleeves, respectively.

Effect of long-term treatment of L-ornithine on visual function and retinal histology in the rats.

L-Ornithine is a non-proteinogenic amino acid, abundant in freshwater clams and commercially available as an oral nutritional supplement. L-Ornithine is metabolized by ornithine-δ-aminotransferase. Deficiency of this enzyme causes gyrate atrophy of the choroid and retina, an autosomal recessive hereditary disease characterized by the triad of progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy, with hyperornithinemia.

Structural and functional changes in retinal vasculature induced by retinal ischemia-reperfusion in rats.

Recent studies have shown retinal blood vessel damage in experimental models of retinal degeneration. The present study aimed to provide a detailed description of the structural and functional changes in retinal vasculature induced by retinal ischemia-reperfusion (I/R) in rats. Retinal ischemia was induced for 60 min by raising the intraocular pressure to 130 mmHg.

Impaired retinal vasodilator response to acetylcholine in a rat model of NMDA-induced retinal degeneration.

Previous studies have shown that degeneration of retinal capillaries occurs following N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity, but it is unclear whether vasodilatory mechanisms are altered in retinal blood vessels. The purpose of the present study was to determine whether retinal vasodilator responses are affected in a rat model of NMDA-induced retinal damage. At 14 days after a single intravitreal injection of NMDA (200 nmol), retinal vasodilator responses were assessed by measuring the diameter of retinal arterioles in fundus images.

4-Hydroxy-2-nonenal attenuates β2-adrenoceptor-mediated vasodilation of rat retinal arterioles.

4-Hydroxy-2-nonenal (4-HNE) is a major reactive aldehyde formed by lipid peroxidation, and it plays an important role in the pathogenesis of several vascular diseases, including diabetes mellitus. In this study, we examined the effects of 4-HNE on the vasodilatory mechanisms of rat retinal arterioles. The retinal vasodilator responses were assessed by measuring the diameter of retinal arterioles in the fundus images.

Treatment of newborn mice with inhibitors of vascular endothelial growth factor receptor tyrosine kinase induces abnormal retinal vascular patterning.

We have previously reported that treatment of newborn mice with KRN633, a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, delayed retinal vascularization leading to abnormal retinal vascular growth and patterns. To determine whether similar abnormalities are observed in newborn mice treated with other VEGF receptor tyrosine kinase inhibitors, we administered axitinib to mice on the day of birth and on the following day. When compared with control pups, a significant delay in retinal vascularization was observed in pups treated with axitinib (5 mg/kg).

Effects of mTOR inhibition on normal retinal vascular development in the mouse.

We aimed to determine the role of age-related changes in the mammalian target of rapamycin (mTOR) activity in endothelial cell growth during retinal vascular development in mice. Mice were administered the mTOR inhibitor rapamycin as follows: (i) for 6 days from postnatal day 0 (P0) to P5, (ii) for 2 days on P6 and P7, and (iii) for 2 days on P12 and P13. For comparison, we examined the effects of KRN633, an inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinase, on retinal vascular development.

Anti-angiogenic effects of mammalian target of rapamycin inhibitors in a mouse model of oxygen-induced retinopathy.

Ocular pathologic angiogenesis is a causative factor for retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. In the present study, we examined the effects of rapamycin and everolimus, inhibitors of mammalian target of rapamycin (mTOR), on retinal pathologic angiogenesis in mice with oxygen-induced retinopathy (OIR), an animal model of proliferative ischemic retinopathy. Mice were exposed to 80% oxygen from postnatal day (P) 7 to P10, and were then brought into room air and subcutaneously injected with rapamycin and everolimus.

Regression of retinal capillaries following N-methyl-D-aspartate-induced neurotoxicity in the neonatal rat retina.

Degeneration of retinal capillaries occurs following N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity, and the degree of capillary degeneration decreases in an age-dependent manner. To determine the role of vascular endothelial growth factor (VEGF) in the high susceptibility of capillaries to neuronal damage during the early postnatal stage, this study compares the vascular regression patterns between NMDA-treated retinas and retinas treated with N-[2-chloro-4-{(6,7-dimethoxy-4-quinazolinyl)oxy}phenyl]-N'-propylurea (KRN633), a VEGF receptor tyrosine kinase inhibitor, in neonatal rats. Two days after a single intravitreal injection of NMDA (200 nmol/eye) on postnatal day (P) 7, substantial retinal neuron loss and delayed expansion of the retinal vascular bed were observed.

Age-dependent changes in the severity of capillary degeneration in rat retina following N-methyl-D-aspartate-induced neurotoxicity.

Purpose: Previous studies have shown that injury to the retinal vasculature, including capillary degeneration, occurs following N-methyl-d-aspartate (NMDA)-induced neuronal cell loss, but it is unclear whether there are age-dependent differences in the severity of vascular damage. The purpose of the present study was to determine age-related changes in retinal capillary degeneration in NMDA-induced retinal damage rat model.

Materials And Methods: A single intravitreal injection of NMDA (200 nmol/eye) was performed in 1-, 2-, 3-, 7- and 15-week-old male Sprague-Dawley rats.

Activation of the TRPV1 channel attenuates N-methyl-D-aspartic acid-induced neuronal injury in the rat retina.

Capsaicin, a transient receptor potential vanilloid type1 (TRPV1) agonist, has been reported to protect against ischemia-reperfusion injury in various organs, including the brain, heart, and kidney, whereas activation of TRPV1 was also reported to contribute to neurodegeneration, including pressure-induced retinal ganglion cell death in vitro. We histologically investigated the effects of capsaicin and SA13353, TRPV1 agonists, on retinal injury induced by intravitreal N-methyl-d-aspartic acid (NMDA; 200 nmol/eye) in rats in vivo. Under ketamine/xylazine anesthesia, male Sprague-Dawley rats were subjected to intravitreal NMDA injection.

Rapamycin prevents N-methyl-D-aspartate-induced retinal damage through an ERK-dependent mechanism in rats.

Recent studies have demonstrated that inhibition of the mammalian target of rapamycin (mTOR) protects against neuronal injury, but the mechanisms underlying this protection are not fully understood. The present study investigates whether rapamycin, an inhibitor of the mTOR pathway, protects against N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity and whether the extracellular signal-regulated kinase (ERK) pathway contributes to this protective effect in rats. Significant cell loss in the ganglion cell layer and a reduction in thickness of the inner plexiform layer were observed 7 days after a single intravitreal injection of NMDA (200 nmol/eye).

Comparison of the effects of single doses of elcatonin and pregabalin on oxaliplatin-induced cold and mechanical allodynia in rats.

Oxaliplatin frequently causes peripheral neuropathy. Clinical studies have indicated that pregabalin ameliorates oxaliplatin-induced peripheral neuropathy. However, pregabalin frequently causes dizziness and somnolence.

Histological protection by nilvadipine against neurotoxicity induced by NOC12, a nitric oxide donor, in the rat retina.

In the present study, we histologically examined the effects of nilvadipine on neuronal injury induced by intravitreal (i.v.) N-methyl-D-aspartate (NMDA) (200 nmol/eye) and intravitreal NOC12 (400 nmol/eye), a nitric oxide donor, in the rat retina.

Effects of pre- and post-natal treatment with KRN633, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, on retinal vascular development and patterning in mice.

The impaired function of angiogenic factors, including vascular endothelial growth factor (VEGF), during pregnancy is associated with preeclampsia and intrauterine growth restriction. To determine how the attenuation of VEGF signals during retinal vascular development affects retinal vascular growth and patterns, we examined the effects of pre- and post-natal treatment of mice with KRN633, a VEGF receptor tyrosine kinase inhibitor, on retinal vascular development and structure. Delays in retinal vascular development were observed in the pups of mother mice that were treated daily with KRN633 (5 mg/kg/day) from embryonic day 13.

Hydrogen sulfide attenuates NMDA-induced neuronal injury via its anti-oxidative activity in the rat retina.

Although hydrogen sulfide (H2S) is generally thought to be a toxic gas, it has been reported to protect various tissues against ischemia-reperfusion injury. In the present study, we histologically investigated whether H2S, using sodium hydrosulfide (NaHS) as its donor, had a protective effect on N-methyl-d-aspartate (NMDA)-induced retinal injury in the rat in vivo. Under ketamine/xylazine anesthesia, male Sprague-Dawley rats were subjected to intravitreal NMDA injection.

[Elucidation of dysfunctional mechanisms of retinal circulation in the rat models of glaucoma and exploration of novel therapeutic drugs].

In recent times, glaucoma has become the leading cause of acquired blindness among the Japanese. As visual disorders markedly decrease the quality of life (QOL), it is important to develop new strategies for preventing the onset of and delaying the progression of glaucoma. Glaucoma has long since been recognized as a serious disease caused by increased intraocular pressure and subsequent injury and death of the neuronal retinal cells.

Neurovascular interactions in the retina: physiological and pathological roles.

Increasing evidence suggests that the complex interactions among multiple cell types including neuronal, glial, and vascular cells, are critical for maintaining adequate cerebral blood flow that is necessary for normal brain function and survival. The disturbance of these interactions contributes to the pathogenesis of central nervous system disorders such as stroke and Alzheimer's disease. The retina is part of the central nervous system, and the properties of vasculature in the retina are similar to those in the brain.

ISO-1, a macrophage migration inhibitory factor antagonist, prevents N-methyl-D-aspartate-induced retinal damage.

Macrophage migration inhibitory factor (MIF) has been shown to play an important role in a variety of inflammatory and immune-mediated diseases. The inflammatory responses contribute to retinal neuronal degeneration. However, the role of MIF in the progression of retinal degeneration has not yet been elucidated.

KRN633, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, induces intrauterine growth restriction in mice.

We previously reported that treatment with KRN633, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, during mid-pregnancy caused intrauterine growth restriction resulting from impairment of blood vessel growth in the labyrinthine zone of the placenta and fetal organs. However, the relative sensitivities of blood vessels in the placenta and fetal organs to vascular endothelial growth factor (VEGF) inhibitors have not been determined. In this study, we aimed to examine the effects of KRN633 on the vasculatures of organs in mother mice and their newborn pups by immunohistochemical analysis.

Role of vascular endothelial growth factor in maintenance of pregnancy in mice.

It is well known that withdrawal of progesterone from the maternal circulation is a critical stimulus to parturition in rodents, such as rats and mice. However, mechanisms that determine the timing of progesterone withdrawal are not completely understood. In the present study, we examined whether the vascular endothelial growth factor (VEGF) system in the corpus luteum (CL) contributes to the regulation of circulating progesterone levels and acts as a determinant of the timing of parturition in mice.

Protective effects of TGF-β inhibitors in a rat model of NMDA-induced retinal degeneration.

Recent studies have shown that the retinal blood vessels are damaged in experimental models of retinal degeneration, but the mechanisms underlying their damage are not fully understood. In this study, we examined the possible role of transforming growth factor (TGF)-β in retinal neuron loss and capillary degeneration induced in rats by an intravitreal injection of N-methyl-d-aspartate (NMDA). The number of cells in the ganglion cell layer was significantly decreased 2 days after NMDA treatment, and a further decrease was observed at 7 days.