Purpose: Retinal ischemia-associated ocular disorders are vision threatening. This study examined whether the flavonoid baicalein is able to protect against retinal ischemia/reperfusion. Methods: Using rats, the intraocular pressure was raised to 120 mmHg for 60 min to induce retinal ischemia. In vitro, an ischemic-like insult, namely oxidative stress, was established by incubating dissociated retinal cells with 100 mM ascorbate and 5 mM FeSO 4 (iron) for 1 h. The rats or the dissociated cells had been pretreated with baicalein (in vivo: 0.05 or 0.5 nmol; in vitro: 100 mM), vehicle (1% ethanol), or trolox (in vivo: 5 nmol; in vitro: 100 mM or 1 mM). The effects of these treatments on the retina or the retinal cells were evaluated by electrophysiology, immunohistochemistry, terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling (TU-NEL) staining, Western blotting, or in vitro dichlorofluorescein assay. In addition, real-time-polymerase chain reaction was used to assess the retinal expression of hypoxia-inducible factor-1a (HIF-1a), matrix metalloproteinase-9 (MMP-9), vascular endothelium growth factor (VEGF), and heme oxygenase-1 (HO-1). Results: The retinal changes after ischemia included a decrease in the electroretinogram b-wave amplitude, a loss of choline acetyltransferase immunolabeling amacrine cell bodies/neuronal processes, an increase in vimentin immunoreactivity, which is a marker for Mü ller cells, an increase in apoptotic cells in the retinal ganglion cell layer linked to a decrease in the Bcl-2 protein, and changes in the mRNA levels of HIF-1a, VEGF, MMP-9, and HO-1. Of clinical importance, the ischemic detrimental effects were concentration dependently and/or significantly (0.05 nmol and/or 0.5 nmol) altered when baicalein was applied 15 min before retinal ischemia. Most of all, 0.5 nmol baicalein significantly reduced the upregulation of MMP-9; in contrast, 5 nmol trolox only had a weak attenuating effect. In dissociated retinal cells subjected to ascorbate/iron, there was an increase in the levels of reactive oxygen species, which had been significantly attenuated by 100 mM baicalein and trolox (100 mM or 1 mM; a stronger antioxidative effect at 1 mM). Conclusions: Baicalein would seem to protect against retinal ischemia via antioxidation, antiapoptosis, upregulation of HO-1, and downregulation of HIF-1a, VEGF, and MMP-9. The antioxidative effect of baicalein would appear to play a minor role in downregulation of MMP-9. IntroductionC entral retinal artery occlusion, central retinal vein occlusion, branch retinal artery occlusion, branch retinal vein occlusion, glaucoma, and age-related macular degeneration (AMD) are all associated with retinal ischemia.1-3 All these diseases may lead to severe sequelae and therefore the management of retinal ischemia is crucial. After ischemia/ reperfusion (I/R), large amounts of reactive oxygen species (ROS) are produced.1,2 These ROS attack nearby cells and
Purpose: Retinal ischemia-associated ocular disorders, such as retinal occlusive disorders, neovascular agerelated macular degeneration, proliferative diabetic retinopathy, and glaucoma are vision-threatening. In this study, we examined whether and by what mechanisms resveratrol, a polyphenol found in red wine, is able to protect against retinal ischemia/reperfusion injury. Methods: In vivo rat retinal ischemia was induced by high intraocular pressure (HIOP), namely, 120 mmHg for 60 min. The mechanism and management was evaluated by electroretinogram (ERG) b-wave amplitudes measurement, immunohistochemistry, and real-time polymerase chain reaction. Results: The HIOP-induced retinal ischemic changes were characterized by a decrease in ERG b-wave amplitudes, a loss of choline acetyltransferase immunolabeling of amacrine cell bodies/neuronal processes, and increased vimentin immunoreactivity, which is a marker of Mü ller cells, together with upregulation of matrix metalloproteinase-9 (MMP-9), heme oxygenase-1 (HO-1), and inducible nitric oxide (iNOS), and downregulation of Thy-1, both at the mRNA level. The detrimental effects due to the ischemia were concentration-dependent (weaker effect at 0.05 nmole) and/or significantly (at 0.5 nmole) altered when resveratrol was applied 15 min before or after retina ischemia. Conclusion: This study supports the hypothesis that resveratrol may be able to protect the retina against ischemia by downregulation of MMP-9 and iNOS, and upregulation of HO-1.
Growing evidence indicates that there is an interaction between the transmission of dopamine (DA) and norepinephrine (NE) in the noradrenergic and dopaminergic projections that converge in the medial prefrontal cortex (mPFC). The effects of the noradrenergic alpha1 and alpha2 receptors and the NE transporters on the DA outflow and those of the dopaminergic D1 and D2 receptors on NE release in the mPFC were investigated. Local infusions of NE (90, 150, and 300 nM) into the mPFC increased the extracellular release of DA in anesthetized rats. The alpha1 receptor antagonist (10 microM prazosin), but not the alpha2 receptor antagonist (100 microM piperoxan), blocked the NE-induced increase of DA in the mPFC. In addition, local infusion of alpha1 receptor agonist (10 microM phenylephrine) enhanced DA release in the mPFC. Local application of DA in different concentrations into the mPFC increased extracellular NE levels. Intra-mPFC infusion of a D1 receptor antagonist (10 nM SCH23390), inhibited the DA-induced increase of NE; this did not happen with a D2 receptor antagonist (1 nM eticlopride). Local administration of a selective NE uptake inhibitor (1 microM desmethylimipramine) into the mPFC increased the outflows of both DA and NE in the mPFC. However, co-infusion of DMI and prazosin blunted, but did not totally abolish, the DMI-increase in the extracellular levels of DA and NE. These results suggest that in the mPFC, 1) extracellular NE could enhance DA release by activating the alpha1 receptors; and 2) extracellular DA increased the extracellular levels of NE by activating the D1 receptors.
SAC would seem to protect against retinal ischemia by acting as an antioxidant and inhibiting the upregulation of HIF-1α, VEGF, and MMP-9.
We evaluated the effect and action mechanisms of cocaine on electroencephalographic (EEG) activity in adult male Sprague-Dawley rats anesthetized with chloral hydrate (400 mg/kg, i.p., with 80 mg/kg/h supplements). On-line and real-time power spectral analysis of the EEG activity continuously quantified its root mean square (RMS) and mean power frequency (MPF) values, and the power of its spectral frequency components (low frequency: 0-4 Hz; high frequency: 4-20 Hz). Administration of cocaine (1.5 or 3.0 mg/kg, i.v.) dose-dependently induced EEG desynchronization, as manifested by a reduction in RMS and an elevation in MPF values, coupled with a differential decrease in both high and low frequency components. Samples collected by in vivo microdialysis at the medial prefrontal cortex (mPFC) and analyzed by HPLC showed that the elevation of cocaine and dopamine (DA) level in the dialysate reached its peak during the time interval when maximal activation of EEG occurred. This EEG activation was antagonized by microinfusion into the mPFC via reverse microdialysis of R(+)-SCH 23390, a selective antagonist for D-1 receptors; sulpiride, a selective antagonist for D-2 receptors; or haloperidol, a nonspecific dopamine antagonist. These results suggest that dopaminergic neurotransmission at the mPFC may be intimately related to the specific spectral pattern of alteration in EEG activity elicited by cocaine in the rat and that both D-1 and D-2 receptors may be involved in the process.
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