Samin Hong

Agmatine: clinical applications after 100 years in translation.

Agmatine (decarboxylated arginine) has been known as a natural product for over 100 years, but its biosynthesis in humans was left unexplored owing to long-standing controversy. Only recently has the demonstration of agmatine biosynthesis in mammals revived research, indicating its exceptional modulatory action at multiple molecular targets, including neurotransmitter systems, nitric oxide (NO) synthesis and polyamine metabolism, thus providing bases for broad therapeutic applications. This timely review, a concerted effort by 16 independent research groups, draws attention to the substantial preclinical and initial clinical evidence, and highlights challenges and opportunities, for the use of agmatine in treating a spectrum of complex diseases with unmet therapeutic needs, including diabetes mellitus, neurotrauma and neurodegenerative diseases, opioid addiction, mood disorders, cognitive disorders and cancer.

Comparing the ganglion cell complex and retinal nerve fibre layer measurements by Fourier domain OCT to detect glaucoma in high myopia

Aim To compare the diagnostic ability to detect glaucomatous changes between peripapillary retinal nerve fibre layer (RNFL) thickness and the macular ganglion cell complex (GCC) in highly myopic patients using Fourier domain optical coherence tomography. Methods Participants, consecutively enrolled from January 2009 to June 2009, were imaged with RTVue-100 (NHM4 and MM7 scan). The sensitivity and specificity of a colour code less than 5% (red or yellow) for glaucoma diagnosis were calculated. Area under the receiver operator characteristic (AUROC) curves were generated to assess the ability of each parameter to detect glaucomatous changes. Results 73 normal controls and 77 glaucoma patients were included. Participants were categorised as 105 non-high myopes (spherical equivalent >−6.0 dioptres) and 45 high myopes (Spherical equivalent ≤−6.0 dioptres). The GCC thickness showed a strong correlation with RNFL thickness (correlation coefficient=0.763, p<0.001) in all participants. The sensitivity from superior GCC colour code was significantly higher than that from superior RNFL (p=0.019). The ability to detect glaucomatous changes in the highly myopic group by examining the average GCC thickness (AUROC, GCC; 0.889) was higher than when examining RNFL thickness (AUROC, RNFL; 0.825); however, there was no statistical significance (p=0.442). Conclusions The ability to diagnose glaucoma with macular GCC thickness was comparable with that with peripapillary RNFL thickness in high-myopia patients. Macular GCC thickness measurements may be a good alternative or a complementary measurement to RNFL thickness assessment in the clinical evaluation of glaucoma in patients with high myopia.

Spectral-Domain Optical Coherence Tomography for Detection of Localized Retinal Nerve Fiber Layer Defects in Patients With Open-Angle Glaucoma

OBJECTIVE To evaluate and compare time-domain (Stratus) and spectral-domain (Cirrus; both Carl Zeiss Meditec, Dublin, California) optical coherence tomography (OCT) for the detection of localized retinal nerve fiber layer (RNFL) defects in patients with open-angle glaucoma. METHODS Patients with localized RNFL defects and age-matched normal control participants were consecutively enrolled from July 1 to December 31, 2008. Sixty-six eyes from 66 patients and 66 eyes from 66 normal controls were imaged with Stratus OCT (fast RNFL scan mode) and Cirrus OCT (optic disc cube mode). The ability to detect the RNFL defect by using quadrant clock-hour maps from both OCTs and a Cirrus OCT deviation map were compared with red-free RNFL photography, which is the criterion standard for visualizing RNFL defects. RESULTS The Cirrus OCT deviation map exhibited significantly higher overall sensitivity (92.42%) in detecting the RNFL defects compared with the other maps, which were derived from a 3.46-mm-diameter peripapillary cross-sectional RNFL scan of both OCTs (P < .001). The Cirrus OCT quadrant map had a higher specificity; however, it was not statistically significant (P = .07). Compared with the other maps, the Cirrus OCT derivation map had the lowest cutoff angle for the width (10.69°) of the RNFL defect. CONCLUSIONS The deviation map from Cirrus OCT was more sensitive in detecting RNFL defects than the clock-hour and quadrant maps derived from cross-sectional peripapillary RNFL measurements by Stratus and Cirrus OCTs. The ability to detect localized RNFL defects on clock-hour or quadrant RNFL maps did not significantly differ between Stratus OCT and Cirrus OCT.

Agmatine protects retinal ganglion cells from hypoxia-induced apoptosis in transformed rat retinal ganglion cell line

BackgroundAgmatine is an endogenous polyamine formed by the decarboxylation of L-arginine. We investigated the protective effects of agmatine against hypoxia-induced apoptosis of immortalized rat retinal ganglion cells (RGC-5). RGC-5 cells were cultured in a closed hypoxic chamber (5% O2) with or without agmatine. Cell viability was determined by lactate dehydrogenase (LDH) assay and apoptosis was examined by annexin V and caspase-3 assays. Expression and phosphorylation of mitogen-activated protein kinases (MAPKs; JNK, ERK p44/42, and p38) and nuclear factor-kappa B (NF-κB) were investigated by Western immunoblot analysis. The effects of agmatine were compared to those of brain-derived neurotrophic factor (BDNF), a well-known protective neurotrophin for retinal ganglion cells.ResultsAfter 48 hours of hypoxic culture, the LDH assay showed 52.3% cell loss, which was reduced to 25.6% and 30.1% when agmatine and BDNF were administered, respectively. This observed cell loss was due to apoptotic cell death, as established by annexin V and caspase-3 assays. Although total expression of MAPKs and NF-κB was not influenced by hypoxic injury, phosphorylation of these two proteins was increased. Agmatine reduced phosphorylation of JNK and NF-κB, while BDNF suppressed phosphorylation of ERK and p38.ConclusionOur results show that agmatine has neuroprotective effects against hypoxia-induced retinal ganglion cell damage in RGC-5 cells and that its effects may act through the JNK and NF-κB signaling pathways. Our data suggest that agmatine may lead to a novel therapeutic strategy to reduce retinal ganglion cell injury related to hypoxia.

Agmatine protects cultured retinal ganglion cells from tumor necrosis factor-alpha-induced apoptosis

AIMS We investigated the protective effects of agmatine against tumor necrosis factor (TNF)-alpha-induced apoptosis in transformed rat retinal ganglion cells (RGC-5 cell line). MAIN METHODS The RGC-5 cells were exposed to 50 ng/mL TNF-alpha for 48 h with or without presence of 100 microM agmatine as indicated. Cell viability was determined by lactate dehydrogenase (LDH) assay. Double staining with Hoechst 33342 and propidium iodide for morphological analysis was performed. Subsequently, using annexin V assay, the proportion of cells actively undergoing apoptosis was determined. KEY FINDINGS After 48 h of exposure to 50 ng/mL TNF-alpha, 17.00% of RGC-5 cells were lost, as evident by LDH assay. TNF-alpha-induced RGC-5 cell death was reduced to 8.14% with 100 microM agmatine treatment. This observed cell loss was due to apoptotic cell death, as established by annexin V assay. SIGNIFICANCE Our results reveal that agmatine has neuroprotective effects against TNF-alpha-induced apoptosis in retinal ganglion cells in vitro.

Neuroprotective effects of agmatine on oxygen-glucose deprived primary-cultured astrocytes and nuclear translocation of nuclear factor-kappa B.

To better understand the neuroprotective actions of agmatine in ischemic insults, its effects on astrocytes were investigated using an in vitro oxygen-glucose deprivation (OGD) model. After primary culture, cortical astrocytes were moved into a closed anaerobic chamber and incubated in glucose-free culture media. 4 h later, the cells were restored to normoxic conditions and supplied with glucose for 20 h. The ability of agmatine to rescue astrocytes from OGD only and OGD followed by restoration (OGD-R) was assessed. Cell viability was monitored with or without 100 muM agmatine, using the lactate dehydrogenase (LDH) assay and annexin V flow cytometric assay. For morphological analysis, Hoechst 33258 and propidium iodide double nuclear staining was performed. Expression and phosphorylation of nuclear factor-kappa B (NF-kappaB) family proteins were also investigated by immunoblotting. Results showed that astrocytes had decreased viability following OGD and OGD-R and that agmatine treatment increased cell viability and induced NF-kappaB translocation into the nucleus. Finally, our studies revealed that agmatine can rescue astrocytes from death caused by ischemic and/or ischemic-perfusion neuronal injuries in vitro. Our findings provide new insights that may lead to a novel therapeutic strategy to reduce these kinds of neuronal injuries.

Comparison of macular ganglion cell complex thickness by Fourier-domain OCT in normal tension glaucoma and primary open-angle glaucoma.

PurposeTo compare perimacular ganglion cell complex (GCC) parameters between patients with normal tension glaucoma (NTG) and primary open-angle glaucoma (POAG). MethodsParticipants, consecutively enrolled from January 2009 to June 2009, underwent optical coherence tomographic imaging with RTVue-100 (Optovue Inc, Fremont, CA). Optic nerve head (ONH) parameters, retinal nerve fiber layer (RNFL) parameters, and GCC parameters were acquired. Mean measurements of ONH, RNFL, and GCC parameters among the normal, NTG, and POAG groups were compared using analysis of variance. Area under the receiver operator characteristic curve was used to assess the ability of each parameter to detect glaucomatous changes. ResultsFifty-eight normal controls, 51 patients with NTG, and 52 patients with POAG were included. Mean measurements of ONH parameters were similar between the NTG and POAG groups (all P>0.05). Average RNFL thickness did not differ between the NTG and POAG groups (P=0.053), whereas average GCC thickness significantly differed between the NTG and POAG groups (P=0.001). In terms of pattern-based parameters of GCC, focal loss volume did not differ between the NTG and POAG groups (P=0.165), whereas global loss volume was significantly higher in the POAG group (P<0.001). There were no statistically significant differences between RNFL and GCC measurements with respect to the ability to detect glaucomatous changes. ConclusionsGCC loss in the NTG group was more localized compared with diffuse GCC loss in the POAG group. Perimacular GCC parameters could be a good alternative or supplement to peripapillary RNFL measurements for diagnosis and research in patients with NTG.

Reproducibility of peripapillary retinal nerve fiber layer thickness with spectral domain cirrus high-definition optical coherence tomography in normal eyes.

PurposeTo assess the reproducibility of the new spectral domain Cirrus high-definition optical coherence tomography (HD-OCT; Carl Zeiss Meditec, Dublin, CA, USA) for analysis of peripapillary retinal nerve fiber layer (RNFL) thickness in healthy eyes.MethodsThirty healthy Korean volunteers were enrolled. Three optic disc cube 200 × 200 Cirrus HD-OCT scans were taken on the same day in discontinuous sessions by the same operator without using the repeat scan function. The reproducibility of the calculated RNFL thickness and probability code were determined by the intraclass correlation coefficient (ICC), coefficient of variation (CV), test-retest variability, and Fleiss’ generalized kappa (κ).ResultsThirty-six eyes were analyzed. For average RNFL thickness, the ICC was 0.970, CV was 2.38%, and test-retest variability was 4.5 μm. For all quadrants except the nasal, ICCs were 0.972 or higher and CVs were 4.26% or less. Overall test-retest variability ranged from 5.8 to 8.1 μm. The κ value of probability codes for average RNFL thickness was 0.690. The κ values of quadrants and clock-hour sectors were lower in the nasal areas than in other areas.ConclusionsThe reproducibility of Cirrus HD-OCT to analyze peripapillary RNFL thickness in healthy eyes was excellent compared with the previous reports for time domain Stratus OCT. For the calculated RNFL thickness and probability code, variability was relatively higher in the nasal area, and more careful analyses are needed.

Level of vascular endothelial growth factor in aqueous humor and surgical results of ahmed glaucoma valve implantation in patients with neovascular glaucoma.

PurposeTo determine the associations between the levels of growth factors in aqueous humor and the surgical outcomes of Ahmed glaucoma valve implantation in patients with neovascular glaucoma (NVG). MethodsFrom 19 NVG eyes of 19 patients, a sample of aqueous humor was taken just before Ahmed glaucoma valve implantation. Levels of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1, and TGF-β2 in aqueous humor aspirates were measured using a sandwich enzyme-linked immunosorbent assay method. When the postoperative intraocular pressures were ≥21 mm Hg with or without antiglaucoma medications at 2 successive visits or when any other surgical interventions were needed to lower intraocular pressure, that surgery was considered a failure. After patients were classified into success versus failure groups, the levels of the growth factors between the 2 groups was compared. The cumulative probability of success according to Kaplan-Meier analysis was also determined. ResultsMean postoperative follow-up period was 40.9±19.6 months and cumulative probability of success was 43% at 57 months after surgery. Mean VEGF level in the failure group was higher than that of the success group (P=0.014). However, there was no statistical difference in the levels of TGF-β1, TGF-β2, and protein between 2 study groups (all P>0.05). ConclusionsThe level of VEGF in aqueous humor was significantly higher in the failure group after the Ahmed glaucoma implantation compared with the success group. Our results imply that VEGF may play a role in determining surgical success after Ahmed valve implantation in patients with NVG.

Anterior Chamber Measurements by Pentacam and AS-OCT in Eyes With Normal Open Angles

Purpose To assess the reproducibility and agreement of anterior chamber measurements between the Pentacam (PTC) and the Anterior segment optical coherence tomography (AOCT) in normal healthy eyes with open angle. Methods Prospective cross-sectional comparative case series. A total of 162 eyes of 81 healthy volunteers with normal open angle were included in this study. Anterior chamber angle (ACA) and anterior chamber depth (ACD) were measured with PTC and AOCT. Intra-observer variability and inter-methods agreement of both instruments for ACA and ACD were evaluated. Results Values of temporal and nasal ACA measured by two instruments were similar, and the results of ACD were also not significantly different between modalities (p>0.01). ACA and ACD measurements by PTC and AOCT showed good intra-observer and inter-method agreements (all >0.9). Conclusions PTC and AOCT are presumed to be very useful for the anterior chamber angle examination. They may provide good images and quantitative data about the angle structures including ACA and ACD.