Neuroprotection in glaucoma

Neuroprotective therapies in glaucoma may play a role in preventing ischemia and oxidative damage that results in apoptosis of retinal ganglion cells and optic nerve damage. Although intraocular pressure (IOP) is the only known modifiable risk factor for glaucoma, disease progression commonly occurs despite IOP control, suggesting that factors other than IOP play a role in its pathogenesis and can potentially act as targets for neuroprotection. Factors including mediators of apoptosis, ischemic changes, poor ocular blood flow and neurotoxins have been hypothesized to play a role in glaucoma progression. Neuroprotective targets include glutamate-induced neurotoxicity, nitric oxidase synthetase, neurotropins, calcium channel receptors, free radicals, vascular insufficiency, the rho-kinase pathway, and more. Drugs related to these factors are being evaluated for their role in neuroprotection, although this area of investigation faces several challenges including limited evidence for these agents’ efficacy in clinical studies. Additionally, while IOP-lowering therapies are considered neuroprotective as they generally slow the progress of glaucoma progression, they are limited by the extent of their effect beyond IOP control. The aim of this article is to review the current treatment options available for neuroprotection and to explore the drugs in the pipeline.     

Podophyllum hexandrum Offers Radioprotection by Modulating Free Radical Flux: Role of Aryl-Tetralin Lignans

We have evaluated the effect of variation in aryl-tetralin lignans on the radioprotective properties of Podophyllum hexandrum. Two fractionated fractions of P. hexandrum [methanolic (S1) and chloroform fractions (S2)], with varying aryl-tetralin lignan content were utilized for the present study. The peroxyl ion scavenging potentials of S1 and S2 were found to be comparable [i.e. 45.88% (S1) and 41% (S2)] after a 48 h interval in a time-dependent study, whereas in a 2 h study, S2 exhibited significant (P < 0.05) antioxidant activity in different metal ion + flux states. In the aqueous phase, S2 exhibited non-site-specific reactive oxygen species scavenging activity, i.e. 73.12% inhibition at 500 mug ml(-1). S1 exhibited 58.40 +/- 0.8% inhibition (at 0.025 mug ml(-1)) of the formation of reactive nitrite radicals, comparable to S2 (52.45 +/- 0.825%), and also showed 45.01% site-specific activity (1000 mug ml(-1)), along with significant (P < 0.05) electron donation potential (50-2000 mug ml(-1)) compared to S2. Such activities of S1 could be attributed to the significantly (P < 0.05) higher levels of podophyllotoxin beta-d-glucopyranoside (16.5 times) and demethyl podophyllotoxin glucoside (2.9 times) compared with S2. Together, these findings clearly prove that aryl-tetralin lignan content influences the radiation protective potential of the Podophyllum fractions to a great extent.     

CEACAM-1 Induced CSF3-receptor Downregulation in Bone Marrow Associated With Refractory Neutropenia in Advanced Cirrhosis

Background and Aims: Cirrhosis patients exhibit cyto-penia, and, at times refractory neutropenia to granulocyte colony-stimulating factor (G-CSF), which acts th...     

The effect of aqueous extract of Embelia ribes Burm on serum homocysteine, lipids and oxidative enzymes in methionine induced hyperhomocysteinemia

Objective:

The present study was designed to evaluate the effect of the aqueous extract of Embelia ribes Burm fruits on methionine-induced hyperhomocysteinemia, hyperlipidemia and oxidative stress in albino rats.

Materials and Methods:

Adult male Wistar albino rats were fed with the aqueous extract of Embelia ribes (100 and 200 mg/kg, p.o.) for 30 days. Hyperhomocysteinemia was induced by methionine treatment (1 g/kg, p.o.) for 30 days and folic acid (100 mg/kg, p.o.) was used as a standard drug. The animals were evaluated for various biochemical parameters in serum and brain homogenates, followed by histopathological studies at the end of the study.

Results:

Administration of methionine (1 g/kg, p.o.) for 30 days to vehicle control rats produced significant increase (P < 0.01) in homocysteine, lactate dehydrogenase (LDH), total cholesterol, triglycerides, low density lipoprotein (LDL-C), very low density lipoprotein (VLDL-C) levels in serum and lipid peroxides (LPO) levels in brain homogenates, with reduction in high density lipoprotein (HDL-C) levels in serum, and glutathione (GSH) content in brain homogenates, as compared to vehicle control rats. Administration of the aqueous extract of Embelia ribes (100 and 200 mg/kg, p.o.) for 30 days, to hyperhomocysteinemic rats, significantly (P < 0.01) decreased the levels of homocysteine, LDH, total cholesterol, triglycerides, LDL-C and VLDL-C and increased the HDL-C levels in serum. In addition, a significant (P < 0.01) decrease in LPO levels with increase in GSH content was observed in hyperhomocysteinemic rats treated with the aqueous extract of Embelia ribes. The results were comparable to those obtained with folic acid, a standard antihyperhomocysteinemic drug.

Conclusion:

The present results provide clear evidence that the aqueous extract of Embelia ribes treatment enhances the antioxidant defense against methionine-induced hyperhomocysteinemia, hyperlipidemia and oxidative stress in brain.     

Characterization of GP110, a neutrophil surface protein.

Localized juvenile periodontosis is associated with a defect of neutrophil chemotaxis that is characterized by selective depletion of a surface protein with a molecular mass of 110 kDa (GP110). Data on partial characterization of GP110 suggest that it is a glycoprotein which is enriched in Lys, Glu, His, Leu, and Ala residues.     

Neuroprotective Potential of Novel Multi-Targeted Isoalloxazine Derivatives in Rodent Models of Alzheimer’s Disease Through Activation of Canonical Wnt/β-Catenin Signalling Pathway

Previous reports suggest that Alzheimer’s disease is protected by cholinesterase inhibitors. We synthesized some isoalloxazine derivatives and evaluated them using in vitro cholinesterase inhibition assay. Two of the compounds (7m and 7q) were figured out as potent cholinesterase inhibitors. They further showed anti-Aβ aggregatory activity in the in vitro assay. The current study deals with the evaluation of neuroprotective potentials of the potent compounds (7m and 7q) using different in vitro and in vivo experiments. The compounds were first assessed for their tendency to cross blood–brain barrier using in vitro permeation assay. They were evaluated using scopolamine-induced amnesic mice model. Additionally, ROS scavenging and anti-apoptotic properties of 7m and 7q were established against Aβ_1–42-induced toxicity in rat hippocampal neuronal cells. 7m and 7q were also evaluated using Aβ_1–42-induced Alzheimer’s rat model. Lastly, their involvement in Wnt/β-catenin pathway was also demonstrated. The results indicated good CNS penetration for 7m and 7q. The neuroprotective effects of 7m and 7q were evidenced by improved cognitive ability in both scopolamine and Aβ_1–42-induced Alzheimer’s-like condition in rodents. The in vivo results also confirmed their anti-cholinesterase and anti-oxidant potential. Immunoblot results showed that treatment with 7m and 7q decreased Aβ_1–42, p-tau, cleaved caspase-3, and cleaved PARP levels in Aβ_1–42-induced Alzheimer’s rat brain. Additionally, immunoblot results demonstrated that 7m and 7q activated the Wnt/β-catenin pathway as evidenced by increased p-GSK-3, β-catenin, and neuroD1 levels in Aβ_1–42-induced Alzheimer’s rat brain. These findings have shown that isoalloxazine derivatives (7m and 7q) could be the potential leads for developing effective drugs for the treatment of AD.     

In Vitro and In Vivo Antiviral Activity and Resistance Profile of the Hepatitis C Virus NS3/4A Protease Inhibitor ABT-450

The development of direct-acting antiviral agents is a promising therapeutic advance in the treatment of hepatitis C virus (HCV) infection. However, rapid emergence of drug resistance can limit efficacy and lead to cross-resistance among members of the same drug class. ABT-450 is an efficacious inhibitor of HCV NS3/4A protease, with 50% effective concentration values of 1.0, 0.21, 5.3, 19, 0.09, and 0.69 nM against stable HCV replicons with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, and 6a, respectively. In vitro, the most common amino acid variants selected by ABT-450 in genotype 1 were located in NS3 at positions 155, 156, and 168, with the D168Y variant conferring the highest level of resistance to ABT-450 in both genotype 1a and 1b replicons (219- and 337-fold, respectively). In a 3-day monotherapy study with HCV genotype 1-infected patients, ABT-450 was coadministered with ritonavir, a cytochrome P450 3A4 inhibitor shown previously to markedly increase peak, trough, and overall drug exposures of ABT-450. A mean maximum HCV RNA decline of 4.02 log₁₀ was observed at the end of the 3-day dosing period across all doses. The most common variants selected in these patients were R155K and D168V in genotype 1a and D168V in genotype 1b. However, selection of resistant variants was significantly reduced at the highest ABT-450 dose compared to lower doses. These findings were informative for the subsequent evaluation of ABT-450 in combination with additional drug classes in clinical trials in HCV-infected patients. (Study M11-602 is registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01074008","term_id":"NCT01074008"}}NCT01074008.)     

A microfluidic electrochemical cell for studying the corrosion of uranium dioxide (UO2)

We have developed a specialized microfluidic electrochemical cell that enables in situ investigation of the electrochemical corrosion of microgram quantities of redox active solids. The advantage of downscaling is the reduction of hazards, waste, expense, and greatly expanding data collection for hazardous materials, including radioactive samples. Cyclic voltammetry was used to monitor the oxidation–reduction cycle of minute quantities of micron-size uraninite (UO₂) particles, from the formation of hexavalent uranium (U(vi)), U₃O₇ and reduction to UO_2+x. Reaction progress was also studied in situ with scanning electron microscopy. The electrochemical measurements matched those obtained at the bulk-scale and were consistent with ex situ characterization of the run products by X-ray photoelectron spectroscopy, scanning transmission electron microscopy, and atomic force microscopy; thus, demonstrating the utility of the microfluidic approach for studying radioactive materials.

Highlight of the multimodal characterization of corrosion behaviour of microgram quantities of UO₂, enabled by a novel particle-attached microfluidic electrochemical cell.