Peptide-binding GRP78 protects neurons from hypoxia-induced apoptosis.

Brain ischemia has major consequences leading to the apoptosis of astrocytes and neurons. Glucose-regulated protein 78 (GRP78) known for its role in endoplasmic reticulum stress alleviation was discovered on several cell surfaces acting as a receptor for signaling pathways. We have previously described peptides that bind cell surface GRP78 on endothelial cells to induce angiogenesis. We have also reported that ADoPep1 binds cardiomyocytes to prevent apoptosis of ischemic heart cells. In this study we describe the effect of hypoxia on astrocytes and neurons cell surface GRP78. Under hypoxic conditions, there was an increase of more than fivefold in GRP78 on cell surface of neurons while astrocytes were not affected. The addition of the GRP78 binding peptide, ADoPep1, to neurons decreased the percentage of GRP78 positive cells and did not change the percent of astrocytes. However, a significant increase in early and late apoptosis of both astrocytes and neurons under hypoxia was attenuated in the presence of ADoPep1. Intravitreal administration of ADoPep1 to mice in a model of optic nerve crush significantly reduced retinal cell loss after 21 days compared to the crush-damaged eyes without treatment or by control saline vehicle injection. Histological staining demonstrated reduced GRP78 after ADoPep1 treatment. The mechanism of peptide neuroprotection was demonstrated by the inhibition of hypoxia induced caspase 3/7 activity, cytochrome c release and p38 phosphorylation. This study is the first report on hypoxic neuronal and astrocyte cell surface GRP78 and suggests a potential therapeutic target for neuroprotection.

Poststreptococcal keratouveitis associated with group C streptococcus pharyngitis.

PURPOSE: To report the first case of poststreptococcal syndrome uveitis (PSU) in association with group C streptococcus (GCS). PATIENTS AND METHODS: Chart review of a 24-year-old man who presented with bilateral ocular redness, pain, and photophobia for 5 days and "white rings" around his eyes for a duration of 3 days. The patient further reported fever and sore throat in the preceding week. Slit-lamp examination showed bilateral keratouveitis. A thorough uveitis workup, antistreptolysin O (ASLO) titer, and throat culture were obtained. The patient was treated with frequent topical steroids and systemic doxycycline. The uveitis and keratitis subsided over the next few weeks, leaving extensive peripheral keratolysis. RESULTS: The results of laboratory diagnostic testing revealed an elevated ASLO, C-reactive protein, as well as HLA-B27 positivity. Throat cultures grew beta-hemolytic GCS; group A streptococcus was culture negative. CONCLUSION: GCS pharyngitis may be a causative organism of PSU.