Stroke patients develop antibodies that react with components of N-methyl-D-aspartate receptor subunit 1 in proportion to lesion size.

BACKGROUND AND PURPOSE: Antibodies against neuronal antigens develop in patients after stroke and some may serve as biomarkers of neuronal injury. We aimed to determine whether antibodies against subunit 1 (GluN1) of the N-methyl-D-aspartate receptor also develop after stroke and if so, whether they correlate with stroke characteristics. METHODS: Forty-eight patients with ischemic stroke and 96 healthy controls were tested for the presence of serum antibodies targeting GluN1. Testing was conducted using 20-kDa recombinant GluN1-S2 peptide (by ELISA and Western blotting) and on rat brain tissue (by Western blotting and immunohistochemistry). Clinical examinations and computed tomographic brain scans were performed to assess clinical state and infarct size and location. RESULTS: Of the 48 patients with ischemic stroke, 21 (44%) had antibodies that reacted with the recombinant GluN1-S2. There was no evidence of antibody binding to intact GluN1 in brain tissue. Western blot appearances suggested reactivity with GluN1 degradation products. Patients with anti-GluN1-S2 antibodies were more likely to have higher National Institutes of Health Stroke Scale scores, larger infarcts, and more frequent cortical involvement. Of the 96 controls, only 3 (3%), all aged>50 years, had antibodies that reacted with GluN1-S2 at low levels. CONCLUSIONS: Antibodies that bind recombinant GluN1-S2 peptides (but not the intact GluN1 protein) develop transiently in patients after stroke in proportion to infarct size, suggesting that these antibodies are raised secondarily to neuronal damage. The anti-GluN1-S2 antibodies may provide useful information about the presence and severity of cerebral infarction. This will require confirmation in larger studies.

Newly weaned nonobese diabetic mice show heightened early diabetes sensitivity to multiple low doses of streptozotocin than nondiabetes-prone CD-1 mice: initial beta-cell damage a key trigger for type 1 diabetes?

OBJECTIVES: We determined if newly weaned female nonobese diabetic (NOD) mice show greater diabetes sensitivity to dose-adjusted regimens of multiple low doses of streptozotocin (Stz) than nondiabetes-prone CD-1 mice. METHODS: Female NOD mice received 5 daily doses of Stz from day 21 (0, 5, 10, 15, 20, 30, and 40 mg/kg body weight) and CD-1 mice 20, 30, and 40 mg. RESULTS: : Streptozotocin, at the 15-, 20-, 30-, and 40-mg dose, induced rapid diabetes in NOD mice. By day 100, 90% to 95% of NOD mice became diabetic after the 40- and 30-mg dose and 33% to 40% with the 15- and 20-mg dose. In comparison, only about 50% and 33% of CD-1 mice developed diabetes with the 40- and 30-mg dose, respectively, and 5.5% with the 20-mg dose. In NOD mice, the 20-mg dose also partially suppressed spontaneous diabetes. All diabetic mice displayed insulitis, variable immunostaining for insulin, and redistribution of glucagon and somatostatin cells. Glucose transporter-2 was markedly attenuated in selective beta cells. CONCLUSIONS: Newly weaned female NOD mice show heightened early sensitivity to low doses of Stz than CD-1 mice. At diabetes, several beta cells remain and show variable immunostaining for insulin and an attenuated expression for glucose transporter-2. Specific low doses of Stz may also suppress spontaneous diabetes.