Pharmacologic amelioration of severe hypoglycemia-induced neuronal damage

Abstract

Hypoglycemia is a common complication for insulin treated people with diabetes. Severe hypoglycemia, which occurs in the setting of excess or ill-timed insulin administration, has been shown to cause brain damage. Previous pre-clinical studies have shown that memantine (an Nmethyl-D-aspartate receptor antagonist) and erythropoietin can be neuroprotective in other models of brain injury. We hypothesized that these agents might also be neuroprotective in reponse to severe hypoglycemia-induced brain damage. To test this hypothesis, 9-week old, awake, male Sprague-Dawley rats underwent hyperinsulinemic (0.2 U.kg −1 .min −1 ) hypoglycemic clamps to induce severe hypoglycemia (blood glucose 10-15 mg/dl for 90 minutes). Animals were randomized into control (vehicle) or pharmacological treatments (memantine or erythropoietin). One week after severe hypoglycemia, neuronal damage was assessed by Fluoro-Jade B and hematoxylin and eosin staining of brain sections. Treatment with both memantine and erythropoietin significantly decreased severe hypoglycemia-induced neuronal damage in the cortex by 35% and 39%, respectively (both p<0.05 vs controls). These findings demonstrate that memantine and erythropoietin provide a protective effect against severe hypoglycemia-induced neuronal damage.

Influence of Erythropoietin on Cognitive Performance during Experimental Hypoglycemia in Patients with Type 1 Diabetes Mellitus: A Randomized Cross-Over Trial

“…Our findings, however, support the results of these studies [17], [19] and add to the results from cellular and animal studies showing that EPO protects and enhances the function of cerebral cells lacking substrate [13]–[15], [31]. Moreover, a recent study by Silverstein and coworkers has shown that erythropoietin ameliorates hypoglycemic brain damage in rats [16].…”

“…At supraphysiological circulating concentrations EPO penetrates the intact human blood brain barrier [12]. In vitro studies suggest that EPO preserves cellular function during hypoglycemia [13]–[16]. In healthy adults high dose intravenous EPO treatment modulates neuronal processing and may improve cognitive function 7 days after administration of EPO [17], [18].…”

Severe Hypoglycemia–Induced Lethal Cardiac Arrhythmias Are Mediated by Sympathoadrenal Activation

“…Four to ten days postsurgery, overnight fasted, precannulated, awake, unrestrained rats were subjected to hyperinsulinemic (0.2 units ⋅ kg −1 ⋅ min −1 ) severe hypoglycemic (10–15mg/dL) clamps as previously described (28–30). Hypoglycemia was maintained for a predetermined duration (60 min for studies 1 and 2, 90 min for study 3, and 180 min for studies 4 and 5).…”

Early Transient Hypoglycemia Is Associated with Increased Albumin Nitration in the Preterm Infant

“…Protein nitration has previously been reported in animal models to be a potential link between hypoglycemia and cell damage. These findings may therefore contribute to the development of novel targeted strategies for the prevention of brain lesions which may occur in severe neonatal hypoglycemia [61] .…”