title: 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 N-methyl-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 response 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 min). 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.
authors.affiliation: Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine,Washington University, St. Louis, MO 63110, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Silverstein
authors.forename: Daniel
authors.initials: D
authors.lastname: Musikantow
authors.forename: Erwin C
authors.initials: EC
authors.lastname: Puente
authors.forename: Dorit
authors.initials: D
authors.lastname: Daphna-Iken
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bree
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Fisher
mesh_terms: D000818:Animals; D002452:Cell Count / Q000379:methods; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D004921:Erythropoietin / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007003:Hypoglycemia / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D007328:Insulin / Q000009:adverse effects; D008297:Male; D008559:Memantine / Q000627:therapeutic use*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy*; D009474:Neurons / Q000473:pathology*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007328:Insulin; D018696:Neuroprotective Agents; D004921:Erythropoietin; D008559:Memantine