Hypoglycemic seizures during transient hypoglycemia exacerbate hippocampal dysfunction.
Severe hypoglycemia constitutes a medical emergency, involving seizures, coma and death. We hypothesized that seizures, during limited substrate availability, aggravate hypoglycemia-induced brain damage. Using immature isolated, intact hippocampi and frontal neocortical blocks subjected to low glucose perfusion, we characterized hypoglycemic (neuroglycopenic) seizures in vitro during transient hypoglycemia and their effects on synaptic transmission and glycogen content. Hippocampal hypoglycemic seizures were always followed by an irreversible reduction (>60% loss) in synaptic transmission and were occasionally accompanied by spreading depression-like events. Hypoglycemic seizures occurred more frequently with decreasing "hypoglycemic" extracellular glucose concentrations. In contrast, no hypoglycemic seizures were generated in the neocortex during transient hypoglycemia, and the reduction of synaptic transmission was reversible (<60% loss). Hypoglycemic seizures in the hippocampus were abolished by NMDA and non-NMDA antagonists. The anticonvulsant, midazolam, but neither phenytoin nor valproate, also abolished hypoglycemic seizures. Non-glycolytic, oxidative substrates attenuated, but did not abolish, hypoglycemic seizure activity and were unable to support synaptic transmission, even in the presence of the adenosine (A1) antagonist, DPCPX. Complete prevention of hypoglycemic seizures always led to the maintenance of synaptic transmission. A quantitative glycogen assay demonstrated that hypoglycemic seizures, in vitro, during hypoglycemia deplete hippocampal glycogen. These data suggest that suppressing seizures during hypoglycemia may decrease subsequent neuronal damage and dysfunction.
Abdelmalik
Peter A
PA
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network MCL12-413, Toronto Western Hospital, 399 Bathurst St., Toronto, Ontario, 416-603-5040, Canada M5T2S8.
Shannon
Patrick
P
Yiu
Adelaide
A
Liang
Philip
P
Adamchik
Yana
Y
Weisspapir
Michael
M
Samoilova
Marina
M
Burnham
W McIntyre
WM
Carlen
Peter L
PL
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D013181:Cortical Spreading Depression / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000032:analysis / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D007003:Hypoglycemia / Q000150:complications* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008874:Midazolam / Q000494:pharmacology; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D012640:Seizures / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D009435:Synaptic Transmission / Q000502:physiology
D058916:Adenosine A1 Receptor Antagonists; D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D043682:Receptor, Adenosine A1; D006003:Glycogen; D005947:Glucose; D008874:Midazolam