Neuroprotective effects of brain-derived neurotrophic factor in seizures during development.
Although the immature brain is highly susceptible to seizures, it is more resistant to seizure-induced neuronal loss than the adult brain. The developing brain contains high levels of neurotrophins which are involved in growth, differentiation and survival of neurons. To test the hypothesis that neurotrophins may protect the developing brain from seizure-induced neuronal loss, brain-derived neurotrophic factor up-regulation was blocked by intracerebroventricular infusion of an 18mer antisense oligodeoxynucleotide sequence to brain-derived neurotrophic factor in 19-day-old rats using micro-osmotic pumps. Control rats were infused with sense or missense oligodeoxynucleotide. Status epilepticus was induced by intraperitoneal administration of kainic acid 24 h after the start of oligodeoxynucleotide infusion. Seizure duration was significantly increased in the antisense oligodeoxynucleotide plus kainic acid group compared to groups that received kainic acid alone or kainic acid plus sense or missense oligodeoxynucleotide. There was no difference between groups in the latency to forelimb clonus. A twofold increase in brain-derived neurotrophic factor levels was observed in the hippocampus 20 h following kainic acid-induced seizures. This kainic acid-induced increase was absent in animals receiving infusion of antisense oligodeoxynucleotide to brain-derived neurotrophic factor at time of seizure induction. Hippocampi of rats in this group (antisense oligodeoxynucleotide plus kainic acid) showed a loss of CA1 and CA3 pyramidal cells and hilar interneurons. This neuronal loss was not dependent upon seizure duration since animals injected with diazepam to control seizure activity in the antisense plus kainic acid group also showed similar neuronal loss. Administration of kainic acid or infusion of antisense alone did not produce any cell loss in these regions. Induction of seizures at postnatal day 20, in the presence or absence of antisense oligonucleotide, did not produce an impairment in learning and memory when tested 15 days later in the Morris water maze. The hippocampi of these animals did not show any synaptic reorganization as assessed by growth-associated protein-43 immunostaining and Timm staining. Our findings confirm prior studies demonstrating that seizures in the immature brain are associated with little, if any, cell loss. However, when seizure-induced increase in brain-derived neurotrophic factor is blocked, seizures do result in neuronal loss in the developing brain. Thus, brain-derived neurotrophic factor appears to provide protection against kainic acid seizure-induced neuronal damage in the developing brain.
Tandon
P
P
Department of Neurology, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Yang
Y
Y
Das
K
K
Holmes
G L
GL
Stafstrom
C E
CE
D000818:Animals; D001921:Brain / Q000473:pathology*; D001923:Brain Chemistry / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis / Q000494:pharmacology*; D002452:Cell Count; D004797:Enzyme-Linked Immunosorbent Assay; D019922:GAP-43 Protein / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000473:pathology* / Q000523:psychology; D013569:Synapses / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D019922:GAP-43 Protein; D018696:Neuroprotective Agents; D016376:Oligonucleotides, Antisense