Single-dose ketamine administration induces apoptosis in neonatal mouse brain.
The activity of N-methyl-D-aspartate (NMDA) receptors is critical for neuronal survival in the immature brain. Studies have reported that chronic blockage of these receptors mediates apoptosis in neonatal animals. We investigated the apoptotic effect of a clinically relevant single dose of ketamine, an NMDA receptor antagonist, in the brain of neonatal mice. Seven-day-old ICR mice were injected with ketamine (1.25, 2.5, 5, 10, 20, and 40 mg/kg body weight, subcutaneously in 0.9% NaCl) or with 0.9% NaCl alone as control. Righting reflex testing was performed and mouse brains were examined at 24, 48, and 72 h and 7 days after injection. The number of degenerating neurons was measured using silver staining. Apoptosis was confirmed by DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling). We observed in the sensorimotor cortex and cerebellum of ketamine-treated mice extensive apoptosis, which was clearly dose-dependent and present even after a low dose of ketamine (5 mg/kg). The most prominent apoptotic damage was detected 72 h post-injection (P < 0.001 vs control), at doses ranging from 10 to 40 mg/kg. After 7 d the number of neurodegenerative neurons, at doses ranging from 5 to 40 mg/kg, remained significantly high. The brain weight was comparable to that of untreated control mice and no gross neurobehavioral effects in the righting reflex test or alteration in the pattern of behavior was observed. The results indicate that the administration of ketamine in a clinically relevant single dose triggers long-lasting neuronal apoptosis in certain brain areas of neonatal mice.


CONCLUSIONS
The administration of ketamine in a clinically relevant single dose to 7-d-old mice induced apoptosis in the sensorimotor cortex and cerebellum. This effect was dose-dependent and long lasting.
Rudin
Michael
M
Dept. of Anesthesiology, HaEmek Medical Center, Afula, Israel.
Ben-Abraham
Ron
R
Gazit
Vered
V
Tendler
Yevgeney
Y
Tashlykov
Vadim
V
Katz
Yeshayahu
Y
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000473:pathology*; D004396:Coloring Agents; D004801:Eosine Yellowish-(YS); D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006416:Hematoxylin; D020287:In Situ Nick-End Labeling; D007649:Ketamine / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D009410:Nerve Degeneration / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D016622:Silver Staining
D004396:Coloring Agents; D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine; D004801:Eosine Yellowish-(YS); D006416:Hematoxylin