Massive cell death of cerebellar granule neurons accompanied with caspase-3-like protease activation and subsequent motor discoordination after intracerebroventricular injection of vincristine in mice.
Vincristine, a microtubule-depolymerizing agent, is known to induce neuronal cell damage. Biochemical, histological and behavioral alterations were investigated after intracerebroventricular injection of vincristine in mice. Intracerebroventricular injection of vincristine caused caspase-3-like protease activation followed by nucleosomal release in the cerebellum. Histological examinations showed that vincristine-induced damage was relatively specific to granule cells in the cerebellum, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling-positive cells were observed among these cells. Chromatin condensation, one of the criteria for apoptosis, was seen on electron microscopy. Behavioral changes, namely head movements, pivoting and backward walking, were observed in parallel with the increase of caspase-3-like protease activity and nucleosomal release. Furthermore, motor function tests (bulb balance test and rotating rod test) showed deficits of motor coordination ability. These observations suggest that intracerebroventricular vincristine causes massive apoptosis of cerebellar granule cells accompanied with caspase-3-like protease activation, leading to motor dysfunction, in this model. These vincristine-treated mice should be a useful in vivo model for examination of neuronal apoptosis, which might be involved in a variety of neurodegenerative diseases.
Shimizu
H
H
Eisai Tsukuba Research Laboratories, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. h3-shimizu@hhc.eisai.co.jp
Ohgoh
M
M
Momose
Y
Y
Nishizawa
Y
Y
Ogura
H
H
D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002531:Cerebellum / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019957:Motor Skills Disorders / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D014750:Vincristine / Q000633:toxicity*
D014750:Vincristine; D010450:Endopeptidases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases