title: Primate neurons show different vulnerability to transient ischemia and response to cathepsin inhibition.
abstract: Previously, we reported "calpain-induced leakage of lysosomal enzyme cathepsin" as a mechanism of ischemic neuronal death specific for primates. Cathepsin inhibitors such as CA-074 and E-64c were demonstrated to significantly inhibit hippocampal neuronal death. Pyramidal neurons of the hippocampus, Purkinje cells in the cerebellum, and neurons in the caudate nucleus, outer putamen and cortical III, V layers, are known to be vulnerable to ischemia. However, regional differences of the vulnerability and response to neuroprotectants, have not been studied in detail. Here, the monkey brains undergoing transient ischemia were studied to clarify such regional differences by the microscopic counting of surviving neurons. The dead neurons were characterized by eosinophilic coagulation necrosis without apoptotic bodies. The control postischemic brain without treatment showed surviving neurons in caudate nucleus (55.8%), outer putamen (44.4%), cortical III layer (37.8%), CA4 (35.3%), cortical V layer (34.1%), cerebellum (28.2%), CA3 (24.3%), CA2 (16.2%), and CA1 (2.0%). Only the CA1 showed an almost total neuronal loss. In contrast, a single postictal injection of CA-074 or E-64c led to significant inhibition of postischemic neuronal death in all brain regions studied. Overall, more surviving neurons were seen after E-64c treatment than with CA-074: cerebellum, 91.6% vs 85.6%; CA4, 88.6% vs 77.3%; caudate nucleus, 86.1% vs 89.8%; CA2, 83.6% vs 53.0%; outer putamen, 81.3% vs 87.7%; CA1, 80.1% vs 47.4%; CA3, 79.6% vs 60.3%; cortical layer III, 75.5% vs 67.7%; and cortical layer V, 75.0% vs 65.9%, for E-64c and CA-074, respectively. Cathepsin plays a critical role in ischemic neuronal death, and its inhibitors may protect neurons throughout the brain.
authors.affiliation: Department of Neurosurgery, Shiga Medical School, Shiga, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yoshida
authors.forename: Tetsumori
authors.initials: T
authors.lastname: Yamashima
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Kohda
authors.forename: Anton B
authors.initials: AB
authors.lastname: Tonchev
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsuda
authors.forename: Eiki
authors.initials: E
authors.lastname: Kominami
mesh_terms: D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000201:enzymology / Q000473:pathology*; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008251:Macaca; D009336:Necrosis; D009410:Nerve Degeneration / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D018696:Neuroprotective Agents; C068250:N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline; C032425:N-(N-(3-carboxyoxirane-2-carbonyl)leucyl)isoamylamine; D002154:Calpain; D002401:Cathepsin B; D007930:Leucine