Neurotrophin-3 promotes cell death induced in cerebral ischemia, oxygen-glucose deprivation, and oxidative stress: possible involvement of oxygen free radicals.
To explore the role of neurotrophin-3 (NT-3) during cerebral ischemia, NT-3-deficient brains were subjected to transient focal ischemia. Conditional mutant brains produced undetectable amounts of NT-3 mRNA, whereas the expression of the neurotrophin, BDNF, the NT-3 receptor, TrkC, and the nonselective, low-affinity neurotrophin receptor p75NTR, were comparable to wild-type. Baseline absolute blood flow, vascular and neuroanatomical features, as well as physiological measurements were also indistinguishable from wild-type. Interestingly, the absence of NT-3 led to a significantly decreased infarct volume 23 h after middle cerebral artery occlusion. Consistent with this, the addition of NT-3 to primary cortical cell cultures exacerbated neuronal death caused by oxygen-glucose deprivation. Coincubation with the oxygen free radical chelator, trolox, diminished potentiation of neuronal death. NT-3 also enhanced neuronal cell death and the production of reactive oxygen species caused by oxidative damage inducing agents. We conclude that endogenous NT-3 enhanced neuronal injury during acute stroke, possible by increasing oxygen-radical mediated cell death.
Bates
Brian
B
Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA. bbates@genetics.com
Hirt
Lorenz
L
Thomas
Sunu S
SS
Akbarian
Schahram
S
Le
Dean
D
Amin-Hanjani
Sepideh
S
Whalen
Michael
M
Jaenisch
Rudolf
R
Moskowitz
Michael A
MA
D000818:Animals; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D005609:Free Radicals / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008818:Mice, Neurologic Mutants; D009474:Neurons / Q000166:cytology; D020933:Neurotrophin 3 / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010100:Oxygen / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor / Q000235:genetics; D020812:Receptor, trkC / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; D005609:Free Radicals; D020933:Neurotrophin 3; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D020800:Receptor, Nerve Growth Factor; D020812:Receptor, trkC; D005947:Glucose; D010100:Oxygen