CuZn-SOD deficiency, rather than overexpression, is associated with enhanced recovery and attenuated activation of NF-kappaB after brain trauma in mice.
Superoxide-dismutases (SOD) catalyze O2- conversion to hydrogen peroxide (H2O2) and with other antioxidant enzymes and low molecular weight antioxidants (LMWA) constitute endogenous defense mechanisms. We first assessed the effects of SOD1 levels on outcome after closed head injury (CHI) and later, based on these results, the effects of SOD1 deficiency on cellular redox homeostasis. Superoxide-dismutase 1-deficient (SOD1-/-) and -overexpressing (transgenic (Tg)) mice and matched wild-type (WT) controls were subjected to CHI and outcome (neurobehavioral and memory functions) was assessed during 14 days. Brain edema, LMWA, and SOD2 activity were measured along with histopathological analysis. Transactivation of nuclear factor-kappa B (NF-kappaB) was evaluated by electromobility shift assay. Mortality, motor, and cognitive outcome of Tg and WT mice were comparable. Mortality and edema were similar in SOD1-/- and WT mice, yet, unexpectedly, SOD1-/- displayed better neurobehavioral recovery (P<0.05) at 14 days after CHI. Basal LMWA were higher in the cortex and liver of SOD1-/- mice (P<0.05) and similar to WT in the cerebellum. Five minutes after CHI, cortical LMWA decreased only in SOD1-/- mice. One week after CHI, SOD2 activity decreased fourfold in WT cortex (P<0.001), but was preserved in the SOD1-/-. Constitutive NF-kappaB transactivation was comparably low in SOD1-/- and WT; however, CHI induced a robust NF-kappaB activation that was absent in SOD1-/- cortices (P<0.005 versus WT). At the same time, immunohistochemical analysis of brain sections revealed that astrogliosis and neurodegeneration were of lesser severity in SOD1-/- mice. We suggest that SOD1 deficiency impairs H2O2-mediated activation of NF-kappaB, decreasing death-promoting signals, and leading to better outcome.
Beni
Sara M
SM
Department of Pharmacology, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
Tsenter
Jeanna
J
Alexandrovich
Alexander G
AG
Galron-Krool
Nili
N
Barzilai
Ari
A
Kohen
Ron
R
Grigoriadis
Nikolas
N
Simeonidou
Constantina
C
Shohami
Esther
E
D000818:Animals; D000975:Antioxidants / Q000032:analysis; D001929:Brain Edema / Q000209:etiology; D001930:Brain Injuries / Q000378:metabolism* / Q000503:physiopathology; D003071:Cognition; D006706:Homeostasis; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction; D013482:Superoxide Dismutase / Q000032:analysis / Q000172:deficiency* / Q000235:genetics; D015996:Survival Rate; D014945:Wound Healing; D000099156:Superoxide Dismutase 2
D000975:Antioxidants; D016328:NF-kappa B; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2