Neurotoxic zinc translocation into hippocampal neurons is inhibited by hypothermia and is aggravated by hyperthermia after traumatic brain injury in rats.
Hypothermia reduces excitotoxic neuronal damage after seizures, cerebral ischemia and traumatic brain injury (TBI), while hyperthermia exacerbates damage from these insults. Presynaptic release of ionic zinc (Zn2+), translocation and accumulation of Zn2+ ions in postsynaptic neurons are important mechanisms of excitotoxic neuronal injury. We hypothesized that temperature-dependent modulation of excitotoxicity is mediated in part by temperature-dependent changes in the synaptic release and translocation of Zn2+. In the present studies, we used autometallographic (AMG) and fluorescent imaging of N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) staining to quantify the influence of temperature on translocation of Zn2+ into hippocampal neurons in adult rats after weight drop-induced TBI. The central finding was that TBI-induced Zn2+ translocation is strongly influenced by brain temperature. Vesicular Zn2+ release was detected by AMG staining 1 h after TBI. At 30 degrees C, hippocampus showed almost no evidence of vesicular Zn2+ release from presynaptic terminals; at 36.5 degrees C, the hippocampus showed around 20% to 30% presynaptic vesicular Zn2+ release; and at 39 degrees C vesicular Zn2+ release was significantly greater (40% to 60%) than at 36.5 degrees C. At 6 h after TBI, intracellular Zn2+ accumulation was detected by the TSQ staining method, which showed that Zn2+ translocation also paralleled the vesicular Zn2+ release. Neuronal injury, assessed by counting eosinophilic neurons, also paralleled the translocation of Zn2+, being minimal at 30 degrees C and maximal at 39 degrees C. We conclude that pathological Zn2+ translocation in brain after TBI is temperature-dependent and that hypothermic neuronal protection might be mediated in part by reduced Zn2+ translocation.
Department of Neurology, University of California, San Francisco, California 94121, USA. swsuh@itsa.ucsf.edu
Sang Won
SW
Suh
Christopher J
CJ
Frederickson
Gorm
G
Danscher
D000818:Animals; D001831:Body Temperature; D001835:Body Weight; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006979:Hyperthermia, Induced; D007036:Hypothermia, Induced; D007089:Image Enhancement / Q000379:methods; D017136:Ion Transport; D008297:Male; D008859:Microscopy, Polarization / Q000379:methods; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D013194:Staining and Labeling; D015032:Zinc / Q000378:metabolism* / Q000633:toxicity
D015032:Zinc