1. ¹Department of Neurology, University of California, San Francisco, California, USA
2. ²NeuroBioTex, Inc., Galveston, Texas, USA
3. ³Department of Neurobiology, Institute of Anatomy, University of Aarhus, Aarhus C, Denmark

Correspondence: Dr SW Suh, Department of Neurology (127), 4150 Clement Street, UCSF, VAMC, San Francisco, CA 94121, USA. E-mail: swsuh@itsa.ucsf.edu

Received 9 March 2004; Revised 5 May 2005; Accepted 23 May 2005; Published online 29 June 2005.

Abstract

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 (Zn^{2 +}), translocation and accumulation of Zn^{2 +} 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 Zn^{2 +}. 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 Zn^{2 +} into hippocampal neurons in adult rats after weight drop-induced TBI. The central finding was that TBI-induced Zn^{2 +} translocation is strongly influenced by brain temperature. Vesicular Zn^{2 +} release was detected by AMG staining 1 h after TBI. At 30°C, hippocampus showed almost no evidence of vesicular Zn^{2 +} release from presynaptic terminals; at 36.5°C, the hippocampus showed around 20% to 30% presynaptic vesicular Zn^{2 +} release; and at 39°C vesicular Zn^{2 +} release was significantly greater (40% to 60%) than at 36.5°C. At 6 h after TBI, intracellular Zn^{2 +} accumulation was detected by the TSQ staining method, which showed that Zn^{2 +} translocation also paralleled the vesicular Zn^{2 +} release. Neuronal injury, assessed by counting eosinophilic neurons, also paralleled the translocation of Zn^{2 +}, being minimal at 30°C and maximal at 39°C. We conclude that pathological Zn^{2 +} translocation in brain after TBI is temperature-dependent and that hypothermic neuronal protection might be mediated in part by reduced Zn^{2 +} translocation.