Molecular cross talk in traumatic brain injury.

Editor's Note: These short reviews of a recent paper in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to mimic the journal clubs that exist in your own departments or institutions. For more information on the format and purpose of the Journal Club, please see Review of Lau et al. Peroxynitrite (PN), a product of the near-diffusion-limited reaction between nitric oxide (NO) and mitochondrially derived superoxide (O 2 Ϫ), is a potent and versatile oxidant produced after brain trauma. PN can cause lipid peroxidation, DNA fragmentation, and protein nitration (Hall et al., 2004). Although the precise targets of posttranslational PN-mediated nitration and oxidation have not been fully elucidated, the activity of this radical contributes to the susceptibility of neu-rons to secondary injury posttrauma (Arundine and Tymianski, 2004). Recent work from Lau et al. (2006) in The Journal of Neuroscience reports novel, trauma-induced cross talk between peroxynitrite and caspases, traditional mediators of ap-optotic neuronal death after traumatic contend that peroxynitrite inhibits caspase-3-mediated apoptosis through cysteinyl oxidation after in vivo and in vitro neurotrauma, effectively switching the mode of cell death from apoptotic to oxidant mediated (Fig. 1). To probe the relationship between peroxynitrite and apoptotic signaling, Lau et al. (2006) used an in vitro neuronal stretch model of TBI. The authors observed apoptotic-like cell death (characterized by terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling staining and DNA laddering similar to that observed with stau-rosporine) in neurons exposed to NMDA and sublethal neuronal stretch [Lau et al. F1)]. Although the cells demonstrated cy-tochrome c translocation and PN formation [Lau et al. they lacked activated caspase-3, a traditional feature of apoptotic neurons [Lau et al. (2006) hypothesized that PN directly inhibited apoptosis in addition to causing the observed DNA fragmentation in mechanically injured cells. The authors believed that this might underlie their observation of cytochrome c release in the absence of caspase-3 activation. Lau et al. (2006) asked whether PN directly inhibited caspase-3 or whether it interfered with the steps between cyto-chrome c release and subsequent activation of caspase-3. Using an antibody to 3-nitrotyrosine, the authors immunopre-cipitated the inactive form of caspase-3 (procaspase; a 32 kDa band) after trauma [Lau et al. In an ex vivo system, Lau et al. (2006) also observed direct inhibition of fluorogenic caspase-3 activity by the PN donor 3-morpholinosydnonimine (SIN-1) and a complete block by PN itself [Lau et al. Additional exposure of …