Effects of Phenelzine Administration on Mitochondrial Function, Calcium Handling, and Cytoskeletal Degradation after Experimental Traumatic Brain Injury.

Abstract

Traumatic brain injury (TBI) results in the production of peroxynitrite (PN), leading to oxidative damage of lipids and protein. PN-mediated lipid peroxidation (LP) results in production of reactive aldehydes 4-hydroxynonenal (4-HNE) and acrolein. The goal of these studies was to explore the hypothesis that interrupting secondary oxidative damage following a TBI via phenelzine (PZ), analdehyde scavenger, would protect against LP-mediated mitochondrial and neuronal damage. Male Sprague-Dawley rats received a severe (2.2 mm) controlled cortical impact (CCI)-TBI. PZ was administered subcutaneously (s.c.) at 15 min (10 mg/kg) and 12 h (5 mg/kg) post-injury and for the therapeutic window/delay study, PZ was administered at 1 h (10 mg/kg) and 24 h (5 mg/kg). Mitochondrial and cellular protein samples were obtained at 24 and 72 h post-injury (hpi). Administration of PZ significantly improved mitochondrial respiration at 24 and 72 h compared with vehicle-treated animals. These results demonstrate that PZ administration preserves mitochondrial bioenergetics at 24 h and that this protection is maintained out to 72 hpi. Additionally, delaying the administration still elicited significant protective effects. PZ administration also improved mitochondrial Ca2+ buffering (CB) capacity and mitochondrial membrane potential parameters compared with vehicle-treated animals at 24 h. Although PZ treatment attenuated aldehyde accumulation post-injury, the effects were insignificant. The amount of α-spectrin breakdown in cortical tissue was reduced by PZ administration at 24 h, but not at 72 hpi compared with vehicle-treated animals. In conclusion, these results indicate that acute PZ treatment successfully attenuates LP-mediated oxidative damage eliciting multiple neuroprotective effects following TBI.