Phenelzine Mitochondrial Functional Preservation and Neuroprotection after Traumatic Brain Injury Related to Scavenging of the Lipid Peroxidation-Derived Aldehyde 4-Hydroxy-2-Nonenal

Abstract

Phenelzine (PZ) is a scavenger of the lipid peroxidation (LP)-derived reactive aldehyde 4-hydroxynonenal (4-HNE) due to its hydrazine functional group, which can covalently react with 4-HNE. In this study, we first examined the ability of PZ to prevent the respiratory depressant effects of 4-HNE on normal isolated brain cortical mitochondria. Second, in rats subjected to controlled cortical impact traumatic brain injury (CCI-TBI), we evaluated PZ (10 mg/kg subcutaneously at 15 minutes after CCI-TBI) to attenuate 3-hour post-TBI mitochondrial respiratory dysfunction, and in separate animals, to improve cortical tissue sparing at 14 days. While 4-HNE exposure inhibited mitochondrial complex I and II respiration in a concentration-dependent manner, pretreatment with equimolar concentrations of PZ antagonized these effects. Western blot analysis demonstrated a PZ decrease in 4-HNE in mitochondrial proteins. Mitochondria isolated from peri-contusional brain tissue of CCI-TBI rats treated with vehicle at 15 minutes after injury showed a 37% decrease in the respiratory control ratio (RCR) relative to noninjured mitochondria. In PZ-treated rats, RCR suppression was prevented (Po0.05 versus vehicle). In another cohort, PZ administration increased spared cortical tissue from 86% to 97% (Po0.03). These results suggest that PZ's neuroprotective effect is due to mitochondrial protection by scavenging of LP-derived 4-HNE.

Chronic traumatic encephalopathy-integration of canonical traumatic brain injury secondary injury mechanisms with tau pathology

“…LP terminates with formation of neurotoxic aldehydes, such as 4-hydroxynonenal (4-HNE) and 2-propenal (acrolein). Both LP and its derivatives, 4-HNE and acrolein, are well known to be increased following TBI (Bayir et al , 2007; Hall et al , 2004; Mustafa et al , 2010; Mustafa et al , 2011; Singh et al , 2013) (Cebak et al , 2016; Hill et al , Submitted).…”

“…As a major site of PN formation, mitochondria are particularly susceptible to attack by LP-derived neurotoxic aldehydes. Binding of 4-HNE and acrolein to mitochondria results in extensive mitochondrial dysfunction through impairment of mitochondrial respiration and enhanced generation of ROS/RNS (Singh et al , 2013; Vaishnav et al , 2010) (Cebak et al , 2016; Hill et al , Submitted; Miller et al , 2013; Picklo et al , 1999; Picklo and Montine, 2001). Following TBI, the mitochondrial dysfunction induced by LP-derived neurotoxic aldehydes and increased intra-mitochondrial calcium concentrations leads to formation of the mitochondrial permeability transition pore (mPTP) (Bringold et al , 2000; Hansson et al , 2008; Sullivan et al , 2005).…”

Lipid peroxidation in brain or spinal cord mitochondria after injury

“…Detailed explanation of mechanisms for the lipid peroxyl radical (LOO•) scavengers U-83836 and U-101033 are presented in references 5, 27 and 31. The carbonyl scavenging chemistry of phenelzine is explained in reference 27.…”

“…Detailed explanation of mechanisms for the lipid peroxyl radical (LOO•) scavengers U-83836 and U-101033 are presented in references 5, 27 and 31. The carbonyl scavenging chemistry of phenelzine is explained in reference 27. For an understanding of the mechanism by which cyclosporine A (and NIM811) inhibit mitochondrial permeability transition, see references 9, 14 and 36.…”

“…Furthermore, spinal cord mitochondria were found to be significantly more susceptible that brain mitochondria. However, scavenging of these carbonyl-containing compounds with the carbonyl scavenging compound phenelzine has been shown to attenuate mitochondrial respiratory depression along with a reduction in the levels of aldehyde-modified mitochondrial proteins [27]. …”