Phenelzine Protects Brain Mitochondrial FunctionIn VitroandIn Vivofollowing Traumatic Brain Injury by Scavenging the Reactive Carbonyls 4-Hydroxynonenal and Acrolein Leading to Cortical Histological Neuroprotection

Abstract

Lipid peroxidation (LP) is a key contributor to the pathophysiology of traumatic brain injury (TBI). Traditional antioxidant therapies are intended to scavenge the free radicals responsible for either initiation or propagation of LP. A more recently explored approach involves scavenging the terminal LP breakdown products that are highly reactive and neurotoxic carbonyl compounds, 4-hydroxynonenal (4-HNE) and acrolein (ACR), to prevent their covalent modification and rendering of cellular proteins nonfunctional leading to loss of ionic homeostasis, mitochondrial failure, and subsequent neuronal death. Phenelzine (PZ) is a U.S. Food and Drug Administration-approved monoamine oxidase (MAO) inhibitor (MAO-I) used for treatment of refractory depression that possesses a hydrazine functional group recently discovered by other investigators to scavenge reactive carbonyls. We hypothesized that PZ will protect mitochondrial function and reduce markers of oxidative damage by scavenging LP-derived aldehydes. In a first set of in vitro studies, we found that exogenous application of 4-HNE or ACR significantly reduced respiratory function and increased markers of oxidative damage (p < 0.05) in isolated noninjured rat brain cortical mitochondria, whereas PZ pre-treatment significantly prevented mitochondrial dysfunction and oxidative modification of mitochondrial proteins in a concentration-related manner (p < 0.05). This effect was not shared by a structurally similar MAO-I, pargyline, which lacks the hydrazine group, confirming that the mitochondrial protective effects of PZ were related to its carbonyl scavenging and not to MAO inhibition. In subsequent in vivo studies, we documented that PZ treatment begun at 15 min after controlled cortical impact TBI significantly attenuated 72-h post-injury mitochondrial respiratory dysfunction. The cortical mitochondrial respiratory protection occurred together with a significant increase in cortical tissue sparing.

The 4‑hydroxynonenal mediated oxidative damage of blood proteins and lipids involves secondary lipid peroxidation reactions

“…Following quantitatively measuring the oxidative damage induced by 4-HNE at two end points (protein carbonyl and TBARS formation), the aim was to elucidate the mechanism by which 4-HNE produces these effects. Phenelzine is a drug that contains a hydrazine moiety that allows it to function as an aldehyde scavenger (28), and 4-HNE is an aldehyde free radical species that results from lipid peroxidation (29). It was therefore hypothesized that phenelzine could reverse the oxidative damage produced by 4-HNE if these effects were associated with its chemical character as a free aldehyde radical.…”

Blueberry Supplementation Mitigates Altered Brain Plasticity and Behavior after Traumatic Brain Injury in Rats

“…We presently found that TBI caused a marked increase in 4‐HNE levels indicative of decreased neuronal excitability. Elevated levels of 4‐HNE can form adducts with proteins, promotes oxidative stress, and contributes to membrane damage following TBI . BB is considered to have strong antioxidant capacity, important in its ability to attenuate oxidative stress .…”

Cognition based bTBI mechanistic criteria; a tool for preventive and therapeutic innovations

“…Such molecules are of particular interest due to our prior work studying aldehyde-mediated effects in spinal cord injury and multiple sclerosis 64 – 66 , in addition to independent links between reactive aldehydes and neurodegenerative diseases 67 . Aldehyde reduction therapies are still in early stages of development and testing, but show promise for brain injuries of both ischemic and traumatic aetiology 68 – 70 .…”