Neuroprotective role of hydralazine in rat spinal cord injury‐attenuation of acrolein‐mediated damage

Abstract

Acrolein, an α,β-unsaturated aldehyde and a reactive product of lipid peroxidation, has been suggested as a key factor in neural post-traumatic secondary injury in SCI, mainly based on in vitro and ex vivo evidence. Here we demonstrate an increase of acrolein up to 300%; the elevation lasted at least two weeks in a rat SCI model. More importantly, hydralazine, a known acrolein scavenger can provide neuroprotection when applied systemically. Besides effectively reducing acrolein, hydralazine treatment also resulted in significant amelioration of tissue damage, motor deficits, and neuropathic pain. This effect was further supported by demonstrating the ability of hydralazine to reach spinal cord tissue at a therapeutic level following intraperitoneal application. This suggests that hydralazine is an effective neuroprotective agent not only in vitro, but in a live animal model of SCI as well. Finally, the role of acrolein in SCI was further validated by the fact that acrolein injection into the spinal cord caused significant SCI-like tissue damage and motor deficits. Taken together, available evidence strongly suggests a critical causal role of acrolein in the pathogenesis of spinal cord trauma. Since acrolein has been linked to a variety of illness and conditions, we believe that acrolein-scavenging measures have the potential to be expanded significantly ensuring a broad impact on human health.

Molecular mechanisms of acrolein-mediated myelin destruction in CNS trauma and disease

“…Binding of acrolein to hydralazine is initiated through a Michael addition reaction between the carbonyl and hydrazine functional groups, respectively [97]. Hydralazine application has demonstrated significant benefit by exhibiting therapeutic concentrations in CNS only 2 hours after application [63]. Specifically, 20 μmol/L of hydralazine was detected in spinal cord tissue 2 hours following an intraperitoneal (IP) injection, which is comparable with a previous established therapeutic concentration [98].…”

“…The presence of acrolein has been implicated in cases of enhanced oxidative stress, particularly where elevated tissue and systemic levels of acrolein have been shown in both SCI [55, 56, 61–64] and MS [57]. In fact, acrolein can increase up to 300% at 24 hours post-SCI and remain elevated for at least two weeks in a clinically relevant rat spinal cord contusion injury model [63]. Given that demyelination is a hallmark of both MS and SCI, this evidence points toward acrolein-mediated myelin damage as a key factor underlying symptoms of CNS trauma and disease.…”

Drug delivery, cell-based therapies, and tissue engineering approaches for spinal cord injury

“…Studies have been conducted to mitigate acrolein mediated oxidative damage and neuronal injury by use of acrolein scavengers, most notably hydralazine (59). Park et al showed that daily intraperitoneal injections of hydralazine were effective in reducing acrolein levels, motor deficits and neuropathic pain in contusive SCI model (60). Hydralazine has a half-life period of a few hours (61) and this can be a limiting factor for experimental and clinical studies.…”

Acrolein is a critical mediator of alcohol-induced liver and intestinal injury in alcoholic liver disease.

“…In this study, we used an acrolein scavenger, hydralazine, which is known to neutralize free acrolein [78,79] and acrolein-protein adducts [47,80], both of which are cytotoxic. Also, hydralazine was shown to effectively prevent acrolein-mediated cell death and tissue damage in spinal cord injury [46,81]. Additionally, we also used carnosine (beta-alanyl histidine, an endogenous dipeptide) that is known to scavenge aldehydes such as acrolein, and to have beneficial effects against acetaminophen-induced liver injury [82].…”

“…Hydralazine (5mg/kg body weight, dose based on previous literature [79,81]) was administered by daily intraperitoneal injection during the 10-day alcohol feeding regimen. As noted previously, consumption of the alcohol diet resulted in significant hepatic acrolein adduct accumulation and steatosis in the liver, and the acrolein scavenger hydralazine effectively blocked alcohol-induced acrolein formation and adduct accumulation ( Figure 14B) and dramatically reduced hepatic steatosis as seen by histological examination and confirmed by Oil Red O staining ( Figure 14B).…”