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

Abstract

Myelin is a critical component of the nervous system facilitating efficient propagation of electrical signals and thus communication between the central and peripheral nervous systems and organ systems they innervate throughout the body. In instances of neurotrauma and neurodegenerative disease, injury to myelin is a prominent pathological feature responsible for conduction deficits and leaves axons vulnerable to damage from noxious compounds. Although the pathological mechanisms underlying myelin loss have yet to be fully characterized, oxidative stress appears to play a prominent role. Specifically, acrolein, a neurotoxic aldehyde that is both a product and instigator of oxidative stress, has been observed in studies to elicit demyelination through calcium-independent and -dependent mechanisms and also by affecting glutamate uptake and promoting excitotoxicity. Furthermore, pharmacological scavenging of acrolein has demonstrated a neuroprotective effect in animal disease models by conserving myelin structural integrity and alleviating functional deficits. This evidence is indicative that acrolein may be a key culprit of myelin damage while acrolein scavenging could potentially be a promising therapeutic approach for patients suffering from nervous system trauma and disease.

Dimercaprol is an acrolein scavenger that mitigates acrolein‐mediated PC‐12 cells toxicity and reduces acrolein in rat following spinal cord injury

“…This is likely because the lipid‐rich nervous system provides a virtually unlimited source of compounds for acrolein generation and reaction (Shi et al . , ; Tully and Shi ). Neurons are particularly vulnerable to acrolein‐mediated injury as a result of the lack of specific enzymes that are critical in eliminating acrolein such as some subtypes of aldehyde dehydrogenase (O'Brien et al .…”

“…; Stevens and Maier ; Shi et al . , ). The chemical mechanism of acrolein scavenging by hydralazine, a well‐known acrolein scavenger, is mainly through reaction at C=O group of acrolein and formation of adducts (Burcham et al .…”

“…This results from acrolein's capacity for destroying biomacromolecules (Kehrer and Biswal ; Stevens and Maier ), poisoning mitochondria (Luo and Shi ), compromising the integrity of neuronal membranes, and degrading myelin (Shi et al . , , ; Luo and Shi ). Treatments targeting acrolein may be a promising strategy for alleviating post‐SCI neurodegeneration (Hamann and Shi ; Park et al .…”

Acrolein contributes to TRPA1 up‐regulation in peripheral and central sensory hypersensitivity following spinal cord injury

“…; Shi et al . ). More importantly, acrolein has been identified as a specific agonist of a transient receptor potential ankyrin 1 (TRPA1) cation channel in nociceptors (Bandell et al .…”

“…Recent advances in the understanding of secondary injury after SCI have triggered the investigation of the role of unsaturated aldehydes, especially acrolein, in sensory dysfunction after SCI (Due et al 2014;Park et al 2014b). Acrolein has been identified as both a product and initiator of lipid peroxidation, and therefore a key perpetuator of oxidative stress, a hallmark of post-SCI secondary injury (Uchida et al 1998;Uchida 1999;Luo et al 2005;Shi and Luo 2006;Hamann et al 2008;Hamann and Shi 2009;Park et al 2014a;Shi et al 2015). More importantly, acrolein has been identified as a specific agonist of a transient receptor potential ankyrin 1 (TRPA1) cation channel in nociceptors (Bandell et al 2004;Bautista et al 2006).…”