Secondary Injury Mediating Myelin Damage following Traumatic Injury to the Central Nervous System

Jessica C Page, Purdue University

Abstract

Traumatic injury to the brain and/or spinal cord results in various structural and functional deficits. Among them, demyelination and associated functional deficits are recognized as one of the key pathologies not only in neurotrauma, but also in neurodegenerative diseases such as multiple sclerosis (MS). In the case of spinal cord injury (SCI), demyelination is shown to be triggered through an initial physical impact and exacerbated by secondary biochemical pathological mechanisms including oxidative stress and glutamate excitotoxicity. Generation of reactive oxygen species (ROS) during oxidative stress enhances a perpetuating cycle where lipid peroxidation (LPO) leads to subsequent generation of the highly reactive aldehydes, such as 4- hydroxynonenal (HNE) and acrolein. Both acrolein and glutamate have been shown to cause significant demyelination, a detrimental mechanism exposing underlying juxtaparanodal K+ channels and their consequential activation results in conduction block. Although acrolein and glutamate are both elevated following CNS trauma, the interaction between these two myelin-damaging mechanisms remains unknown. Given the highly reactive nature of acrolein, it is possible that acrolein, in addition to its direct toxicity to myelin, may enhance glutamate toxicity, where both mechanisms work synergistically to cause myelin damage. We further speculate that acrolein may damage glutamate transporters to elevate extracellular glutamate and further exacerbate myelin damage. This is based on the knowledge that HNE, another well-known LPO-derived aldehyde, was shown to interact with glutamate transporter GLT-1 (EAAT2), a protein that is crucial for maintaining lower levels of extracellular glutamate. Consistent with our hypothesis, we observed a down regulation of GLT-1 in CNS tissue following traumatic injury in vivo, as well as in ex vivo preparation when acrolein was applied. In addition, evidence of acrolein association with GLT-1 was revealed after in vivo trauma. Furthermore, functional restorative therapeutic strategies seeking to reverse resulting conduction block have contributed to the development of the significant, however, marginally effective blocker 4-aminopyridine (4-AP or AMPYRA), and a new promising derivative, 4-amino-3-methanol (4-AP-3-MeOH), shown to have a 10-fold increased efficacy. Our parallel studies of 4-AP and 4-AP-3-MeOH after ex vivo acrolein application and ex vivo SCI indicated increased effectiveness of 4-AP-3-MeOH for restoring axonal conduction, as well as improved motor function and mitigated hypersensitivity when applied following in vivo SCI. We believe that these findings are consistent with the hypothesis that acrolein can damage myelin through two distinct and cooperative mechanisms, direct and indirect interaction with myelin and through elevation of extracellular glutamate, respectively, where resulting axonal conduction loss can be restored more readily by 4-AP-3-MeOH and offer analgesic effects.

Degree

Ph.D.

Advisors

Shi, Purdue University.

Subject Area

Neurosciences

COinS