Jonathan Tang Dissertation.pdf (2.66 MB)
Pathological role of acrolein in neurotrauma and neurodegeneration
thesisposted on 2021-07-08, 21:29 authored by Jonathan An TangJonathan An Tang
Oxidative stress has been implicated in the pathology of neurotrauma and neurodegeneration. However, direct antioxidant treatments have largely failed in clinical trials. Reactive unsaturated aldehyde byproducts of oxidative stress, such as acrolein, are potentially critical in mediating oxidative damage due to greater persistence in the body and while retaining significant reactivity with nucleophilic macromolecules. This study further characterizes the role of acrolein in the pathogenesis of neurotrauma and neurodegeneration. We observed elevated levels of acrolein metabolites in neuronal tissue and in systemic biofluids in animal models of multiple sclerosis, Parkinson’s disease, spinal cord injury, and traumatic brain injury. These findings were partially corroborated with a pilot clinical study in which acrolein metabolites were elevated in the urine and serum of multiple sclerosis patients. Indeed, in vitro incubation of α-synuclein, a major component of Lewy bodies, with acrolein revealed that acrolein covalently modifies α-synuclein in a manner that induces formation of oligomers. Furthermore, carbonyl scavenging treatments, such as hydralazine, were found to protect dopaminergic nerve terminals in a model of Parkinson’s disease, and to alleviate mechanical hyperalgesia in animal models of multiple sclerosis and spinal cord injury. Pharmacokinetic analysis of two hydrazine-based scavengers indicated a short half-life and suggests that efficacy of scavenging can be improved with alternative drugs or extended-release formulations. ALDH2 was investigated as an endogenous method of acrolein detoxification. Motor symptom severity and acrolein metabolite levels were significantly improved in EAE mice treated with Alda-1, an ALDH2 agonist, and significantly worse in ALDH2*2 knock-in mice compared to wild-type EAE mice. Furthermore, myeloperoxidase was found to correlate with acrolein modified proteins in spinal cord white matter. Taken together, acrolein appears to be a key pathological convergence point in the pathogenesis of neurotrauma and neurodegenerative disease. Accordingly, anti-acrolein treatment may be an effective treatment strategy for multiple pathological conditions in the nervous system.
- Doctor of Philosophy
- Biomedical Engineering
- West Lafayette