Discovery of Novel Acrolein Scavengers and Their Neuroprotective Effects
Oxidative stress is known to involve in the pathogenesis and development of many diseases in the central nervous system. Acrolein, a byproduct of lipid peroxidation, can damage critical biomolecules, deplete endogenous antioxidant defenses, and cause mitochondrial dysfunction, which catalyzes and perpetuates oxidative stress. Acrolein has been demonstrated to be involved in many central nervous system diseases, such as neurotrauma, Multiple Sclerosis, Alzheimer’s disease, Parkinson’s disease, etc. In this dissertation, we also indicated that acrolein could induce hypersensitivity to pain stimuli and involved in the neuropathic pain post neurotrauma or accompanying with an autoimmune demyelinated disease Multiple Sclerosis. Therefore, neutralizing acrolein has been demonstrated as an effective intervention to attenuate neuronal degeneration and provide neuroprotection. Based on our studies, acrolein scavengers hydralazine and phenelzine were shown to be able to reduce acrolein level, mitigate neuronal death and enhance functional recovery in vitro and in vivo. However, hydralazine and phenelzine have potential side effects. We intend to establish viable alternatives to minimize the side effects. Here, we present two new acrolein scavengers, dimercaprol and a designed phenelzine analogue. Our studies illustrated that both scavengers could react with acrolein, halt acrolein-mediated neuronal damage and render neuroprotective functions. Dimercaprol, a FDA approved drug, possesses thiol groups and is capable of binding both the carbon-carbon double bond and the aldehyde group of acrolein. At a safe dose, systemic administration of dimercaprol reduced acrolein levels and associated tissue damage, promoted locomotor behavioral recovery, and alleviated neuropathic pain in a rat contusive spinal cord injury model. Meanwhile, we indicated that a phenelzine analogue, obtained from structure-based chemical modification, maintained acrolein scavenging abilities, and presented similar cytotoxicity and comparable neuroprotective effects as phenelzine, while with diminished monoamine oxidases inhibitory activities. Taken together, these studies suggest that both dimercaprol and the modified phenelzine analogue may be efficacious acrolein scavengers which could serve as feasible alternatives to existing scavengers. In addition, structure-based chemical modification is proved to be an effective strategy to develop new acrolein scavengers.
Shi, Purdue University.
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