Neuroprotection and functional restoration in an animal model of multiple sclerosis

Gary D Leung, Purdue University

Abstract

Our investigations have aimed to reveal more details in the mechanisms underlying the autoimmune neurodegenerative disease, multiple sclerosis (MS). These experiments have explored the oxidative stress pathway, axonal membrane damage, and also potassium channel blockade. Furthermore, there is evidence that potential therapeutics can provide neuroprotection by reducing myelin and axolemmal damage and restore function through conduction of demyelinated axons. Multiple sclerosis is an inflammatory autoimmune disease of the central nervous system that leads to symptoms of fatigue, loss of coordination, paralysis, bowel and bladder dysfunction, and poor cognition. These physical indicators are a result of inflammation, demyelination, and axonal degeneration in the spinal cord and brain. In order to study MS, an animal model called experimental autoimmune encephalomyelitis (EAE) has been utilized for decades. An important area of MS research has focused on oxidative stress. Acrolein, a toxic aldehyde with a longer half-life than oxygen free radicals, is both a by-product and initiator of oxidative stress. Our studies confirmed a significant increase of acrolein in EAE mice as well as reduced levels when treated with an acrolein scavenger, hydralazine. In addition, morphological studies demonstrated increased demyelination in EAE mice which was decreased after hydralazine administration. Anti-acrolein therapy of hydralazine or phenelzine translated to improved behavioral deficit in both severity and onset of symptoms. Even though MS is usually considered a demyelinating disease, research has been focusing more on axonal degeneration which may be the culprit in causing chronic, irreversible damage. The lipid bilayer surrounding the axon called the axolemma is important in preventing toxic molecules from entering and causing degradation. Our studies revealed the presence of axonal membrane damage in EAE mice. In addition, treatment with polyethylene glycol (PEG), a known membrane sealant, improved axolemmal integrity and behavioral function in the animal model. PEG has also shown to protect neuronal mitochondria which may be a contributing factor to oxidative stress in MS. Evidence supports the idea of PEG directly interacting with mitochondria and improving their function after injury. With the recent approval of Ampyra (4-aminopyridine (4-AP)), potassium channel blockade has become another form of treatment for patients suffering from MS. Ampyra improves walking in MS patients by restoring axonal conduction in demyelinated axons. However, there is a narrow therapeutic window for this molecule. We have demonstrated that a derivative of 4-AP, 4-aminopyridine-3-methanol, is able to significantly increase axonal conduction in ex vivo spinal cord of EAE mice. This compound may be able to provide an alternative option if 4-AP treatment was not beneficial to the patient.

Degree

Ph.D.

Advisors

Shi, Purdue University.

Subject Area

Neurosciences

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