Background
Standard medications that are available to treat MS work by influencing the activity of the immune system. The development of these medications is based on the observation that MS is predominantly driven by an autoimmune response, in which the body’s natural defenses start to attack healthy tissues. While these treatments have demonstrated efficacy, they come with risks such as a weakening of the immune system which could affect the ability of the body to fight infection.
A smaller, but equally important, body of evidence on the mechanism of MS shows that there is a significant neurodegenerative component to the disease. This means that the well-established inflammation that typifies MS is accompanied by a breakdown of nerve tissue. This is especially the case in progressive MS, which is marked by more severe disability and worsening of symptoms when compared to the relapsing-remitting form. Understanding how and why tissues in the central nervous system (CNS) are breaking down is a critical piece to the MS puzzle.
Recently, a research team led by Dr. Fang Liu at the Centre for Addiction and Mental Health Department of Neuroscience discovered that the interaction of certain proteins in the CNS leads to demyelination, nerve damage, and loss of neurons and oligodendrocytes. These are all characteristics of MS and may contribute to neurodegeneration. In a new MS Society-funded study published in Annals of Clinical and Translational Neurology, Dr. Liu and her team tested whether therapeutically targeting and thus blocking these protein interactions could prevent nerve damage and improve MS symptoms.
The Study
The study involved manipulating the interaction between two proteins found in the AMPA receptor, which is a chemical receptor that is found at the junction between two nerves and serves as a docking station for a neurotransmitter called glutamate. Glutamate is the most common neurotransmitter in the brain and is involved in transmitting information throughout the CNS. Although glutamate is essential for proper brain function, problems with the way it is regulated can lead to a phenomenon called excitotoxicity that results in cell death and nerve damage in the CNS, most notably in cases of brain injury and stroke. It has been discovered that the interaction between two key AMPA receptor proteins is partly responsible for excitotoxicity and the resulting nerve damage.
In this MS Society-funded study, Dr. Liu and her team sought to determine whether the interaction between these two proteins in the AMPA receptor is involved in the nerve damage that occurs during MS. To do this, they first looked at post-mortem tissues from the spinal cords of people with MS and mice with MS-like disease to see if this protein complex is present at higher levels compared to healthy neural tissue. Second, they administered a therapeutic agent they developed (named G-Gpep) to block the interaction between these proteins in mice with an MS-like disease to see if they could reverse neurological damage and alleviate symptoms.
Results
Upon observation of post-mortem tissue samples from eight individuals with MS and eight healthy controls, the researchers found a significantly greater amount of the key AMPA receptor protein complex in MS lesions compared to both healthy regions from MS tissues and in tissues from the healthy controls. This protein complex was also observed in greater quantities in spinal cords from mice with MS-like disease compared to their healthy counterparts.
The researchers then administered the therapeutic agent G-Gpep to mice with MS-like disease in order to block the interaction between the two AMPA receptor proteins. They found that G-Gpep significantly improved motor function compared to treatment with an inactive control drug. Interestingly, they also found that paralysis in the hind limbs of mice with the MS-like disease had subsided after treatment with G-Gpep, indicating that the drug may be able to reverse some MS symptoms.
Additional studies demonstrated that treatment with G-Gpep can prevent nerve cell death, promote oligodendrocyte survival, and repair damage. The researchers also reported that treatment with G-Gpep did not negatively affect the natural immune defenses in the mice, and did not have a negative impact on normal brain functioning, a problem that has been previously observed for other interventions that target the AMPA receptor.
Comment
Dr. Liu’s work funded by the MS Society is an elegant example of translational research. The basic knowledge generated from years of work in the laboratory surrounding these proteins and their involvement in nerve damage and cell death has led to the early developmental stages of an exciting potential treatment for MS. Testing experimental treatments in animals that have an MS-like disease is an important step in translational research in that it can provide a great deal of critical information about the safety and benefits of the treatment before it is tested in humans. What is also interesting is that the molecule developed by the researchers has previously demonstrated similar benefits in stroke, an area where Dr. Liu’s research began before shifting focus to MS. This research not only paves the way for a new treatment strategy for MS, but also sheds light on the neurodegenerative aspect of MS that remains poorly understood. Delving deeper into how nerve cells and oligodendrocytes are damaged or lost in MS may have critical implications for progressive MS, for which there are still no therapeutic options.
Source
Zhai D et al. Blocking GluR2-GAPDH ameliorates experimental autoimmune encephalomyelitis. Ann Clin Transl Neurol. 2015 Feb. [Epub Ahead of Print]