More Brain Points

How Do We Target and Treat Multiple Sclerosis?

            Multiple Sclerosis (MS) is an inflammatory, autoimmune disease caused by the degeneration of myelin sheaths surrounding neuronal axons, particularly in the Central Nervous System (CNS). Demyelination is accompanied by oligodendrocyte loss (cells that synthesize the myelin surrounding axons) and axonal degeneration. Lesions in the brain attributable to autoimmune responses result in a damaged blood brain barrier that leads to the loss of the oligodendrocytes. This common demyelination disease affects about one in 1000 people and the disease is easiest to treat in its early stages.

            Research in this field of medicine has greatly progressed, but the exact mechanism is not completely understood just yet. Dr. Brian Popko of The University of Chicago studied the effects of inducing MS in an in vivo mouse model. His initial observations demonstrated how MS lesions could be characterized by oligodendrocyte apoptosis, an absence of demyelication, and an absence of T cells. This was an important discovery because it clearly illustrated how oligodendrocyte death occurs first, before the immune response attacks that brain, because T cells are absent. Originally the belief was that oligodendrocyte death was due to an autoimmune reaction.

            Dr. Popko further studied the role of oligodendrocytes in the progression of MS. By selectively killing oligodendrocytes, he discovered that oligodendrocyte loss was maximum by 21 days post-injections, but because oligodendrocytes are renewed so rapidly, the loss was never greater than 20%. 35 days post-injection there was extensive demyelination and it was not until 70 days later that oligodendrocytes were, not completely though, restored. Unfortunately, a relapse occurred nine months later and most of the mice died. Dr. Popko then proceeded to look at the mechanism behind MS and discovered that the disease's progression was caused by an increasing stress response on the endoplasmic reticulum (ER) of the oligodendrocyte. The initial activation of this stress response results in the activation of the protein PERK, which in turn activates eLF2α, a protein that reduces translation in the cell but induces cytoprotective genes. These genes protect the cell from further harm until the GADD34 protein, induced by IFN-γ and produced by stress in the ER, inactivates eLF2α and reduces the protective state of the cell. By preventing the GADD34 protein from inactivating eLF2α through the binding of the drug guanabenz to GADD34, the protective state of the oligodendrocyte can be prolonged, increasing the life of the cell. Guanabenz was also found to reduce the severity of MS and delay the onset with increasing doses. Thus, guanabenz treatment protects oligodendrocytes, prevents relapse, and promotes remyelination in the CNS.

            A novel medicine is now on the market that shows considerable promise with relapsing-remitting MS. BG-12 is the third oral drug available on the market to MS patients of nine drugs for the treatment of early-stage MS.¹ Studies concluded that this drug reduced relapse rates of MS by about 50% as well as significantly reducing the frequency of new brain lesions. Interferons and another new oral drug called Aubagio only reduce relapses by about 30%, so BG-12 looks very promising. Two other drugs, Gilenya and Tysabri, are more effective but come with the rare risk of death, so they are used as secondary approaches to treating MS. Studies with BG-12 also showed a reduction of 71-99% of new or newly enlarging brain lesions and a reduction of 38% is the progression of MS to disability. This drug is a fumaric acid that increases levels of glutathione in cells which inhibits NF-ĸB translocation into the nucleus.² This NF-ĸB protein regulates the inflammation cascade, so BG-12 prevents this cascade from initiating in the first place consequentially reducing inflammation. Side effects are minimal and seemed to diminish after just a few weeks.¹ All in all, this drug looks very promising as a treatment for those in the early-stages of MS.

            While guanabenz and BG-12 both look promising as treatment options, only time will tell exactly how effective they really are. Unfortunately, there are still no treatments for those with progressive MS, which more than half of patients develop leading to permanent disabilities. Ultimately, more research needs to be done on MS as a disease to develop a treatment for those with progressive MS.

Works Cited

1.   Tarkan, Laurie. "Pill Found Promising in Treatment of M.S." The New York Times. The New York Times, 19 Sept. 2012.

< http://www.nytimes.com/2012/09/20/health/research/bg-12-pill-shows-promise-in-suppressing-multiple-sclerosis-relapses.html?_r=0>

2.  Moharregh-Khiabani, D., R. A. Linker, R. Gold, and M. Stangel. "Fumaric Acid and Its Esters: An Emerging Treatment for Multiple Sclerosis." Current Neuropharmacology 7.1 (2009): 60-64. Print.