Multiple sclerosis is an inflammatory disease of the nervous system caused by the degradation of myelin, the insulating substance which envelopes nerve fibres called axons. MS is characterized by cycles of relapse and recovery as the disease progresses. Steroid drugs are often effective in improving recovery time following a relapse, but are not a permanent cure for MS. As the myelin is depleted in a patient with MS, common symptoms include speech disturbances, poor coordination, and muscle weakness. Neurons, or individual nerve cells, are strongly affected by MS, as the disease interferes with their ability to transmit chemical and electrical signals. These signals serve as traffic lights which can promote or inhibit actions of various body parts, such as muscles and glands. During a relapse of MS, neurons experience a type of power failure, which causes reduced activity within the nerve cells. As a result of this decrease in energy, sodium and calcium ions accumulate in the neurons. This buildup occurs because there is reduced function of the enzymes which normally pump these ions out of the cell. When toxic levels of sodium and calcium are reached within the neurons, immune cells called microglia launch their attack on the myelin sheaths.
The optic nerve, which innervates the eye, is a common target for the microglia. More than fifty percent of MS patients report vision loss, a condition referred to as acute demyelinating optic neuritis. This is caused by the destruction of the myelin layer of the optic nerve and damage to its fibres in the retina, the region of the eye where images are formed.
Raftopoulos et al., 2016, have discovered a new method for inhibiting further damage of the optic nerve in MS patients. This phenomenon, known as neuroprotection, is provided by partially blocking the microscopic channels which permit the passage of sodium ions into and out of neurons. These channels, called voltage-gated sodium channels, are composed of a protein that spans the membrane of the neuron like a tunnel; they have a central pore which can be in an opened or closed conformation, depending on the internal state of the neuron. When opened, the voltage-gated sodium channels allow sodium ions to enter the neuron, producing an impulse or action potential within the cells. These impulses are necessary in order for the brain to perceive visual stimuli. Thus, the challenge faced by Raftopoulos and his team of researchers was to only partially block these channels so that vision could be preserved; if all of the voltage-gated sodium channels were completely blocked, the impulses for sight would not occur, and blindness would result.
The voltage-gated sodium channel blockade was created with phenytoin, a drug more commonly used to prevent seizures in patients suffering from epilepsy. Blocking the voltage-gated sodium channels reduced the toxic accumulation of sodium ions in the neurons of the optic nerve, as seen in a flare-up of MS. Neuroprotection by partially blocking voltage-gated sodium channels helps to prevent the onset of a microglial attack, thus preserving the myelin sheath surrounding the optic nerve.
The effectiveness of phenytoin as a neuroprotective agent was evaluated by measuring the thickness of the retinal nerve fibre layer (RNFL). Degradation of the myelin of the optic nerve leads to damage of the RNFL, an unmyelinated axon which transmits visual information to processing centres in the brain. Reduction in the thickness of the RNFL is associated with vision loss. Phenytoin is not the first drug to be tested for neuroprotection of the optic nerve and retinal fibres, but it is advantageous due to its rapid effects; it is critical that neuroprotective drug treatment begins promptly during an inflammatory relapse of MS in order to sustain the myelin layer and prevent further damage. When compared, patients who used phenytoin had thirty percent less reduction in RNFL thickness than those who were not given the drug in this trial. Therefore, neuroprotection by phenytoin in MS patients is a promising method of treating future relapses in MS patients with acute demyelinating optic neuritis.
Source: Raftopoulos, R., Hickman, S.J., Toosy, A., Sharrack, B., Mallik, S., Paling, D., Altmann, D.R., Yiannakas, M.C., Malladi, P., Sheridan, R., Sarrigiannis, P.G., Hoggard, N., Koltzenburg, M., Wheeler-Kingshot, C.A., Schmierer, K., Giovannoni, G., Miller, H.D., and Kapoor, R. (2016). Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. The Lancet Neurology 15(3): 259-269.
