Neuroprotection

When you think about inflammation, perhaps you imagine spraining your ankle and how it swells up and the skins becomes red (or inflamed). This is the classic picture of inflammation. But why does that happen?

After suffering an injury, your body detects that damage has occurred so it reacts with two main strategies: it sends various cells to the site of injury to fix the problem, and it increases the flow of fluid to the area so as to enable many repair cells to arrive at the problem spot. The situation is akin to a car accident: when you call 911, emergency vehicles are dispatched and the police block off traffic so the ambulance and fire engine can arrive quickly.

Unfortunately, in both scenarios, these emergency responses can cause secondary problems. Blocking traffic may increase the chance of another car accident, just as the swelling in your ankle (edema) may cause damage to the tissues. That is why people try to reduce swelling by icing the injured ankle and raising the leg.

This is, in effect, what anti-inflammatory treatments do: they try to stop the damage caused by inflammation. But we shouldn’t forget that the initial purpose of this inflammatory response was to repair tissues. Isn’t inflammation supposed to be beneficial? Is inflammation somehow beneficial in MS?

In fact, inflammation does appear to be highly important for the repair and maintenance of tissues throughout the body – which includes the damaged tissues of the CNS in people with MS. How does this work? And is there a way to stimulate inflammatory processes to repair tissues rather than damage them?

Repair and damage in the CNS

In MS, researchers haven’t been able to identify the source of the initial “911 call” that mobilizes the immune system. It may be that this reaction is abnormal, or there may be as yet unidentified damage somewhere in the CNS that triggers the immune response. In either event, the immune system becomes activated and immune cells (T cells) cross the blood-brain barrier into the brain and spinal cord. The result is discrete areas of swelling, calledlesions or plaques, that can be seen with MRI.

Within these lesions, immune cells try to mop up the damage, which includes myelin debris. Unfortunately, this activity can also strip the nerve cells of much of the myelin that they need to protect the underlying nerves. As a result, the exposed nerve fibres begin to degenerate.

The problem appears to be made worse by the activity of the nervous system itself. When nerve cells are injured, the damage tends to spread to the surrounding neurons. This phenomenon is seen in other medical conditions, such as stroke, where a localized injury can result in a larger area of tissue destruction; even a small stroke can cause significant loss of function. Why is this made worse by nervous system activity? Imagine if you cut an electrical cord. If the cord isn’t plugged in, the damage is confined to the area that’s been cut. If the cord is plugged in, the wire will send off sparks and can cause a fire. The damage to the cord and the insulation will be far worse.

The nervous system does have ways to control the amount of damage. As part of the body’s repair process, immune cells release chemicals called neurotrophins. “Neurotrophin” means “nerve growth factor”, which is also the name of the first of these chemicals that was identified. After the discovery of nerve growth factor (NGF), other examples of this type of chemical were isolated. Of particular interest was one called brain-derived neurotrophic factor (BDNF).

During normal development, neurotrophins stimulate the growth and development of nerve cells. They are proteins that act like a fertilizer, enabling nerve fibres to sprout, extend and make connections with other nerves. Later on in the life of a neuron, neurotrophins trigger adaptive changes so the neuron can take on new tasks. Neurotrophins also act to inhibit or delay a nerve cell’s aging and degeneration.

One curiosity of neurotrophins is that they are produced by two bodily systems: the immune system and the nervous system. Activated T cells that enter the CNS, as well as other cells of the immune system (such as B cells and monocytes), have been shown to produce BDNF. Within MS lesions, immune cells are also the major source of BDNF.

The relationship between the immune system and BDNF is a crucial one. Experimental studies have shown that T cells are required for remyelination to occur. If you remove T cells from the area, the myelin will not grow back. This has been shown in animal studies of nerve damage. Following an injury to the nerve, there was less damage to the injured nerve as well as less secondary damage to surrounding nerve fibres when activated T cells were present.

Cells inside MS lesions also produce BDNF. This is probably because the T cells entering the damage zone have “recruited” help from cells in the area, just as a fireman will recruit volunteers if he can’t put out the fire by himself.

However, the primary source of BDNF in the nervous system is the nerve cells themselves. Maintaining nerve function would appear to be so critical that nerves have the ability to repair themselves. This is a phenomenon seen throughout nature: a lobster can regenerate a severed claw. An earthworm can regrow its missing other half if it is cut in two. Higher organisms, including people, have lost much of this ability, but we still have the potential to fix at least some of the damage.

So to summarize, it appears that the immune system in MS detects a problem in the CNS and sends in its emergency crew of immune cells. Once on the scene, these immune cells try to mop up the damage, try to repair the damage, and try to limit the spread of damage to adjoining tissues. BDNF is a central player, enhancing the survival of injured neurons and stimulating the repair of myelin and axons.

With repeated episodes of inflammation, however, this repair process appears to become less effective. The reasons for this aren’t well understood. It may be that the “emergency crew” becomes exhausted, or it can no longer keep up with the amount of ongoing damage. Components of the repair system, such as oligodendrocytes, may themselves break down and no longer do the job effectively.

The two faces of inflammation

Inflammation seems to have a Jekyll-and-Hyde nature. During an autoimmune reaction, the body’s own immune cells have the potential to cause great damage when they enter the CNS. But to counter this autoimmunity there also appears to be “protective autoimmunity” – T cells and other components of the immune system have the capacity to repair the damage they cause.

In a sense, the protective autoimmune response is an insurance policy. It isn’t able to stop the damage from occurring, but it can restore what is lost if something happens. But MS and other conditions involving brain injury (such as neurodegenerative diseases or stroke) show us that we are underinsured. If you suffer $50,000 worth of damage in a house fire but are only insured for $40,000, you will have a net loss. If you have enough fires – such as two or three relapses a year – you will eventually go bankrupt, even though you are getting some compensation every time an outbreak occurs.

This raises the question: is there a way to increase the amount of insurance coverage so you are fully protected? That is what researchers are trying to do now.

Enhancing nervous system repair

At the beginning of Robert Louis Stevenson’s story of Dr. Jekyll and Mr. Hyde, good and evil were balanced and it was only later that Mr. Hyde came to dominate the good doctor.

Similarly, it may be that in the earlier phases of MS, the amount of damage that inflammation causes is counterbalanced by an equal amount of ongoing repair and rewiring. Some studies have shown that the level of BDNF and other growth factors is higher in people with MS compared to control subjects. In addition, BDNF has been shown to increase during MS relapses, indicating that a great deal of repair work is being done. Thus, the autoimmune injury is restored by the protective autoimmune response. This might explain why the symptoms of nerve injury in MS, such as tingling or numbness, are followed by repair and recovery – the times when symptoms go into remission.

At a later stage, this balance appears to be lost and damage starts to accumulate. For example, older people and those with long-standing MS have been shown to have reduced BDNF production. BDNF levels are also lower in people with secondary-progressive MS, which may be why the accumulation of neuronal damage accelerates during this progressive phase of the disease.

But what if the amount of repair being done were somehow enhanced? Could this maintain the balance of damage/repair longer, or prevent the accumulation of damage and disability seen in MS?

This intriguing possibility is now being researched. One approach might be to develop a medication that would boost the amount of neurotrophins in the CNS in the hope of enhancing the growth and repair of neurons. Alternatively, a medication might be able to adjust the feedback mechanisms involved so that the inflammatory processes are more controlled, or there is selective release of key neurotrophins.

Both of these approaches have been studied in animal models of MS. For example, the addition of BDNF has been shown to prevent the death of neurons following damage or transection. In addition, BDNF has been shown to support remyelination following injury to the CNS, and supports neuronal growth and sprouting as nerve fibres try to regenerate.

Experimental studies have also shown that BDNF acts as an immune modulator, downregulating the expression of key components of the immune system in the brain. This may serve to reduce the overexpression ofautoimmune reactions or may make the immune response less toxic to the CNS

The future of neuroprotection

BDNF was only cloned 15 years ago so much of the research on this fascinating protein is still in its preliminary stages. But it has already fundamentally changed how we view the processes of nerve degeneration and repair.

For scientists, BDNF and the other neurotrophins bring them one step closer to that “holy grail” of neurology: being able to repair neurons and restore nerve function. This is the all-important goal not only for people with MS, but also for the millions of individuals with spinal cord injuries, CNS diseases and neurodegenerative disorders.

So the story of MS has expanded. MS was once seen as an autoimmune reaction that resulted in damaging inflammation in the CNS. Now we understand that MS is a complex disorder in which inflammation can produce benefits as well as damage to the CNS. These twin processes may balanced in the earlier stages of MS, and the opportunity exists to re-establish this equilibrium so that any damage that does occur is then repaired.

Some studies have suggested that the imbalance in MS is very slight. Rather than a 50-50 split between damage and repair, there may be a 52-48 division that is just enough to result in a slow accumulation of tissue destruction. This is hopeful news because it means that even a slight correction of one or two percent with a neuroprotective treatment could significantly prolong the time it takes for tissue damage to accumulate, and might even prevent permanent disability. This may well be achievable in the not-too-distant future.