Preventing environmental damage in the central nervous system to promote repair and regeneration
One of the most significant challenges to repairing the central nervous system (CNS) is the hostile environment unleashed when the brain or spinal cord suffers damage. In cases of injury and disease, the precisely controlled microenvironment of the CNS is greatly disrupted, contributing directly to tissue damage and a lack of significant functional repair and nerve regeneration. Myelin, the sheath that insulates and protects axons, is particularly vulnerable.
A promising avenue of research at Mayo Clinic's campus in Rochester, Minnesota, is uncovering precisely how this "environmental damage" occurs. These discoveries have the potential to spawn new therapies for a range of neurological conditions, particularly those involving damage to myelin, including multiple sclerosis (MS) and spinal cord injury.
"Our goal is to bring the CNS microenvironment back under control," says Isobel A. Scarisbrick, Ph.D., director of the CNS Injury and Neurorehabilitation Laboratory at Mayo Clinic in Rochester. "We hope to make this environment one that is conducive to innate repair and that facilitates therapeutic interventions such as stem cell therapies."
Cascade of damage
When the CNS is injured by trauma or disease, a cascade of secondary damage ensues. Vascular, cellular and chemical responses to the injury include tissue inflammation, reduced blood flow and scar formation. Demyelination occurs on injured axons, slowing the conduction of nerve impulses and stripping axons of protection against further damage.
These changes are brought about in part by multiple proteases, notably the kallikrein family of enzymes. Kallikreins are a family of 15 secreted serine proteases that are increasingly associated with neurological conditions including Alzheimer's disease, Parkinson's disease and frontotemporal dementia. Dr. Scarisbrick's lab discovered one member of the kallikrein family, called kallikrein 6.
In laboratory studies, the Mayo researchers further found that kallikreins wreak neurologic havoc through a limited set of receptors, known as protease activated receptors (PAR). Specifically, aberrant activation of these receptors promotes damage to the axonal wires that conduct electrical impulses across the brain and spinal cord as well as to oligodendrocytes, the cells that produce myelin.
The kallikrein-PAR axis in fact delivers a one-two punch. "Some of these enzymes not only degrade myelin. They also signal to the oligodendrocytes to stop making myelin," Dr. Scarisbrick says. "The oligodendrocyte precursor cells are ready; they want to remyelinate the denuded axons. But they are inhibited from doing so."
Fortunately, protease activated receptors are known to be potent drug targets. "Because of their location, partly inside and partly outside the cell, they are highly 'druggable,' " Dr. Scarisbrick says. "It's difficult to target all the multiple proteases. But we can go after the receptors. They may be a common pathway to block the multiple effects of the proteases."
Success in vitro
In a study published in the September 2013 issue of Glia, the Mayo researchers reported that overactivating the PAR1 receptors in mouse oligodendrocyte cultures caused the cells to stop expressing myelin genes. When a PAR1 inhibitor was added to the culture, the cells resumed myelin production.
"We have shown that blocking the kallikrein-PAR pathway can result in remyelination — in a dish," Dr. Scarisbrick notes. "This is very exciting, but now we want to translate that work into animal models of MS as well as spinal cord injury. Eventually, of course, the goal is to translate this into therapies for patient use. If we continue the progress we have had until now, we're very optimistic that could happen in a few years."
In a study published in the November 2013 issue of the Journal of Neuropathology & Experimental Neurology, Dr. Scarisbrick and colleagues demonstrated in postmortem human tissue the contribution of kallikreins to the pathophysiology of spinal cord injury.
Dr. Scarisbrick notes that in cases of disease and spinal cord injury, there is likely to be an early window of opportunity for treatment aimed at halting environmental damage in the CNS. But lab tests indicate that it may also be possible to promote remyelination at sites where damage occurred previously.
"It would make a lot of sense to target these proteases early," Dr. Scarisbrick says. "But we hope there is an opportunity to target the same protease-PAR axis and promote repair in patients with chronic MS lesions and spinal cord injury."
Although myelin is associated most commonly with MS and spinal cord injury, myelin regeneration has therapeutic applications for other neurological conditions. "The biology that we uncover in an MS lesion looks very similar to what we see in spinal cord injury, and is likely to play parallel roles in stroke and other CNS disorders, as well as glioblastoma multiforme," Dr. Scarisbrick says.
"For conditions as complicated as MS and spinal injury and stroke, I don't think there ever will be a single magic bullet," she adds. "But remyelination is going to be a very important piece of the puzzle."
For more information
Radulovic M, et al. Kallikrein cascades in traumatic spinal cord injury: In vitro evidence for roles in axonopathy and neuron degeneration. Journal of Neuropathology & Experimental Neurology. 2013;72:1072.
Burda JE, et al. Critical role for PAR1 in kallikrein 6-mediated oligodendrogliopathy. Glia. 2013;61:1456.
Yoon H, et al. Kallikrein 6 signals through PAR1 and PAR2 to promote neuron injury and exacerbate glutamate neurotoxicity. Journal of Neurochemistry. 2013;127:283.
Scarisbrick IA, et al. Kallikrein 6 regulates early CNS demyelination in a viral model of multiple sclerosis. Brain Pathology. 2012;22:709.