The Center for Neuroscience and Regeneration Research at Yale University is helping scientists better understand how to repair incomplete nerve injuries and treat neuropathic pain.
More than two decades ago, Paralyzed Veterans of America (PVA) helped establish the Center for Neuroscience and Regeneration Research at Yale University on the campus of West Haven VA Connecticut Healthcare System. The goal was to increase research on recovery of function after injury to the brain and spinal cord.
“PVA was a major force in building spinal-cord research into a strong and exciting field,” remarked Stephen Waxman, MD, PhD, director of the Center for Neuroscience and Regeneration Research at Yale, as he delivered a lecture at the PVA Summit and Expo in Orlando, Fla., last year. “And I am most proud of this collaboration between Yale University and Paralyzed Veterans.”
Waxman, a distinguished professor of neurology and pioneer in the field of neuroscience, leads the center’s robust research program. Armed with a multidisciplinary team of highly skilled scientists, he has built neuroscience research infrastructure while capitalizing on the genomic revolution and extrapolating from laboratory findings to human disease in translational studies.
Like an Electrical Wire
During his lecture, Waxman described the precise organization of myelinated nerve fiber and how that helps nerve signals to
A myelinated nerve fiber is like an electrical wire where myelin is the outer insulation and axon is the inner core. However, unlike the insulation of an electrical wire, myelin is laid out in short segments, leaving small unmyelinated gaps between the segments.
These gaps, known as nodes of Ranvier, are hot spots for sodium channels—the molecular machinery that is necessary to relay signals along the transmission line. Unfortunately, in people with nerve injuries, including those with incomplete spinal-cord injuries (SCI), nerve signals hit a roadblock.
These images show "sodium channels" — the molecular machinery that relays signals along the transmission line.
This is because the injured axonal regions, stripped of their myelin, lack the molecular machinery needed to relay signals. For a long time, it remained a puzzle as to how some MS patients are able to experience remission, even with extensive myelin damage.
In an early but seminal discovery, Waxman showed that MS patients in remission experience redistribution of sodium channels to areas of myelin damage, which provides a way for nerve signals to be transmitted.
This discovery not only highlighted the importance of sodium channels to recovery of function following myelin damage as occurs in MS but also set the stage for further investigations on how to coax sodium channels to sprout in the barren areas of myelin damage.
The goal of his research now is to induce remissions in all people with incomplete nerve injuries involving myelin damage.
Protecting Injured Neurons
The human body contains at least nine varieties of sodium channels, each with a unique physiological signature.
For example, Nav1.6 is the variety present at the nodes of Ranvier, Nav1.5 is in the heart muscle, and others such as Nav1.7, Nav1.8 and Nav1.9 are predominant in pain-sensing neurons.
Waxman shared with the audience that each has a slightly different kinetics of activation and firing that can be differentiated by skilled electrophysiologists using specialized tools and equipment. When a given variety of sodium channel “expresses” itself at a wrong time or the wrong place, as can happen after nerve injury, it causes havoc in the already vulnerable nervous system.
Importantly, his research team was the first to show that abnormal activity of sodium channels causes chemical changes that are harmful to the integrity of the axon and can potentially lead to death of the neuron—a point of no return, because it is damage that is permanent and irreparable.
With this knowledge, Waxman and his team designed a pharmacological approach that can protect injured neurons from more harm. This promising finding makes neuroprotection an achievable goal in people with nerve injuries.
Waxman also discussed the problem of neuropathic pain or pain due to nerve injury.
While paralysis can be seen and is widely appreciated as impacting quality of life, neuropathic pain also occurs in people with nerve injuries and poses a significant burden.
Although the sensation of pain involves a large number of players, sodium channels Nav1.3, Nav1.7, Nav1.8 and Nav1.9 stand out as being particularly important because they reset the gain in sensory neurons that signal pain. They can also be targeted with medications that do not produce dose-limiting side-effects in the brain or heart.
Studies at the center have shown injury to sensory neurons, or presence of mutant versions of Nav1.7 in such neurons, causes them to become hyper and fire pain signals when they should not. They showed that painful neuromas (tangled masses of nerves that develop after an amputation or trauma) surgically removed from patients with intractable pain after nerve injury and traumatic limb amputation show accumulation of Nav1.3, Nav1.7 and Nav1.8.
They also revealed that patients with pain disorders such as erythromelalgia, small fiber neuropathy, and paroxysmal extreme pain disorder, contain mutant forms of Nav1.7 that cause the sensory neurons in which they are present to fire abnormally and at the merest hint of provocation.
Finally, Waxman shared that his research team is engaged across international and institutional boundaries, in a multinational battle against neuropathic pain.
Collaborations with two of the largest centers, one at Peking University in China and another at University Medical Center, St. Radboud, Nijmegen, Netherlands, gives them access to precious information from rare but highly informative patients and enables them to work back and forth between the clinic and the laboratory toward discovery of better treatments for neuropathic pain.
For more information, visit medicine.yale.edu/cnrr.
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