Drug helps sensory neurons regrow in the mouse central nervous system
Targeting support cells with cholesterol drug could improve recovery
after spinal cord injury

Date:
October 19, 2021
Source:
Washington University School of Medicine
Summary:
Researchers have discovered that an FDA-approved drug acts on
support cells in the central nervous system to encourage sensory
neurons to regrow after injury.



FULL STORY ==========================================================================
A spinal cord injury damages the lines of communication between the body
and brain, impeding the signals that drive movement and sensation. Injured motor and sensory neurons in the central nervous system -- the brain and
spinal cord -- have limited ability to heal, so people who survive such injuries can be left with chronic paralysis, numbness and pain.


========================================================================== Researchers at Washington University School of Medicine in St. Louis
have identified a drug that helps sensory neurons in the central nervous
system heal. Neurons are surrounded by support cells that protect and
nurture them. In this study, the researchers gave mice with injured
sensory neurons a drug called fenofibrate that is approved by the Food
and Drug Administration to treat high cholesterol. The drug activated the support cells surrounding sensory neurons and helped them regrow about
twice as fast as sensory neurons in mice that received a placebo. The
study is available online in eLife.

"When people think of spinal cord injury, they tend to think of paralysis,
but there are a lot of problems with sensory processing and pain after
spinal cord injury as well," said senior author Valeria Cavalli, PhD,
the Robert E. and Louise F. Dunn Professor of Biomedical Research and
a professor of neuroscience. "Addressing those sensory issues could
go a long way toward improving quality of life for survivors. Our data
indicate that fenofibrate has the potential to activate these support
cells and improve recovery, which means we could potentially repurpose
this FDA-approved compound to help restore sensory function after nerve injuries." Unlike neurons in the brain or spinal cord, sensory nerves
in the periphery of the body heal after injury, which is why a gash on
your leg doesn't leave part of your leg permanently numb. To understand
why regeneration occurs in the peripheral but not the central nervous
system, Cavalli studies a unique cell type that spans both systems:
sensory neurons of the dorsal root ganglia. The cell bodies of such
neurons bundle together into a structure known as a ganglion that sits
just outside the spinal cord. A long, thin arm called an axon branches
out from each cell body in opposite directions, with one branch heading
into the central nervous system via the spinal cord and the other becoming
part of the peripheral nervous system as it descends into the body.

Despite being two parts of the same cell, the peripheral and central
axonal branches do not respond identically after injury. The peripheral
parts regrow and recover much faster and more completely than the
central ones.

Cavalli and first author Oshri Avraham, PhD, a staff scientist, suspected
that the differences in regeneration between the two branches may come
down to differences between the behavior of support cells in response
to injury to the central versus peripheral axon branches.

To investigate that possibility, the researchers compared gene expression
in five kinds of support cells in the ganglion, after injury to the
peripheral and central branches of the sensory neuron. They found that
the patterns of gene expression in the support cells differed depending on which part of the neuron they injured. Most notably, so-called satellite
glial cells ramped up expression of a set of genes known as the PPAR-alpha pathway -- famous for its role in fat metabolism -- only after injury in
the peripheral axon branch. The pathway was not turned up after injury
to central axonal branches, and was actually dialed down after spinal
cord injury in the central nervous system.

To Cavalli and Avraham, this observation suggested that the PPAR-alpha
pathway may promote regeneration. To find out, they fed mice fenofibrate
-- a drug that activates PPAR alpha -- for two weeks before injuring the
mice's sensory axon branch heading into the central nervous system. Three
days after the injury, the central branches of the sensory neuron axons
had regrown about twice as much in the mice that had received fenofibrate
than in those that had received a placebo.

"PPAR alpha is only expressed in satellite glial cells, not in neurons,
so these results tell us that targeting these support cells can improve regeneration and potentially relieve sensory symptoms like pain,"
Cavalli said.

"It gives us an additional tool to design therapies to restore function
after nerve injuries. We haven't fixed spinal cord injury, but we're one
step closer to figuring out how to do it." Cavalli and colleagues are
now planning experiments to combine fenofibrate with other experimental regeneration-promoting therapies targeting neurons or other aspects of
the central nervous system to further enhance regeneration.

========================================================================== Story Source: Materials provided by
Washington_University_School_of_Medicine. Original written by Tamara
Bhandari. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Oshri Avraham, Rui Feng, Eric Edward Ewan, Justin Rustenhoven,
Guoyan
Zhao, Valeria Cavalli. Profiling sensory neuron microenvironment
after peripheral and central axon injury reveals key pathways for
neural repair. eLife, 2021; 10 DOI: 10.7554/eLife.68457 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211019120123.htm

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