Researchers from the Ohio State University College of Medicine have discovered in mice that conditions such as diabetes and vascular diseases commonly diagnosed in people with spinal cord injuries, can be linked to abnormal post-injury neuronal activity that causes abdominal fat tissue compounds to leak and pool in the liver and other organs.

The researchers also discovered that a short course of the drug gabapentin prevented the damaging metabolic effects of the spinal cord injury.

Their findings are published in Cell Reports Medicine in an article titled, “α2δ1-mediated maladaptive sensory plasticity disrupts adipose tissue homeostasis following spinal cord injury.”

“Spinal cord injury (SCI) increases the risk of cardiometabolic disorders, including hypertension, dyslipidemia, and insulin resistance,” the researchers noted. “Not only does SCI lead to pathological expansion of adipose tissue, but it also leads to ectopic lipid accumulation in organs integral to glucose and insulin metabolism. The pathophysiological changes that underlie adipose tissue dysfunction after SCI are unknown. Here, we find that SCI exacerbates lipolysis in epididymal white adipose tissue (eWAT).”

“We believe there is maladaptive reorganization of the sensory system that causes the fat to undergo changes, initiating a chain of reactions—triglycerides start breaking down into glycerol and free fatty acids that are released in circulation and taken up by the liver, the heart, the muscles, and accumulating, setting up conditions for insulin resistance,” said senior author Andrea Tedeschi, PhD, assistant professor of neuroscience in the Ohio State University College of Medicine. “Through administration of gabapentin, we were able to normalize metabolic function.”

Previous research has found that cardiometabolic diseases are among the leading causes of death in people who have experienced a spinal cord injury. Earlier investigations of these diseases in people with neuronal damage have focused on adipose tissue function and the role of the sympathetic nervous system.

Debasish Roy, PhD, a postdoctoral researcher in the Tedeschi lab and first author on the paper, decided to focus on sensory neurons in this context. Tedeschi and colleagues have previously shown that a neuronal receptor protein called alpha2delta1 is overexpressed after spinal cord injury, and its increased activation interferes with post-injury function of axons, the long, slender extensions of nerve cell bodies that transmit messages.

In this new work, researchers first observed how sensory neurons connect to adipose tissue under healthy conditions, and created a spinal cord injury mouse model that affected only those neurons.

Experiments revealed abnormal activity within seven days after the injury in neurons—though only in their communication function, not their regrowth or structure—and in visceral fat tissue.

Expression of the alpha2delta1 receptor in sensory neurons increased as they over-secreted a neuropeptide called CGRP, all while communicating through synaptic transmission to the fat tissue—which, in a state of dysregulation, drove up levels of a receptor protein that engaged with the CGRP.

“These are quite rapid changes. As soon as we disrupt sensory processing as a result of spinal cord injury, we see changes in the fat,” Tedeschi said. “A vicious cycle is established—it’s almost like you’re pressing the gas pedal so your car can run out of gas but someone else continues to refill the tank, so it never runs out.”

The result is the spillover of free fatty acids and glycerol from fat tissue, a process called lipolysis, that has gone out of control. Results also showed an increase in blood flow in fat tissue and recruitment of immune cells to the environment.

“The fat is responding to the presence of CGRP, and it’s activating lipolysis,” Tedeschi said. “CGRP is also a potent vasodilator, and we saw increased vascularization of the fat—new blood vessels forming as a result of the spinal cord injury. And the recruitment of monocytes can help set up a chronic pro-inflammatory state.”

Silencing the genes that encode the alpha2delta1 receptor restored the fat tissue to normal function, indicating that gabapentin—which targets alpha2delta1 and its partner, alpha2delta2—was a good treatment candidate.

Tedeschi’s lab has previously shown in animal studies that gabapentin helped restore limb function after spinal cord injury and boosted functional recovery after stroke. However, in these experiments, Roy discovered something tricky about gabapentin: The drug prevented changes in abdominal fat tissue and lowered CGRP in the blood—and in turn prevented spillover of fatty acids into the liver a month later, establishing normal metabolic conditions. But paradoxically, the mice developed insulin resistance—a known side effect of gabapentin.

The team changed drug delivery tactics, starting with a high dose and tapering off—and stopping after four weeks.

“This way, we were able to normalize metabolism to a condition much more similar to control mice,” Roy said. “This suggests that as we discontinue administration of the drug, we retain beneficial action and prevent spillover of lipids in the liver. That was really exciting.”

The team of researchers then observed how genes known to regulate white fat tissue were affected by targeting alpha2delta1 genetically or with gabapentin, and found both of these interventions after spinal cord injury suppress genes responsible for disrupting metabolic functions.

The combined findings suggest starting gabapentin treatment early after a spinal cord injury may protect against detrimental conditions involving fat tissue that lead to cardiometabolic disease—and could enable discontinuing the drug while retaining its benefits and lowering the risk for side effects.

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