Research on axon repair could lead to treatments in central nervous system

Traumatic brain and spinal cord injuries cause profound neurological deficits and permanent disability. Damage to the adult central nervous system (CNS) disrupts long axonal tracts, leading to severe functional impairment. Although progress has been made in understanding the cellular and molecular mechanisms underlying the pathophysiological changes that affect both structure and function after injury to the brain or spinal cord, there are currently no cures for either condition. This trend may well change with the new knowledge coming out of the lab of Andrea Tedeschi, PhD, assistant professor in the Department of Neuroscience at The Ohio State University College of Medicine.

Dr. Tedeschi has spent much of his career studying the behavioral and systemic changes that occur in response to CNS trauma, with the aim of understanding how to manipulate the self-repair mechanisms of the brain and spinal cord. His work rests on the hypothesis that combining other promising rehabilitations such as epidural stimulation with targeted long-distance axon regeneration, myelin repair and synapse formation can recover CNS functions in adults. To support the breadth of his research, Dr. Tedeschi and his team use a multidisciplinary approach that combines transcriptomics, bioinformatics, and genetic, molecular and pharmacological approaches together with in vivo time-lapse multiphoton microscopy and whole-body optical clearing.

Using early mice model studies, Dr. Tedeschi and his team clinically identified the processes that promote the structural and functional reorganization of neuronal circuits, or interconnected neurons that communicate via axons, after axonal injury. More specifically, they identified the transcriptional and epigenetic-dependent pathways that determine the regenerative response of injured neurons. This study is “taking the first step,” as he says, into what is already considered an emerging therapeutic direction: the epigenetic modulation of nuclear architecture, a treatment that promotes axon regeneration and repair after CNS trauma.

In more recent studies, they reviewed the function of Cacna2d2, a gene encoding the Alpha2delta2 subunit of voltage-gated calcium channels, which are key players in neural communication. They discovered that the encoding gene functions as a developmental switch that limits axon growth and regeneration, and that blocking Alpha2delta2 through systemic gabapentinoid administration promoted robust regeneration of sensory dorsal column axons after spinal cord injury (SCI) in adult mice. In collaboration with Wenjing Sun, PhD, research assistant professor in the Department of Neuroscience at the Ohio State College of Medicine, they recently demonstrated that the same treatment strategy boosted structural plasticity and regeneration of the corticospinal tract after cervical spinal cord injury. The corticospinal tract is one of the most important descending motor pathways that controls voluntary movement in humans.

“We now have evidence that systemic gabapentinoids administration promotes structural plasticity of corticospinal neurons and neurological recovery after stroke in mice,” says Dr. Tedeschi. “Interestingly, a multicenter, cohort study has found that SCI individuals receiving gabapentinoids have enhanced motor recovery, if they are administered within the first months after injury. Together, these exciting results set up an opportunity to repurpose gabapentinoids as a novel treatment strategy to repair the injured CNS.”

Their investigations also reveal that, after mild traumatic brain injury (TBI), slow and progressive cell injury occurs throughout the brain triggering intrinsic self-repair mechanisms. Fibrosis, synaptic remodeling, axon sprouting and angiogenesis occur over the course of days and months after injury.

“While the slow and protracted reorganization of neuronal circuits can promote recovery of function, it can also cause aberrant neuron firing that eventually culminates in the onset of post-traumatic epilepsy or stress, motor impairment, mood and anxiety disorders,” says Dr. Tedeschi.

Traumatic brain injury also increases the risk of developing neurodegenerative diseases such as dementia and parkinsonism, or CNS disorders that impair movement. The mechanisms underlying TBI-induced structural and functional changes as well as progressive neurodegeneration in the brain remain unknown.

The lab has also uncovered notable discoveries in the role cholesterol plays in axon regeneration. Their work in manipulating cholesterol metabolism and uptake suggests that lowering of cholesterol may be necessary to mount a successful regenerative response. After SCI, disruption of cellular membranes and myelin sheaths cause an excess of cholesterol to accumulate in the extracellular space. In turn, adult CNS neurons can scavenge large quantities of cholesterol after injury via receptor mediated endocytosis. Accumulating evidence suggests that an increase in membrane cholesterol contributes to axon growth and regeneration failure. Thus far, their work supports the idea that lowering cholesterol levels creates more permissive conditions for axon growth and regeneration. They are now testing whether lowering cholesterol levels through administration of FDA approved drugs promotes axon regeneration and functional recovery after CNS trauma.

Progress in understanding the post-injury changes in cortical circuits that can be manipulated for therapeutic gain is leading to the development of novel diagnostic tools and new ways to treat mild TBI pathophysiology. In collaboration with John Lannutti, PhD, professor of Materials Science and Engineering at The Ohio State University, Dr. Tedeschi and his team have recently developed a “smart” drug delivery system to counteract maladaptive plasticity and chronic neurodegeneration with spatial and temporal precision after CNS trauma. Their ultimate goal is to develop novel diagnostic tools and new ways to treat mild TBI pathophysiology as a disorder caused by a breakdown in brain homeostasis.

“Our findings suggest that it is no longer impossible to imagine a day when long-term CNS damage can be prevented using cutting-edge therapies based on transformative discoveries and scientific innovation in the field of regenerative medicine,” says Dr. Tedeschi.

The results of their deep science research offer a number of promising pathways for developing innovative treatment therapies for patients with brain and spinal cord injury as well as other neurodegenerative conditions.