Traumatic injuries to the brain, spinal cord and optic nerve of the central nervous system (CNS) are the leading cause of disability and the second leading cause of death worldwide. CNS damage often results in catastrophic loss of sensory, motor, and visual function, which is the most difficult problem facing clinicians and researchers. Neuroscientists from the City University of Hong Kong (CityU) have recently identified and demonstrated a small molecule that can effectively stimulate nerve regeneration and restore visual functions following optic nerve damage, offering great hope to patients suffering from nerve damage. optic nerve, such as glaucoma-related vision loss.
“There is currently no effective treatment available for traumatic CNS injuries, so there is an immediate need for a potential drug to promote CNS repair and ultimately achieve full recovery of functions, such as visual function, in patients,” said Dr. Eddie Ma Chi-lui, Associate Chief and Associate Professor in the Department of Neuroscience and Director of the Laboratory Animal Research Unit at CityU, who led the research.
Improved mitochondrial dynamics and motility is key to successful axon regeneration
Axons, which are a cable-like structure that extends from neurons (nerve cells), are responsible for transmitting signals between neurons and from the brain to muscles and glands. The first step in successful axon regeneration is to form active growth cones and activate a regrowth program, involving the synthesis and transport of materials to regrow axons. These are all energy-demanding processes, requiring active transport from mitochondria (the powerhouse of the cell) to injured axons at the distal end.
Injured neurons therefore face special challenges that require long-range transport from mitochondria in the soma (cell body) to distal regenerating axons, where axonal mitochondria in adults are mostly stationary and local energy consumption is essential for the regeneration of axons.
A research team led by Dr. Ma has identified a small molecule therapeutic, M1, that can increase mitochondrial fusion and motility, resulting in sustained long-distance axon regeneration. The regenerated axons triggered neuronal activities in target brain regions and restored visual functions within four to six weeks following optic nerve injury in M1-treated mice.
Small molecule M1 promotes mitochondrial dynamics and supports long-distance axon regeneration
“Photoreceptors in the eyes [retina] transmit visual information to the neurons of the retina. To facilitate the recovery of visual function following injury, neuron axons must regenerate via the optic nerve and relay nerve impulses to visual targets in the brain via the optic nerve for image processing and formation,” explained Dr. Ma.
To determine whether M1 might promote long-range axon regeneration following CNS injury, the research team assessed the extent of axon regeneration in M1-treated mice four weeks following injury. Strikingly, most regenerating axons from M1-treated mice reached 4 mm distal to the crush site (i.e., near the optic chiasm), whereas no regenerating axons reached was found in vehicle-treated control mice. In M1-treated mice, the survival of retinal ganglion cells (RGCs, neurons that transmit visual stimuli from the eye to the brain) was significantly increased from 19% to 33% four weeks following optic nerve injury.
“This indicates that M1 treatment supports the regeneration of long-distance axons from the optic chiasm, i.e. midway between the eyes and the target brain region, to multiple subcortical visual targets in the brain. . The regenerated axons elicit neural activities in target brain regions and restore visual functions following M1 treatment,” Dr. Ma added.
M1 treatment restores visual function
To further explore whether M1 treatment can restore visual function, the research team had M1-treated mice undergo a pupillary light reflex test six weeks following optic nerve injury. They found that injured eyes of M1-treated mice restored the pupil constriction response to blue light illumination at a similar level to uninjured eyes, suggesting that M1 treatment can restore the pupil constriction response to blue light illumination. Pupil constriction response following optic nerve damage.
Additionally, the research team assessed the mice’s response to an impending stimulus – a visually induced innate defensive response to avoid predators. The mice were placed in an open chamber with a triangular prism-shaped shelter and a rapidly expanding black circle as the impending stimulus, and their freezing and escape behaviors were observed. Half of the M1-treated mice responded to the stimulus by hiding in shelter, showing that M1 induced robust axon regeneration to re-innervate subcortical visual target brain regions for full recovery of their visual function.
Potential clinical application of M1 to repair nervous system damage
The seven-year study highlights the potential of a readily available, non-viral therapy for CNS repair, which builds on the team’s previous research on regenerating peripheral nerves using the therapy gene.
“This time, we used the small molecule, M1, to repair the CNS simply by intravitreal injection into the eyes, which is an established medical procedure for patients, for example for the treatment of macular degeneration. Successful restoration of visual functions, such as pupillary light reflex and response to impending visual stimuli was observed in M1-treated mice four to six weeks following optic nerve damage,” said Dr. Au Ngan-pan, research associate in the Department of Neuroscience.
The team is also developing an animal model to treat glaucoma-related vision loss using M1 and possibly other common eye diseases and visual impairments such as diabetes-related retinopathy, macular degeneration and traumatic optic neuropathy. . Thus, further investigation is warranted to assess the potential clinical application of M1. “This research breakthrough heralds a new approach that might address unmet medical needs by accelerating functional recovery within a limited therapeutic window of time following CNS damage,” Dr. Ma said.