Neuroscientists identify a small molecule that restores visual function after optic nerve injury – ScienceDaily

Neuroscientists identify a small molecule that restores visual function after optic nerve injury – ScienceDaily

Traumatic injuries to the brain, spinal cord, and optic nerve in the central nervous system (CNS) are the leading cause of disability and the second leading cause of death worldwide. CNS injuries often result in catastrophic loss of sensory, motor, and visual functions, which is the biggest problem facing clinicians and researchers. Neuroscientists at the City University of Hong Kong (CityU) recently identified and demonstrated a small molecule that can effectively stimulate nerve regeneration and restore visual function after optic nerve injury, offering great hope for patients with optic nerve injuries such as glaucoma-related vision loss.

“There is currently no effective treatment for CNS traumatic injury, so there is an immediate need for potential drugs to promote CNS repair and ultimately restore full function, such as visual function, in patients,” said Dr. Eddie Ma Chi-him, associate director and associate professor in the Department of Neuroscience and director of the Laboratory Animal Research Unit at CityU, who led the research.

Improving mitochondrial dynamics and motility is key to successful axon regeneration

Axons, 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 for successful axon regeneration is the formation of active growth cones and the activation of a regrowth program that involves the synthesis and transport of axon regrowth materials. All of these are energy-consuming processes that require active transport of mitochondria (the cell’s powerhouses) to injured axons at the distal end.

Injured neurons therefore face unique challenges that require long-distance transport of mitochondria from the soma (cell body) to distal regenerating axons, where axonal mitochondria are mostly stationary in adults and local energy expenditure is crucial for axon regeneration.

A research team led by Dr. Ma identified a therapeutic small molecule, M1, that can increase mitochondrial fusion and motility, resulting in sustained long-distance axon regeneration. Regenerated axons elicited neuronal activity in target brain regions and restored visual functions within four to six weeks after optic nerve injury in M1-treated mice.

The small molecule M1 promotes mitochondrial dynamics and supports long-distance axon regeneration

“Photoreceptors in the eyes [retina] transmit visual information to neurons in the retina. To facilitate the recovery of visual function after injury, the axons of neurons through the optic nerve must regenerate and relay nerve impulses through the optic nerve to visual targets in the brain for image processing and formation,” explained Dr. Ma.

To investigate whether M1 could promote long-distance axon regeneration after CNS injury, the research team measured the extent of axon regeneration in M1-treated mice four weeks after injury. Notably, most of the regenerating axons from M1-treated mice reached 4 mm distal to the crush site (ie, near the optic chiasm), while no regenerating axons were found in vehicle-treated control mice. In mice treated with M1, 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 after optic nerve injury.

“This indicates that M1 treatment sustains axon regeneration over long distances from the optic chiasm, i.e. midway between the eyes and the target region of the brain, to multiple subcortical visual targets in the brain. Regenerated axons trigger neural activity in target brain regions and restore visual function after M1 treatment,” added Dr. Ma.

M1 treatment restores visual function

To further investigate whether M1 treatment can restore visual function, the research team subjected the M1-treated mice to a pupillary light reflex test six weeks after the optic nerve injury. They found that the injured eyes of M1-treated mice restored the pupillary constriction response to blue light illumination to levels similar to eyes without lesions, suggesting that M1 treatment can restore the pupillary constriction response after optic nerve injury .

In addition, the research team assessed the mice’s response to a threatening stimulus – a visually induced innate defense response to evade predators. The mice were placed in an open chamber with a triangular prism-shaped shelter and a rapidly expanding black circle as a threatening stimulus, and their freezing and escape behaviors were observed. Half of the M1-treated mice responded to the stimulus by hiding in a shelter, demonstrating that M1 induced robust axon regeneration to reinnervate target subcortical visual brain regions for full recovery of their visual function.

Potential clinical application of M1 to repair nervous system injuries

The seven-year study underscores the potential of a readily available, non-viral CNS repair therapy that builds on the team’s previous research on peripheral nerve regeneration using gene therapy.

“This time we used the small molecule M1 to repair the CNS simply by intravitreal injection into the eyes, which is a well-established medical procedure for patients, e.g. For example, to treat macular degeneration, four to six weeks after optic nerve damage, a response to emerging visual stimuli was observed in M1-treated mice,” 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 with M1 and potentially other common eye diseases and vision disorders such as diabetes-related retinopathy, macular degeneration and traumatic optic neuropathy. Therefore, further research is warranted to evaluate the potential clinical application of M1. “This research breakthrough heralds a new approach that could address unmet medical needs by accelerating functional recovery within a limited therapeutic window after CNS injury,” said Dr. mom

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