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 lesions often result in a catastrophic loss of sensory, motor, and visual functions, which is the most challenging problem facing physicians and research scientists. 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 functions after optic nerve injury, offering great hope for patients with optic nerve injury, such as glaucoma-related vision loss.
“There is currently no effective treatment available for traumatic CNS injury, so there is an immediate need for a potential drug to promote CNS repair and ultimately achieve full recovery of function, such as visual function. , in patients,” said Dr. Eddie Ma Chi-he, Associate Chair 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 axonal 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 for successful axonal regeneration is the formation of active growth cones and the activation of a regeneration program, which involves the synthesis and transport of materials to regenerate axons. These are all energy-demanding processes, requiring active transport from mitochondria (the powerhouse of the cell) to injured axons at the distal end.
Thus, injured neurons face special challenges requiring long-distance transport of mitochondria from the soma (cell body) to distal regenerating axons, where axonal mitochondria in adults are mostly stationary and local energy consumption. it is critical for axon regeneration.
A research team led by Dr. Ma identified a small therapeutic molecule, M1, that can increase mitochondrial fusion and motility, resulting in long-distance sustained axonal regeneration. The regenerated axons elicited neural activities in the targeted brain regions and restored visual functions within four to six weeks of optic nerve injury in M1-treated mice.
M1 small molecule promotes mitochondrial dynamics and sustains long-distance axon regeneration
“Photoreceptors in the eyes [retina] sends visual information to neurons in the retina. To facilitate recovery of visual function after injury, the axons of neurons must regenerate via the optic nerve and transmit nerve impulses to visual targets in the brain via the optic nerve for imaging and processing.” explained Dr. Ma.
To investigate whether M1 could promote long-distance axon regeneration after CNS injury, the research team evaluated the degree of axon regeneration in M1-treated mice four weeks after injury. Surprisingly, the majority of regenerating axons from M1-treated mice reached 4 mm distal to the crush site (ie, near the optic chiasm), whereas no regenerating axons were found in vehicle-treated control mice. In M1-treated mice, retinal ganglion cell (RGC, neurons that transmit visual stimuli from the eye to the brain) survival increased significantly from 19% to 33% four weeks after optic nerve injury.
“This indicates that M1 treatment maintains long-distance axon regeneration from the optic chiasm, i.e., halfway between the eyes and the target brain region, to multiple subcortical visual targets in the brain. The regenerated axons cause neural activities in the targeted brain regions and restore visual functions after M1 treatment,” added Dr. Ma.
M1 treatment restores visual function
To further explore whether M1 treatment can restore visual function, the research team subjected M1-treated mice to a pupillary light reflex test six weeks after optic nerve injury. They found that the injured eyes of M1-treated mice restored the pupil constriction response upon blue light illumination to a level similar to that of uninjured eyes, suggesting that M1 treatment can restore the constriction response. of the pupil after optic nerve lesions.
In addition, the research team tested the mice’s response to an impending stimulus: a visually induced innate defensive response to avoid predators. Mice were placed in an open chamber with a triangular prism-shaped shelter and a rapidly expanding black circle on top as an impending 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 subcortical visual target brain regions for full recovery of their visual function.
Possible clinical application of M1 to repair nervous system injuries
The seven-year study highlights the potential of a readily available non-viral therapy for CNS repair, building 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 an established medical procedure for patients, for example, for the treatment of macular degeneration. Successful restoration of visual functions , such as the pupillary light reflex and a response to impending visual stimuli were observed in M1-treated mice four to six weeks after the optic nerve was damaged,” said Dr. Au Ngan-pan, a research associate at 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. Therefore, further research is warranted to evaluate the possible clinical application of M1. “This research breakthrough heralds a new approach that could address unmet medical needs to accelerate functional recovery within a limited therapeutic time frame after CNS lesions,” said Dr. Ma.