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 a catastrophic loss of sensory, motor and visual functions, which is the most challenging problem faced by clinicians and research scientists. Neuroscientists from City University of Hong Kong (CityU) have 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 loss of vision. vision related to glaucoma.
“Currently, there is 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 function, such as visual function, in patients” , said Dr. he, Associate Head and Associate Professor in the Department of Neuroscience and Director of CityU’s Laboratory Animal Research Unit, who led the research.
Improving mitochondrial dynamics and motility is the key to successful axon regeneration
Axons, which are a cable-like structure extending from neurons (nerve cells), are responsible for transmitting signals between neurons and the brain to muscles and glands. The first step to successful axonal regeneration is to form active growth cones and activate a regeneration program, involving the synthesis and transport of materials to regenerate the axons. These are all energy-demanding processes that require active transport from the mitochondria (the cell’s powerhouse) to the damaged axons at the far end.
Injured neurons therefore face special challenges requiring long-distance transport from mitochondria from the soma (cell body) to distal regenerating axons, where axonal mitochondria in adults are mostly stationary and local energy consumption is critical for regeneration. of the axon.
A research team led by Dr. Ma has identified a therapeutic small molecule, M1, that can increase mitochondrial fusion and motility, resulting in sustained, long-distance axonal regeneration. The regenerated axons elicited neural activity in targeted brain regions and restored visual functions within four to six weeks after optic nerve injury in M1-treated mice.
The M1 small molecule promotes mitochondrial dynamics and supports long-distance axonal regeneration
“Photoreceptors in the eyes [retina] transmit visual information to neurons in the retina. To facilitate recovery of visual function after injury, axons of neurons 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 investigate whether M1 could promote long-distance axonal regeneration after CNS injury, the research team evaluated the extent of axonal regeneration in mice treated with M1 four weeks after injury. Surprisingly, the majority of regenerating axons from M1-treated mice reached 4 mm distal to the crush site (i.e., near the optic chiasm), whereas 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) increased significantly from 19% to 33% four weeks after optic nerve damage.
“This indicates that the M1 treatment sustains long-distance axonal regeneration from the optic chiasm, ie midway between the eyes and the target brain region, to multiple subcortical visual targets in the brain. The regenerated axons elicit neural activity in the regions target brain cells and restore visual function after M1 treatment,” added Dr. Bad.
M1 treatment restores visual function
To further explore whether M1 treatment can restore visual function, the research team gave M1-treated mice a pupillary light reflex test six weeks after optic nerve injury. They found that injured eyes of M1-treated mice restored the pupillary constriction response after illumination with blue light to a similar level as that of uninjured eyes, suggesting that treatment with M1 can restore the pupillary constriction response after injury to the pupil. optic nerve.
In addition, the research team assessed 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 as an impending stimulus, and their freezing and flight behaviors were observed. Half of the mice treated with M1 responded to the stimulus by hiding in a shelter, showing that M1 induced a robust regeneration of axons to reinnervate visual subcortical regions of the brain for the complete recovery of their visual function.
Potential 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, which 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 an established medical procedure for patients, for example, to treat macular degeneration. Successful restoration of visual functions, such as reflex pupillary light and response to imminent visual stimuli was observed in mice treated with M1 four to six weeks after the optic nerve was damaged,” 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 vision impairments such as diabetes-related retinopathy, macular degeneration, and traumatic optic neuropathy. Thus, further investigations are needed to assess the potential clinical application of M1. “This research breakthrough heralds a new approach that may address unmet medical needs in accelerating functional recovery within a limited therapeutic time window after CNS injuries,” said Dr. Bad.