Traumatic injury to the brain, spinal cord and optic nerve within the central nervous system (CNS) are the leading reason behind disability and the second leading reason behind death worldwide. CNS injuries often lead to a catastrophic lack of sensory, motor and visual functions, which is probably the most difficult problem faced by clinicians and research scientists. Neuroscientists from City University of Hong Kong (CityU) recently identified and demonstrated a small molecule that may effectively stimulate nerve regeneration and restore visual functions after optic nerve injury, offering great hope for patients with optic nerve injury, corresponding to glaucoma-related vision loss.

There’s currently no effective treatment available for traumatic injuries to the CNS, so there’s a direct need for potential drug to advertise CNS repair and ultimately achieve full function recovery, corresponding to visual function, in patients.”

Dr Eddie Ma Chi-him, Associate Head and Associate Professor within the Department of Neuroscience and Director of the Laboratory Animal Research Unit at CityU

Enhancing mitochondrial dynamics and motility is vital for successful axon regeneration

Axons, that are a cable-like structure that extends from neurons (nerve cells), are answerable for transmitting signals between neurons and from the brain to muscles and glands. Step one for successful axon regeneration is to form lively growth cones and the activation of a regrowth programme, involving the synthesis and transport of materials to regrow axons. These are all energy-demanding processes, which require the lively transport of mitochondria (the powerhouse of the cell) to injured axons on the distal end.

Injured neurons subsequently face special challenges that require long-distance transport of mitochondria from the soma (cell body) to distal regenerating axons, where axonal mitochondria in adults are mostly stationary and native energy consumption is critical for axon regeneration.

A research team led by Dr Ma identified a therapeutic small molecule, M1, which might increase the fusion and motility of mitochondria, leading to sustained, long-distance axon regeneration. Regenerated axons elicited neural activities in goal brain regions and restored visual functions inside 4 to 6 weeks after optic nerve injury in M1-treated mice.

Small molecule M1 promotes mitochondrial dynamics and sustains long-distance axon regeneration

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

To research whether M1 could promote long-distance axon regeneration after CNS injuries, the research team assessed the extent of axon regeneration in M1-treated mice 4 weeks after injury. Strikingly, a lot of the regenerating axons of M1-treated mice reached 4mm distal to the crush site (i.e. near optic chiasm), while no regenerating axons were present in vehicle-treated control mice. In M1-treated mice, the survival of retinal ganglion cells (RGCs, neurons that transmit visual stimuli from the attention to the brain) was significantly increased from 19% to 33% 4 weeks after optic nerve injury.

“This means that the M1 treatment sustains long-distance axon regeneration from the optic chiasm, i.e. midway between the eyes and goal brain region, to multiple subcortical visual targets within the brain. Regenerated axons elicit neural activities in goal brain regions and restore visual functions after M1 treatment,” Dr Ma added.

M1 treatment restores visual function

To further explore whether M1 treatment can restore visual function, the research team gave the M1-treated mice a pupillary light reflex test six weeks after the optic nerve injury. They found that the lesioned eyes of M1-treated mice restored the pupil constriction response upon blue light illumination to a level just like that of non-lesioned eyes, suggesting that M1 treatment can restore the pupil constriction response after optic nerve injuries.

As well as, the research team assessed the response of the mice to a looming stimulus – a visually induced innate defensive response to avoid predators. The mice were placed into an open chamber with a triangular prism-shaped shelter and a rapidly expanding overhead-black circle as a looming stimulus, and their freeze and escape behaviours were observed. Half of the M1-treated mice responded to the stimulus by hiding in a shelter, showing that M1 induced robust axon regeneration to reinnervate subcortical visual goal brain regions for complete recovery of their visual function.

Potential clinical application of M1 for repairing nervous system injury

The seven-year-long study highlights the potential of a 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 just by intravitreal injection into the eyes, which is a longtime medical procedure for patients, e.g. for macular degeneration treatment. Successful restoration of visual functions, corresponding to pupillary light reflex and response to looming visual stimuli was observed in M1-treated mice 4 to 6 weeks after the optic nerve had been damaged,” said Dr Au Ngan-pan, Research Associate within the Department of Neuroscience.

The team can also be developing an animal model for treating glaucoma-related vision loss using M1 and possibly other common eye diseases and vision impairments corresponding to diabetes-related retinopathy, macular degeneration and traumatic optic neuropathy. Thus, further investigation is warranted to judge the potential clinical application of M1. “This research breakthrough heralds a recent approach that might address unmet medical needs in accelerating functional recovery inside a limited therapeutic time window after CNS injuries,” said Dr Ma.

The findings were published within the international scientific journal Proceedings of the National Academy of Sciences (PNAS), under the title “A small molecule M1 promotes optic nerve regeneration to revive target-specific neural activity and visual function”.

Dr Au and Dr Ma are the primary creator and corresponding creator, respectively, of the paper. One other collaborator is Dr Vincent Ko Chi-chiu, Associate Professor within the Department of Chemistry at CityU. The research was funded by CityU and the Research Grants Council of Hong Kong.

Source:

City University of Hong Kong

Journal reference:

Au, N.P.B., et al. (2022) A small molecule M1 promotes optic nerve regeneration to revive target-specific neural activity and visual function. PNAS. doi.org/10.1073/pnas.2121273119.