The chicken and the egg question exemplifies many scientific dilemmas, and the origin of the neurological disease multiple sclerosis (MS) is no exception. Scientists typically thought of MS as a disorder that starts when the immune system attacks myelin, the protective coating surrounding neuronal fibers that facilitates communication between neurons (1). Other scientists have proposed that myelin damage occurs first, triggering an immune reaction that further affects brain cells. Whatever the initiating event, protecting neurons might curb MS progression and mitigate disabling symptoms such as muscle weakness and paralysis.
In a study published in Science Advances, Fang Liu, neuroscientist at the Center for Addiction and Mental Health (CAMH), and her team described a small molecule that aims to protect neurons by targeting glutamate receptors known as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (2). The authors showed that the drug had therapeutic effects in two different mouse models of MS, demonstrating potential for further drug development.
The beauty of this project is that our drug can block glutamate induced toxicity but not glutamate-mediated neurotransmission.
- Fang Liu, CAMH
AMPA receptors are important for learning and memory in the healthy brain (3). However, during neurodegenerative diseases like MS, excess glutamate leads to too much AMPA receptor activity, which causes an influx of calcium ions into neurons and cell death (4).
Given the role of AMPA receptors in normal brain function, “A lot of open channel blockers for AMPA receptors have failed,” said Tara DeSilva, a demyelinating disease researcher at the Cleveland Clinic who was not associated with the study. “The fact that [the study authors] made a small molecule that is efficacious is an important finding.”
Liu’s team used an AI-driven method to identify a candidate small molecule, ZCAN262, that binds to an allosteric site on a specific subunit of the AMPA receptor. The researchers conducted electrophysiological recordings to examine the effects of ZCAN262 on glutamate-driven synaptic transmission and found that ZCAN262 did not significantly affect basic signaling mechanisms or measures of recognition memory and spatial learning in live mice. “The beauty of this project is that our drug can block glutamate-induced toxicity but not glutamate-mediated neurotransmission,” said Liu.
ZCAN262 significantly improved mobility and motor function in the experimental autoimmune encephalomyelitis mouse model of MS. The researchers also tried their compound in a MS mouse model that uses cuprizone, a copper chelator that causes loss of myelin and the characteristic symptoms of MS.
Mice with cuprizone-induced demyelination had an almost complete restoration of their myelin after treatment with ZCAN262. This small compound also increased the numbers of myelin-producing oligodendrocytes in the demyelinated animals compared to the cuprizone mice that received no treatment.
The myelin restoration effect is important since protecting myelin benefits neurons, and the underlying inflammation that occurs in MS further amplifies myelin damage. However, it’s unclear whether ZCAN262 provides direct protection to myelin, neurons, or myelin-producing oligodendrocytes. Whatever the mechanism, patients will benefit from new therapies that mitigate the neurodegeneration that inflammation causes. “Most of the drugs currently in clinical use target the immune system,” said Liu. “A significant number of patients are not responsive to current treatments, so a new drug is desperately needed.”
- Luchicchi, A., Preziosa, P., & ‘t Hart, B. Editorial: "inside-out" vs "outside-in" paradigms in multiple sclerosis etiopathogenesis. Front Cell Neurosci 15, 666529 (2021).
- Zhai, D. et al. Small-molecule targeting AMPA-mediated excitotoxicity has therapeutic effects in mouse models for multiple sclerosis. Science Advances 9, eadj6187 (2023).
- Pereyra, M. and Medina, J.H. AMPA receptors: a key piece in the puzzle of memory retrieval. Front Hum Neurosci 15, 729051 (2021).
- Stojanovic, I.R., Kostic, M., Ljubisavljevic, S. The role of glutamate and its receptors in multiple sclerosis. J Neural Transm 121, 945-955 (2014).