Scientists find molecule that may protect nerve cells in SMA
10H-phenothiazine stems loss of motor neurons in animal models
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- A small molecule, 10H-phenothiazine (PTZ), may lessen motor neuron loss.
- PTZ improved nerve cell structure and communication in SMA models.
- Further studies in mammalian models are needed, researchers said.
A small molecule known as 10H-phenothiazine (PTZ) reduced the loss of motor neurons, the nerve cells lost in spinal muscular atrophy (SMA), in animal models of the disease.
The treatment also rescued SMA-related changes in the structure of nerve cells, according to a study. In a mouse model, it increased the number and branching of neurites, which are projections from the cell body that allow neurons to communicate.
“Overall, our results provide valuable insights, both in vitro and in vivo, into the potential of 10H-PTZ repurposing for SMA, although additional functional studies will be required,” the researchers wrote.
The study, “10H-phenothiazine exerts beneficial effects in spinal muscular atrophy in vitro and in vivo models,” was published in Scientific Reports.
SMA is caused in most cases by mutations in the SMN1 gene that result in low levels of SMN protein, which is key to the health of motor neurons, specialized nerve cells that control movement. Without enough functional SMN, motor neurons progressively die, leading to muscle weakness and other SMA symptoms.
Protecting nerve cells
Current SMA treatments aim to increase SMN protein levels. They have been largely effective, particularly when administered early in the disease course. However, their efficacy decreases as the disease progresses, and they do not enable fine-tuning of SMN production, which in some cases may have toxic effects.
“Therefore, identifying combinatorial treatments that, in association with the SMN-dependent therapies, could delay [motor neuron] degeneration by targeting other molecular pathways … known to be altered in SMA, may represent a pivotal therapeutic strategy,” the scientists wrote.
The team, in Italy, investigated the effects of 10H-PTZ, which has been shown to protect neurons in Parkinson’s disease and Alzheimer’s disease.
First, they looked into cortical neurons of the brain (those from its outermost layer). Nerve cells derived from an SMA mouse model showed signs of neurodegeneration, including reduced survival, smaller cell bodies, and both smaller and fewer branching of neurites, a process needed to create complex networks for nerve cell communication.
“Our results indicate that primary cortical neurons from SMA mice show evident phenotypic defects compared to [control] cells, supporting their use as a reliable in vitro model for a preliminary therapeutic screening in SMA,” the team wrote.
They validated the cell model using three drugs previously tested in the SMA context: valproic acid, 4-aminopyridine, and N-acetylcysteine. All treatments improved the survival of SMA neurons and increased their cell body, neurite length, and branching. Similar effects were seen when neurons were treated with a low concentration (10 nanomolar) of 10H-PTZ.
All treatments also increased synapsin distribution along neurites, which was retained close to the cellular bodies in SMA neurons. Synapsin is a protein present at synapses, the sites where nerve cells communicate by releasing chemical molecules known as neurotransmitters.
“This indicates that the treatment is stimulating the expression of one of the major integral membrane proteins of synaptic vesicles, synapsin 1, involved in neurotransmitters’ release,” the researchers wrote.
Next, the scientists investigated the potential of 10H-PTZ for reducing motor neuron loss in a worm (Caenorhabditis elegans) model of SMA. Results showed that 10H-PTZ exerted a protective effect similar to that of N-acetylcysteine.
“Thus, we can conclude that 10H-PTZ exerts a neuroprotective effect in a SMA C. elegans models, consistent with the other beneficial effects obtained on cortical neurons,” the scientists wrote.
Taken together, “these findings may represent valuable insight into the potential neuroprotective role of 10H-PTZ in SMA,” the researchers concluded. However, they added, “functional tests to measure how 10H-PTZ affects biological and physiological processes in mammalian models for SMA are essential to support its use for SMA patients.”
