Migraine drug may protect motor neurons in SMA: Mouse study
Study shows flunarizine reverses abnormal microRNA patterns
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The migraine medication flunarizine may help protect nerve cells in spinal muscular atrophy (SMA) by correcting abnormal levels of microRNA, small molecules that help regulate gene activity.
Researchers identified widespread microRNA abnormalities in cells and in the spinal cords of SMA mice, particularly at the earliest stages of disease. They also found that flunarizine reversed many of these changes and identified a microRNA called miR-128-3p as a potential contributor to the drug’s previously reported neuroprotective effects.
The study, “Flunarizine changes microRNA expression in cell cultures and in a mouse model of spinal muscular atrophy,” was published in Scientific Reports.
SMA is caused mainly by mutations in the SMN1 gene that leave the body unable to produce enough SMN protein. As a result, motor neurons — the specialized nerve cells that control movement — gradually become damaged and die, leading to SMA symptoms such as muscle weakness and wasting, fatigue, and breathing difficulties.
In recent years, therapies designed to boost SMN protein levels have transformed the outlook for many people with SMA, helping to improve motor function and extend survival. Still, “their variable effect on motor function underscores the need for a better understanding of disease mechanisms,” the researchers wrote.
Looking at microRNAs
One area of growing interest involves microRNAs. Studies have shown that levels of several microRNAs are altered in SMA, and some have been linked to motor neuron survival, nerve growth, and disease severity. However, exactly how these changes contribute to SMA remains unclear.
In an effort to identify potential add-on therapies for SMA, the researchers previously screened approved drugs and found that flunarizine produced a range of beneficial effects in SMA mouse models. Treatment improved survival, protected motor neurons, and preserved nerve-muscle connections. However, the mechanisms behind its neuroprotective effects remained largely unknown.
The team of researchers in France set out to investigate whether flunarizine could alter microRNA activity and whether such changes might help explain some of the drug’s benefits in SMA.
They began by analyzing fibroblasts, cells that help provide structural support to tissues throughout the body, derived from a person with severe SMA. After finding that flunarizine altered the expression of multiple microRNAs, the researchers took a closer look at 30 selected microRNAs in both SMA and non-SMA cells.
The analysis identified 15 microRNAs whose levels differed substantially between SMA and non-SMA cells. Some, including miR-146a-5p, were elevated in SMA cells, while others, such as miR-128-3p, were reduced. Eleven of these dysregulated microRNAs had previously been linked to SMA, while four — including miR-128-3p — had not been previously associated with the disease.
Flunarizine also altered the expression of several microRNAs, with the drug generally having a stronger effect in SMA cells than in non-SMA cells.
Because flunarizine altered microRNA expression in SMA fibroblasts, the researchers wondered whether it could have similar effects in nerve cells. Using a mouse-derived cell model with motor neuron-like properties, they found that the drug altered the expression of several of the same microRNAs examined in SMA fibroblasts, including miR-128-3p, whose levels significantly increased after treatment.
Because flunarizine is known to promote neurite outgrowth, the growth of the branch-like extensions that neurons use to communicate with other cells, the team then investigated whether any of the affected microRNAs might contribute to this effect.
Several microRNAs influenced neurite growth. However, miR-128-3p stood out because blocking it significantly shortened neurites. In addition, reducing miR-128-3p levels weakened flunarizine’s ability to promote neurite outgrowth in the motor neuron-like cells, suggesting the microRNA might play a role in the drug mechanism.
Seeking to understand how miR-128-3p exerts these effects, the team searched for genes it might regulate and identified Hipk2 as a likely target. Hipk2 had previously been shown to increase in response to flunarizine and is known to play important roles in neuronal survival and motor neuron biology.
Additional experiments showed that increasing miR-128-3p reduced levels of Hipk2 messenger RNA (mRNA), the genetic blueprint cells use to make a protein. Blocking the microRNA increased them, consistent with Hipk2 behaving as a direct target of miR-128-3p.
The researchers then turned to SMA mice and found widespread microRNA abnormalities, particularly in the spinal cord during the earliest stages of disease. Treatment with flunarizine reversed many of these changes, shifting microRNA levels toward a more normal pattern. The drug also affected Hipk2 gene activity in the spinal cord, though its effects varied with sex and disease status.
Overall, the findings suggest that abnormal microRNA activity may be an early feature of SMA and that flunarizine can normalize many of these changes. The researchers said further studies of “specific microRNA-mRNA interactions may facilitate the identification of novel therapeutic targets to develop adjunct therapies” aimed at slowing disease progression in SMA and other motor neuron disorders.
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