UC Riverside-led mouse study stresses MS treatment should be started early

A team led by a biomedical scientist at the University of California, Riverside, reports that a drug, an estrogen receptor ligand called indazole chloride (IndCl), has the potential to improve vision in patients with multiple sclerosis (MS).

The study, conducted on mice induced with a model of MS, was the first to investigate the effect of IndCl on the pathology and function of the complete afferent visual pathway. It is published in Brain Pathology. The afferent visual pathway includes the eyes, optic nerve, and all brain structures responsible for receiving, transmitting, and processing visual information.

In multiple sclerosis (MS), the immune system attacks the protective covering of nerves, causing inflammation and damage to the optic nerve and other parts of the visual system. Around 50% of MS patients experience optic neuritis, which is inflammation and demyelination of the optic nerve, before showing initial symptoms. Almost all MS patients suffer from impaired vision at some point during the progression of the disease. Symptoms may include eye pain, blurred vision, and progressive vision loss that can ultimately lead to blindness, among other visual impairments.

The optic nerve, which is a heavily myelinated bundle of nerves located at the back of the eye, transfers visual information from the retina to the vision centers of the brain through electrical impulses. Myelin acts as an insulating substance that speeds up the transmission of these electrical impulses. Partial myelin loss slows down the transmission of visual information, and severe myelin loss may even stop the signal altogether.

The researchers utilized IndCl to evaluate its impact on demyelinating visual pathway axons. The therapy prompted remyelination and alleviated some damage to the axons, resulting in partial improvement in vision function.

“Seema Tiwari-Woodruff, a professor of biomedical sciences at the UC Riverside School of Medicine and the study’s lead author, stated that IndCl has previously been shown in mice to reduce motor disability, increase myelination, and provide neuroprotection in the spinal cord and corpus callosum. However, its effects in the visual system had not been evaluated until now. Our study demonstrates that the optic nerve and optic tract, which undergo significant inflammation, demyelination, and axonal damage, show some restoration of function with IndCl treatment, along with successful reduction in inflammation and an increase in remyelination.”

The visual pathway in mice is similar to that in humans, making the mouse brain an excellent model for studying vision impairment. In the lab, Tiwari-Woodruff and her research group first induced the mouse model of MS. They let the disease progress for about 60 days. When the disease reached a peak between 15 and 21 days, they administered IndCl to half of the mice. At the end of the experiment, they performed a functional assay to measure the visual electrical signal and conducted immunohistochemistry to examine the visual pathway. The mice that received the drug showed improvement in myelination, with visual function improving by about 50%.

“Measuring visual function and recovery in the presence of new therapies can be used to screen more effective treatments that will protect axons, stimulate axon remyelination, and prevent ongoing axon damage,” Tiwari-Woodruff said.

Currently approved MS drugs reduce inflammation but do not prevent neurodegeneration or initiate remyelination. Furthermore, they only partially prevent the onset of permanent disability in patients with MS.

“We treated the mice with IndCl at the peak of their disease,” said Tiwari-Woodruff. “If the brain is highly diseased, some of the axons that could potentially restore visual function are too damaged and will not recover. There’s a point of no return. Our research emphasizes that in order to achieve vision improvement, treatment must begin early. Early treatment can restore 75%-80% of the original function.”

Tiwari-Woodruff stressed that although additional studies are required, the new findings show the dynamics of visual pathway dysfunction and disability in MS mice, along with the importance of early treatment to mitigate axon damage.

“There is a strong and urgent need to find a therapeutic candidate that restores neurological function in patients with MS,” Tiwari-Woodruff said. “Therapeutics must target remyelination and prevent further axonal degeneration and neuronal loss. The good estrogens, which ha