Running triggers production of a molecule that repairs the brain in animal models


Running triggers production of a molecule that repairs the brain in animal models
Researchers at the Ottawa Hospital and the University of Ottawa have discovered that a molecule triggered by running can help repair certain kinds of brain damage in animal models. The team includes (from left) Dr. Rashmi Kothary, Dr. Robin Parks, Yves De Repentigny, Keqin Yan and Dr. David Picketts. 

Researchers at The Ottawa Hospital and the University of Ottawa have discovered that a molecule triggered by running can help repair certain kinds of brain damage in animal models. They found that this molecule, called VGF nerve growth factor, helps to heal the protective coating that surrounds and insulates nerve fibres. Their study, published in Cell Reports, could pave the way for new treatments for multiple sclerosis and other neurodegenerative disorders that involve damaged nerve insulation.

 However, if these mice were given the opportunity to run freely on a wheel, they lived over 12 months, a more typical mouse lifespan. The running mice also gained more weight and acquired a better sense of balance compared to their sedentary siblings. However, they needed to keep exercising to maintain these benefits. If the running wheel was removed, their symptoms came back and they did not live as long.

Looking at their brains, the researchers found that the running mice gained significantly more insulation in their cerebellum compared to their sedentary siblings.

To find out why running was causing this insulation, the team looked for differences in gene expression between the running and sedentary mice and identified VGF as a prime candidate. VGF is one of the hundreds of molecules that muscles and the brain release into the body during exercise. It also has an anti-depressant effect that helps make exercise feel good.

When the research team used a non-replicating virus to introduce the VGF protein into the bloodstream of a sedentary mutant mouse, the effects were similar to having the mouse run – more insulation in the damaged area of the cerebellum, and fewer disease symptoms.

“We saw that the existing neurons became better insulated and more stable,” said Dr. Matías Alvarez-Saavedra, the lead author on the paper. “This means that the unhealthy neurons worked better and the previously damaged circuits in the brain became stronger and more functional.”

Dr. Alvarez-Saavedra obtained his PhD in Dr. Picketts’ research group, and is currently a postdoctoral fellow at the New York University School of Medicine and the Howard Hughes Medical Institute.

“We need to do broader research to see whether this molecule can also be helpful in treating and other neurodegenerative diseases,” said Dr. Picketts.

 

Highlights

  • Running promotes the survival of mice with cerebellar ataxia following Snf2h inactivation
  • Running ataxic mice show enhanced oligodendrogenesis and de novo myelination
  • Comparative RNA-seq studies identify VGF as a contributor to brain repair
  • VGF overexpression improves ataxic phenotype in mice without exercise

Summary

Exercise has been argued to enhance cognitive function and slow progressive neurodegenerative disease. Although exercise promotes neurogenesis, oligodendrogenesis and adaptive myelination are also significant contributors to brain repair and brain health. Nonetheless, the molecular details underlying these effects remain poorly understood. Conditional ablation of the Snf2h gene impairs cerebellar development producing mice with poor motor function, progressive ataxia, and death between postnatal days 25–45. Here, we show that voluntary running induced an endogenous brain repair mechanism that resulted in a striking increase in hindbrain myelination and the long-term survival of Snf2h cKO mice. Further experiments identified the VGF growth factor as a major driver underlying this effect. VGF neuropeptides promote oligodendrogenesis in vitro, whereas Snf2h cKO mice treated with full-length VGF-encoding adenoviruses removed the requirement of exercise for survival. Together, these results suggest that VGF delivery could represent a therapeutic strategy for cerebellar ataxia and other pathologies of the CNS.

Early Study Provides First Evidence of Remyelination


A monoclonal antibody improved nerve signaling in acute optic neuritis..

Researchers here say they have the first biological proof of remyelination, with positive results from a phase II study showing that a novel monoclonal antibody improved nerve signaling in acute optic neuritis.

Biogen’s anti-LINGO-1 monoclonal antibody (BIIB033) significantly improved recovery of optic nerve latency — the time it takes for a signal to travel from the retina to the brain’s visual cortex — compared with placebo in a per-protocol analysis, with a difference of 9.13 msec (P=0.01), according to Diego Cadavid, MD, of Biogen.

But there were no differences in retinal thickness or visual function, Cadavid reported during an emerging science session at the American Academy of Neurology meeting here.

“This is the first evidence of remyelination in the clinic,” Cadavid said during the presentation.

The phase II RENEW trial enrolled 82 patients who’d had a first episode of unilateral acute optic neuritis. Patients were randomized to either 100 mg/kg of the drug or placebo, given once every 4 weeks for a total of six doses, and were followed for 32 weeks.

Remyelination was assessed via recovery of optic nerve conduction latency, which was measured by full-field visual evoked potential (FF-VEP). They also assessed neuroprotection via retinal thickness on spectral-domain optical coherence tomography (SD-OCT), as well as eye function on low-contrast letter acuity (LCLA).

In the per-protocol analysis, the researchers found that drug-treated patients had a significantly greater improvement in latency recovery than those on placebo, with a difference of 7.55 msec at 24 weeks (P=0.05) and a difference of 9.13 msec (P=0.01) at 32 weeks.

Those differences, however, were not significant in the intention-to-treat population.

Nor were there any differences in the secondary endpoints of change in thickness of the retinal layers, or in visual function.

“Data indicate that significant retinal layer thinning had taken place before the first treatment was administered — half prior to the first dose, remainder prior to second dose — indicating that anti-LINGO-1 may not have had an opportunity to impact neuroprotection,” Cadavid said in an email to MedPage Today.

The drug was generally well-tolerated, Cadavid said, noting that the most common adverse events with the drug were fatigue, nausea, and paresthesia.

Two drug-treated patients had hypersensitivity reactions that occurred around the time of infusion, and one patient had an asymptomatic elevation in liver transaminases.

Cadavid concluded that the improved conduction of electrical impulses along the optic nerve seen in the trial provides the first evidence that remyelination is biologically possible.

Dean Wingerchuk, MD, of the Mayo Clinic in Arizona, who was not involved in the study, said the “prospect of having a truly neuroprotective or remyelinating therapy is very exciting and this early-phase protocol begins to address the unmet need of limiting the degree of lasting neurological injury that results from acute MS attacks.”

While the preliminary data are promising in terms of both safety and efficacy, Wingerchuk was cautious about its lack of effect on “clinically important visual outcome measures” — suggesting that a “much greater understanding of the mechanisms and durability of the detected changes are needed.”

“Despite these and other limitations,” Wingerchuk added, “the data provide support for further research and cautious optimism.”