Oxidative Stress Interferes With White Matter Renewal After Prolonged Cerebral Hypoperfusion in Mice

And they talk about edaravone (approved for use in Japan since 2001).
Is your doctor working to get this approved in the US?
http://stroke.ahajournals.org/content/44/12/3516.abstract?etoc

1. Nobukazu Miyamoto, MD, PhD;
2. Takakuni Maki, MD, PhD;
3. Loc-Duyen D. Pham, MS;
4. Kazuhide Hayakawa, PhD;
5. Ji Hae Seo, PhD;
6. Emiri T. Mandeville, MD, PhD;
7. Joseph B. Mandeville, PhD;
8. Kyu-Won Kim, PhD;
9. Eng H. Lo, PhD;
10. Ken Arai, PhD

+ Author Affiliations

1. From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (N.M., T.M., L.-D.D.P., K.H., J.H.S., E.T.M., E.H.L., K.A.); Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA (J.B.M.); and NeuroVascular Coordination Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences (J.H.S., K.-W.K.) and Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology (K.-W.K.), Seoul National University, Seoul, Korea.

1. Correspondence to Ken Arai, PhD, Neuroprotection Research Laboratory, Massachusetts General Hospital, E 149-2401, Charlestown, MA 02129. E-mail karai@partners.org

Abstract

Background and Purpose—White matter injury caused by cerebral hypoperfusion may contribute to the pathophysiology of vascular dementia and stroke, but the underlying mechanisms remain to be fully defined. Here, we test the hypothesis that oxidative stress interferes with endogenous white matter repair by disrupting renewal processes mediated by oligodendrocyte precursor cells (OPCs).

Methods—In vitro, primary rat OPCs were exposed to sublethal CoCl₂ for 7 days to induce prolonged chemical hypoxic stress. Then, OPC proliferation/differentiation was assessed. In vivo, prolonged cerebral hypoperfusion was induced by bilateral common carotid artery stenosis in mice. Then, reactive oxygen species production, myelin density, oligodendrocyte versus OPC counts, and cognitive function were evaluated. To block oxidative stress, OPCs and mice were treated with the radical scavenger edaravone.

Results—Prolonged chemical hypoxic stress suppressed OPC differentiation in vitro. Radical scavenging with edaravone ameliorated these effects. After 28 days of cerebral hypoperfusion in vivo, reactive oxygen species levels were increased in damaged white matter, along with the suppression of OPC-to-oligodendrocyte differentiation and loss of myelin staining. Concomitantly, mice showed functional deficits in working memory. Radical scavenging with edaravone rescued OPC differentiation, ameliorated myelin loss, and restored working memory function.

Conclusions—Our proof-of-concept study demonstrates that after prolonged cerebral hypoperfusion, oxidative stress interferes with white matter repair by disrupting OPC renewal mechanisms. Radical scavengers may provide a potential therapeutic approach for white matter injury in vascular dementia and stroke.

Spinal Cord Injury – Therapeutic Strategies May Need to Include Repairing Myelin

I put this one out here because a neurologist I went to once said that after the two year period I wouldn't be able to recover functionality because the myelin sheath covering nerves that lead to my affected side were gone. I don't believe him because I think he was just spouting big words at me to confuse me and shut me up. But in case he was right we would need this. 

Spinal Cord Injury – Therapeutic Strategies May Need to Include Repairing Myelin

In a study in animals, researchers have shown they can improve recovery from spinal cord injuries through an infusion of cells that help rebuild the myelin sheath – a covering around nerve fibers.

There are an estimated 10,000 to 12,000 spinal cord injuries every year in the U.S. These injuries sever or crush the nerve fibers that run through the spinal cord, potentially leading to complete paralysis and loss of sensation below the level of the injury.

A traumatic blow to the spinal cord also typically causes a loss of myelin and the death of cells that make myelin, which are called oligodendrocytes. Myelin is needed to insulate the electrical signals transmitted by nerve fibers. Despite efforts by many investigators to develop therapies that target myelin, there has been a lack of consensus about the extent to which myelin loss has functional consequences in spinal cord injury.

The new study addressed this issue. It was led by Qilin Cao, M.D., associate professor of neurosurgery at the University of Texas Medical School in Houston, and Scott Whittemore, Ph.D., professor of neurological surgery at the University of Louisville School of Medicine in Kentucky.

The National Institute of Neurological Disorders and Stroke (NINDS) provided major funding for the work.

Writing in the Journal of Neuroscience,* the researchers reported that they could improve recovery in rats with spinal cord injury by giving the animals transplants of oligodendrocyte precursor cells (OPCs). The transplants were most effective when the OPCs were genetically modified to make a growth factor that stimulated their survival, growth and maturation into oligodendrocytes.

Drs. Cao and Whittemore and their team isolated OPCs from the healthy adult rat spinal cord. They also created a population of OPCs carrying the gene for ciliary neurotrophic growth factor (CNTF), after establishing that CNTF is a potent inducer of OPC survival and maturation. They injected these genetically modified OPCs into rats eight days after a spinal cord injury, at several sites near the injury. For comparison, some rats were given a sham injection, grafts of skins cells carrying the CNTF gene, or grafts of OPCs carrying a control gene. At seven weeks post-transplant, the modified OPCs significantly improved the animals’ rate of recovery, based on recordings of electrical activity in the spinal cord as well as behavioral tests.

The researchers also showed that the majority of transplanted OPCs matured into oligodendrocytes, which wrapped around nerve fibers to form myelin. Importantly, the extent of myelin repair was closely matched to the recovery of movement in the animals’ hind limbs.

This close correlation “underscores the importance of remyelination in behavioral improvement” after a spinal cord injury, the researchers wrote.

“There has been controversy about the extent to which demyelination contributes to the loss of function after spinal cord injury, and therefore doubts regarding the benefits of therapies to stimulate myelin repair,” said Naomi Kleitman, Ph.D., a program director at NINDS. “This study provides strong evidence that such an approach is indeed beneficial in an animal model of spinal cord injury.”

- By Daniel Stimson, Ph.D.

Image Caption: Oligodendrocytes (blue) wrap around nerve fibers to form myelin