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Prolactin Reportedly Promotes Remeylination in Pregnant Mice — Next Up, Clinical MS Trials

Women with multiple sclerosis (MS) tend to go into remission during pregnancy, especially in the third trimester (N Eng J Med 1998;339:285–291). The immune system apparently stops attacking myelin and symptoms improve.

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Dr. Samuel Weiss: “Current treatments for MS attack the immune component and try to stabilize and prevent new attacks. What were proposing is a new approach to repairing MS-like lesions.”

But could this improvement be a result, at least in part, to robust remyelination of lesions? That is the hypothesis of a new study in the Journal of Neuroscience (2007;27(8):1812–1823).

Based on a mouse study, investigators suggest that prolactin blood levels, which rise steeply in pregnancy, promote the generation of oligodendrocytes — the brain cells that coat axons with myelin — a process that could speed the healing of existing lesions and ameliorate symptoms.

If this is true, administering prolactin could become a viable treatment for men as well as women with MS; men also have prolactin receptors, according to Samuel Weiss, PhD, director of the Hotchkiss Brain Institute in Calgary, Canada, who led the investigators at the University of Calgary.

“Current treatments for MS attack the immune component and try to stabilize and prevent new attacks,” Dr. Weiss told Neurology Today. “What we're proposing is a new approach to repairing MS-like lesions.”

The study was spurred by the discovery that the number and size of lesions in MS patients decrease during pregnancy, suggesting that repair may be taking place. Pre-existing, mature oligodendrocytes, however, cannot contribute to remyelination, which means there must be a proliferation of oligodendrocyte precursor cells (J Anat 2005;207:707–716).

“We focused on prolactin because it is a mitogen for precursor cells within and outside the brain, and when levels increase in pregnancy, different tissues of the body start making new cells,” Dr. Weiss said. “Knowing that new myelin requires new oligodendrocytes, we wondered if, in pregnancy, increased prolactin levels lead to an increase in oligodendrocytes, and in turn, to more myelin.”

STUDY PROTOCOLS

The investigators did not use mice genetically altered to mimic MS. Instead, they injected a detergent, lysolecithin, into their spinal cord, producing demyelination that resembles the lesions created by MS. The lesions in the pregnant mice decreased in size by 37 percent compared to lesions in untreated controls. After injecting bromodeoxyuridine (BrdU), a synthetic nucleoside commonly used in the detection of proliferated cells in living tissues, into pregnant mice, they found an 80 percent increase in oligodendrocytes compared to virgin mice. Pregnant mice also had 75 percent fewer demyelinated axons and a 35 percent increase in remyelinated axons, due most likely to oligodendrocyte generation and enhanced remyelination rather than to neuroprotection provided by pregnancy. The pregnant mice repaired MS-like lesions much more effectively than virgin mice.

To demonstrate that prolactin promoted the healing, investigators implanted an osmotic pump between the shoulder blades of virgin mice and delivered prolactin subcutaneously. Mice injected with BrdU showed increases of up to 260 percent in oligodendrocyte precursor cells (OPCs), which was taken as evidence that prolactin stimulated creation of OPCs.

“We also showed that a pregnant mouse that had only one copy of the prolactin receptor gene made only half as many new oligodendrocytes, and therefore less myelin,” Dr. Weiss said. “Then we conducted the obvious final experiment, and that is, if you give an MS-like lesion to a non-pregnant mouse, and administer prolactin, will you enhance the repair of the lesion? And it does.”

EXPERTS COMMENT

Some MS experts expressed skepticism about the study claims, however. Prolactin promotes inflammation, which erodes the myelin in the first place, and this fact could scuttle attempts to use the hormone therapeutically, according to Rhonda Voskuhl, MD, director of the University of California-Los Angeles Multiple Sclerosis Program.

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Dr. Jack Antel: “If remyelination could be stimulated, it would eliminate the need to promote remyelination through transplantation. Endogenous repair is central to what our program is all about, and I think this paper contributes to the notion that we can stimulate repair.”

“It would make clinicians nervous to give MS patients something with pro-inflammatory properties,” Dr. Voskuhl said, after reading the Weiss paper. “You could use it in traumatic injuries that don't have a large inflammatory component, but in MS, if you have something that's pro-inflammatory, that could be a problem.”

Also, if prolactin is the agent that promotes remyelination, then remission should continue after childbirth in MS patients who breastfeed their babies, which causes prolactin levels to remain high, Dr. Voskuhl said. That, however, is not the case. MS patients who improve in pregnancy frequently relapse shortly after giving birth whether they breastfeed or not, but that could be due to a sudden drop in estriol levels, the estrogen unique to pregnancy, Dr. Voskuhl suggested.

“Estriol is made by the fetal placenta and it rises to high levels during pregnancy. Then it drops suddenly. It could be that the loss of high estrogen causes postpartum relapse. We're doing a multicenter trial that involves giving estriol to women who have MS, and we think that hormone makes things better for them.”

Meanwhile, the investigators of the Calgary study — a collaboration between the laboratories of Dr. Weiss and V. Wee Yong, PhD, at the Hotchkiss Brain Institute — hope to start clinical trials soon to test whether prolactin will promote remyelination of lesions in human MS.

Other researchers were enthusiastic about these findings. “This paper is extremely well done,” said Jack Antel, MD, professor in the department of neurology and neurosurgery at the Montreal Neurological Institute of McGill University, whose research into the interactions between the immune system and the brain earned him the 2005 John Dystel Prize for Multiple Sclerosis Research, given jointly by the National MS Society and the AAN. (Dr. Antel was the coordinator of the grant from the MS Society of Canada Foundation that supported the current study.)

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Dr. Mark S. Freedman was encouraged by the results because some of his patients, even though they develop no new lesions after a transplant, are slow to remyelinate existing lesions.

“If remyelination could be stimulated, it would eliminate the need to promote remyelination through transplantation,” Dr. Antel said. “Endogenous repair is central to what our program is all about, and I think this paper contributes to the notion that we can stimulate repair.”

Mark S. Freedman, MD, professor of neurology at the University of Ottawa, who has used bone marrow transplants to stop MS in some patients, was encouraged by the results because some of his patients, even though they develop no new lesions after a transplant, are slow to remyelinate existing lesions.

“One thought is that remyelination is inhibited by ongoing damaging inflammation, even though some inflammation is probably necessary for good healing,” he said. “Others believe that the lack of healing may be an inherent gene defect. There are definitely good and bad healers.”

Even Dr. Voskuhl, despite her worries about the pro-inflammatory quality of prolactin, was impressed by the Weiss research. “I do respect their work,” she said. “It's rigorous. If they have identified a molecule that can enhance remyelination, that's great. Steps forward are steps forward.”

Dr. Weiss is mindful that the pro-inflammatory potential of prolactin could be a problem. “Prolactin would have to be tested in the background of current MS drugs that dampen any autoimmune component, and that's precisely what we're doing right now in a mouse MS model,” he said.

He also contends that prolactin may help promote remyelination in other situations, such as schizophrenia and bipolar disorder, which might be caused, at least in part, by oligodendrocyte and myelin dysfunction (Lancet 2003;362:798–805).

“It's thought that schizophrenia and bipolar disorder might involve a myelin deficit,” he said. “There's evidence suggesting that myelination is an important component of brain function — more myelin, more brain function; less myelin, reduced brain function — not only in neurological disease, but also in mental health. Presumably, the more axons that are myelinated, the more there are to participate in neural activity.”

ARTICLE IN BRIEF

A new study suggests that prolactin might play a role in remyelination during pregnancy.

REFERENCES

• Gregg C, Shikar V, Weiss S, et al. White matter plasticity and enhanced remyelination in the maternal CNS. J Neurosci 2007;27:1812–1823.
• Polito A, Reynolds R, et al. NG2-expressing cells as oligodendrocyte progenitors in the normal and demyelinated adult central nervous system. J Anat 2005;207:707–716.
• Tkachev D, Mimmack ML, Bahn S, et al. Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 2003;362:798–805.