What Animal Is Used For Neurological Studies

Inquiry January/February 2010

By Gina Shaw

The Ways Neurology Benefits from Research Using Animals

The use of animals in medical inquiry has proven vital to understanding and developing treatments for for almost every neurologic disorder.

Back in the 1930s, patients receiving early on rabies vaccines occasionally developed neurologic complications so severe that the situation was called a "neuroparalytic catastrophe." About one percent of recipients of the vaccines—which had been grown in duck embryos—developed fevers, contradistinct mental status, seizures, and limb weakness. Sometimes the reaction was fatal.

When the brains of people who died subsequently these reactions were examined, the changes in the brain tissue didn't resemble rabies, every bit doctors were expecting. Instead, they resembled a astringent course of multiple sclerosis (MS). Scientists wondered if information technology was possible that the patients had had an allergic reaction to the brain tissue from the duck embryos in the vaccine, and more than tantalizingly, if a similar "allergic reaction" was going on in MS itself.

"The proof of the pudding was when they were able to take duck brain tissue without any rabies in it and recapitulate the disease, first in nonhuman primates, and so rodents," says Richard Ransohoff, Thousand.D., director of the Neuroinflammation Enquiry Center at the Cleveland Dispensary in Ohio. That disease model of MS became known as experimental autoimmune encephalomyelitis (EAE), and it has provided some of the most of import insights into the origins, pathology, and handling of MS. In fact, EAE is one of the oldest animate being models known to be of any man disease.

"Our entire theory of MS has been in large part shaped by feel with EAE," says Dr. Ransohoff.

Earlier virtually any drug manufactured today is tested in a man, it is first studied in animals—usually mice or rats, and sometimes when necessary in other mammals like primates. Scientists can't learn everything almost how a drug will behave in human beings past studying it in animals, just they tin glean many of import insights almost effectiveness, side effects, and dosage levels.

Fifty-fifty before new treatments are developed, research on animals has proven essential to understanding just how complex disease processes like Alzheimer's, Parkinson's, and MS are, what their underlying causes might be, and the all-time approaches for developing new treatments.

Animal enquiry has been instrumental in developing treatments for multiple sclerosis, stroke, Parkinson'south, and other neurologic disorders.

"For almost every disease in neurology, I could identify animate being studies going on now that are making a difference in how we diagnose, understand, and treat it," says Jasper Daube, M.D., professor of neurology at the Mayo Clinic in Rochester, MN. "Combine these studies with other enquiry in animals—some 15, some five, some two years ago—they all add up to giving usa the treatments nosotros accept, or at least identifying the underlying abnormality."

Multiple Sclerosis and Animal Research

For neurologic diseases in particular, sure insights and advances would be virtually impossible without animal models like EAE.

"In nearly neurologic diseases, the peripheral tissues are normal, and studying them doesn't tell you very much," says Dr. Ransohoff. "You tin get your easily on claret or spinal fluid, but you can't become brain tissue until people die, unless they have a biopsy, which is very invasive and not normally done for most neurologic conditions. And people who dice of a neurologic disease, like MS, practise so after many years. That means that the brain tissue at that point is not representative of what's happening in the early to middle office of these diseases, when most of us retrieve they are well-nigh treatable."

It'due south besides almost impossible to study neurologic illness effectively past looking at cells in the laboratory. "The minute you have one of these networked brain cells, rip it out of the brain, and plate it on plastic or drinking glass and feed it serum or growth factors, you lot've made it abnormal," Dr. Ransohoff says. "In many cases, yous've destroyed everything that characterizes how the cell works in the intact brain. So we need living organisms to report these diseases."

Powerful regulations are in place that protect animals used in medical research. More than 50 federal laws exist to protect animals, but the Fauna Welfare Act and the Health Research Extension Act of 1985 are the primary laws governing the use of animals in inquiry. Many states also enact their ain animate being-research laws.

Peradventure because of pressure from animal rights organizations, advancement groups don't talk much about the advances fabricated possible through animal research.

"The animals are treated well, housed well, and there are strict rules about the extent to which you can cause hurting during any phase of enquiry," says Dr. Ransohoff. "And whistleblowers who report violations of these regulations are as well well protected by law."

But some beast rights organizations are now pushing to have animals given the aforementioned legal standing as humans, which would finer ban all animal inquiry since animals cannot give "informed consent."

Perhaps because of this pressure, many advocacy groups for people with neurologic conditions don't talk much about the advances made possible by enquiry using animals. "If yous go to the Spider web sites of many of these groups, they will rarely say what's beingness done in animate being inquiry for that condition," says Dr. Daube. "I've asked some of them if they could highlight the importance of animal enquiry, and their concern is the aforementioned—they might turn off some donors. Simply I think they're wrong. Some groups that are more public about fauna inquiry, like the Parkinson's Foundation, haven't been damaged by this openness, and it gives patients and family unit members a sense of how essential this research is."

In MS, for example, the vast majority of our current understanding of the disease has been worked out in the EAE animal model and and so validated in man patients.

"Although not everything about the mouse immune organization is the same as man, about things are," Dr. Ransohoff explains. "These models are now very refined, using inbred mice for which we know all their genetics. So we tin select or modify individual genes and written report exactly how that gene participates in the MS/EAE affliction procedure."

The model isn't perfect. It's harder to study neurodegeneration—the long secondary progressive phase of MS—in the EAE model, perhaps because mouse and human brains differ more significantly than practise mouse and human immune systems, and because of the short mouse lifespan.

But some of the well-nigh of import treatments for MS available today have been worked out entirely using the EAE model. A recent example is natalizumab. In 1992, a paper in the medical journal Nature identified natalizumab's molecular target, along with the antibody that could be developed into a drug to suppress EAE. Almost exactly 10 years later, the pivotal clinical trials of natalizumab began.

Animal Models of Stroke

When a person has a stroke, a blood vessel gets blocked off, because a clot either forms in the brain or travels there from another part of the trunk. When that vessel is blocked, information technology delivers piffling to no claret, oxygen, or glucose to the brain. That sets off something chosen the "ischemic cascade"—a series of biochemical reactions that harm and destroy brain tissue.

But how exercise these reactions happen? Y'all can't study them directly in human patients, non least considering yous'd have to actually cause a person to have a stroke in order to sentry them from the beginning.

"Animal modeling of stroke has been critical to our understanding of the ischemic cascade," explains Marc Fisher, M.D., professor of neurology at the Academy of Massachusetts Medical School and author of Handbook of Experimental Neurology: Methods and Techniques in Animal Research (Cambridge Academy Printing, 2006). "Information technology's given united states of america a pretty reasonable understanding of how the tissue dies in ischemic stroke. If yous sympathize that, and then you tin can start to recollect about treatments that might interfere with the procedure."

Tissue plasminogen activator (TPA), the "clot-busting" drug that can reverse the effects of a stroke if used appropriately within three to iv and a half hours of the onset of symptoms, was initially studied in an creature model. "Our insights from the creature stroke model, showing that TPA has a beneficial effect, were very important in thinking about how the clinical model might have place," says Dr. Fisher.

Brute research has also provided important insights virtually the other side of the money—the potential drawbacks of TPA. "There are deleterious effects of TPA on tissue, which we've learned from studying animals," Dr. Fisher says. "Nosotros've also learned that after y'all restore blood flow to the encephalon—either using TPA, or mechanically by taking the clot out of the vessel—the rush of blood to the injured tissue can really cause further damage, called 'reperfusion effects.' This is something we need to understand improve."

More recently, improved power to do small-animal imaging with MRI has allowed stroke researchers to await directly at the development of stroke damage in a living animal. "Nosotros tin characterization our clots so that they are piece of cake to see on imaging, and expect at the temporal course of the impairment and how quickly TPA works in dissolving the clot," says Dr. Fisher. "We can then relate that to reperfusion furnishings in the tissue. Information technology volition also let us to compare other thrombolytic [jell-dissolving] agents to TPA to come across if nosotros tin dissolve clots faster and more than extensively with fewer damaging effects, such every bit hemorrhage [bleeding]."

Dr. Fisher and his colleagues have recently published animal-model studies showing that giving loftier-catamenia oxygen might exist able to extend the fourth dimension window in which TPA tin be safely and finer given to stroke patients.

Insight Into Parkinson'due south

A number of different animal models take been used to study the origins and evolution of Parkinson's disease. Perhaps most commonly used, and the one that has yielded the greatest insights, has been the "MPTP" model. MPTP is a chemic that causes permanent symptoms of Parkinson's disease by killing sure neurons in the brain. Used in mice, rats, and sometimes primates, the MPTP model has immune researchers to study the effects of a wide variety of genes that are associated with human Parkinson's.

"Nigh of the current therapies for Parkinson'south symptoms developed over the years were all showtime tested in the experimental mouse, mostly the MPTP model, earlier existence given to people," says Serge Przedborski, K.D., Ph.D., Ph.D. professor of neurology and pathology at Columbia University Medical Center in New York and a leading Parkinson's researcher. "Information technology gives usa a ballpark idea, before clinical trials, if the treatment is going in the right direction or not."

Perhaps an even more exciting direction made possible by MPTP animate being inquiry has been the development of deep brain stimulation (DBS) for Parkinson's disease. DBS uses a surgically implanted, battery-operated device chosen a neurostimulator—similar a pacemaker for the brain—to send an electrical signal to the areas of the encephalon that control movement, blocking the abnormal nerve impulses that lead to Parkinson's symptoms. Although it's not a cure, DBS has significantly reduced symptoms for many people with Parkinson's.

"DBS had been used for years in people with epilepsy, merely the idea to use it in Parkinson's disease came from work that had been done on the chemical neuroanatomy of the encephalon in MPTP monkeys," explains Dr. Przedborski. "Scientists observed that once the neurons in the brain that made dopamine were destroyed, these monkeys given MPTP had hyperactivity in a certain area of the brain called the subthalamic nucleus. They found that if you used a toxin to destroy this nucleus, the Parkinson's symptoms in the monkey disappeared. From that, they theorized that if you implanted a needle to jam this hyperactivity with high-frequency electric stimulation, you'd go the same outcome. And that's exactly what happened—creating a handling that has been the 2d most significant advance in the management of Parkinson's since the discovery of levodopa. If you eliminate the MPTP monkey, this never would have happened."

What'south more, the lessons that have been learned from animal models in one neurologic illness tin can oftentimes be "cross-fertilized" into other brain and central nervous system disorders. For example, Dr. Ransohoff points out, researchers are taking lessons learned from the EAE model and from basic neuroscience and performing crossover experiments in an try to understand how inflammation works in other chronic neurodegenerative diseases.

"If nosotros could get a handle on which aspects of inflammation are helpful and which are harmful, we might have tools in our arsenal of treatments that could exist applied to many forms of neurodegeneration," he says. "This kind of research is something that merely animal models tin can help us do."

Larn more about the use of animals in biomedical inquiry.