보톡스의 예기치 않은 신경계 부작용 경고

Botulinum toxin study proves possibility of remote effects

보톡스의 예기치 않은 부작용 가능성 우려

보툴리눔 톡신(BTX)이 몸 안에 들어오면 체내 이곳저곳으로 확산 돼

예기치 않은 부작용을 일으킬 수 있다는 연구결과가 나왔다.

'보톡스'라는 이름으로 널리 알려진 이 물질은 의료뿐 아니라

미용 재료로 폭넓게 활용되고 있어 제약업계가 주목하고 있다.

사진;jaysactivity

9일 과학전문 저널 사이언스데일리에 따르면 에드윈 채프먼 미국 위스콘신주립대학

신경학 교수 연구팀은 쥐 실험에서 BTX 분자가 주입 부위에서 멀리 떨어진 뉴런(신경세포) 사이를

이동하는 사실을 관찰했다.

뉴런은 감각 정보를 뇌와 척수로 전달하며, 연합신경세포가 정보를 판독한 뒤

운동신경세포로 전달해 운동이 필요한 부분을 자극한다. 연구팀은 독소가 뉴런을 타고

광범위하게 이동하다 중추신경계에 이를 경우 예상하지 못한 위험에 노출될 수 있다고 주장했다.

BTX는 클로스트리듐 박테리아가 만들어내는 독성 물질이다.

말초신경에서 신경전달물질 분비를 차단해 근육 마비를 일으킨다. 다국적 제약사 엘러간은

이 특징을 이용해 물질 독성을 극도로 희석시켜 보톡스로 만들었다.

의료계와 미용계는 특정 부위의 기능을 현저히 떨어뜨리는 목적으로 보톡스를 이용해왔다.

한 예로 코와 입, 양 옆으로 퍼진 팔자주름 부위에 보톡스를 주입하면

주름을 깊게 새기는 세포의 역할을 무력화시켜 주름이 펴지는 효과가 발생한다.

의료계는 수술이나 안면홍조 완화 등 용도를 위해 보톡스를 활용하기도 했다.

 내과와 외과, 신경과, 산부인과, 치과, 성형외과 등 광범위하게 쓰인다.

보톡스가 폭넓게 쓰이면서 국내에서는 치과 의사들과 내과 의사간 활용 범위를 놓고 분쟁을 겪기도 했다.

보톡스가 다양하게 쓰일 수 있었던 건 독소가 주입 주변에만 효과를 발휘한다는

전제가 깔려 있었기 때문이다.

보툴리눔 독소의 4 개의 버전을 판매 앨 러간 PLC는 2015 년에

거의 $ 20 억(2조원) 글로벌 보톡스 매출을 기록했다.

Botulinum toxin study proves possibility of remote effects

Date:August 4, 2016

Source:University of Wisconsin-Madison

The botulinum toxins are among the deadliest substances on Earth, and two specific toxins -- including the popular drug Botox -- have multiple uses for treating many neuromuscular conditions, including frown lines, disabling muscle spasms and migraine headaches.

The botulinum toxins cancel nerve signals to the muscles, creating paralysis that can last for months. Given its extraordinary toxicity, doses are typically measured in trillionths of a gram, and targets are carefully chosen to silence only the desired motor nerves.

When Botox and related botulinum drugs entered the market, "the idea was that they are safe to use, they stay where they are injected, and you don't have to worry about toxin going to the central nervous system and causing weird effects," says Edwin Chapman, an investigator at the Howard Hughes Medical Institute and professor of neuroscience at the University of Wisconsin-Madison.

The concern that this powerful toxin can move beyond the injection site was reinforced in 2009, when the Food and Drug Administration added a prominent warning to prescribing information "to highlight that botulinum toxin may spread from the area of injection to produce symptoms consistent with botulism," including "unexpected loss of strength or muscle weakness. ... Understand that swallowing and breathing difficulties can be life-threatening and there have been reports of deaths related to the effects of spread of botulinum toxin."

Additionally, physicians have seen puzzling results from treatment, adds Ewa Bomba-Warczak, a doctoral candidate in neuroscience. "In many cases, after an injection for a disabling spasm of neck muscles called cervical dystonia, there is no change in muscle tone but the patient finds relief and is perfectly happy. That result can't be explained by the local effects."

In a study published today (Aug. 4, 2016) in Cell Reports, senior author Chapman, first author Bomba-Warczak and colleagues present clear evidence that toxin is moving between neurons in a lab dish.

The study looked at mouse neurons in wells connected by tiny channels that allow growth of axons -- the long fibers that neurons use to communicate. In tests of two botulinum toxins, the researchers saw toxin molecules entering the injected cell, as expected.

Once inside a neuron, botulinum toxin cleaves proteins responsible for fusion of chemical containers, known as vesicles, with the plasma membrane. This fusion event releases chemical signals that underlie communication with muscles, and the inability to fuse leads to the temporary paralysis caused by botulinum toxin.

Using antibodies to identify fragments of the damaged proteins, Chapman's group showed that toxin molecules were moving to nerve cells in wells that had not initially received the harmful molecules. "Every time one fraction of the toxin acts locally (on the first nerve cell it contacts), another fraction acts at a distance," says Chapman. "It's unknown how far they travel, which likely depends on the dose of toxin and other factors."

Co-author Jason Vevea, a UW-Madison postdoctoral fellow, produced videos showing tagged molecules of botulinum toxin moving along the axons connecting neurons.

Botulinum toxins were first described in the 1800s, and have long been a subject of research at UW-Madison. Allergan PLC, which markets four versions of botulinum toxin, reported global Botox sales of nearly $2 billion in 2015.

By finding that toxin molecules don't always stay where they are injected, Chapman says the Wisconsin study answers a long-standing question about mobility, but raises several more. "We have seen that these toxins enter neurons at the injection site, causing the desired local paralysis, but Ewa and Jason have shown unambiguously the existence of a second entry pathway that takes some of the toxin molecules to other neurons."

The research, done in a lab dish, removes variables that have plagued similar studies performed in animals, Chapman says. "We wanted to see if we could build an in vitro (in a dish) system that allows direct visualization of this putative movement, in a way that's simple, easy to interpret, and unambiguous. Do they move, or do they not?"

Chapman wonders about the effects of extraordinarily powerful toxin molecules that travel the neural networks. Local effects have, until now, been deemed the sole effects. But could part of its effects be due to the transported toxin?

These questions could be answered by genetically engineering the Clostridium bacteria that make botulinum toxin to alter the toxin's structure, Chapman says. "We may be in a position to mutate the part of the toxin that attaches to a receptor on the neuron so it can only enter the local pathway, not this new pathway we have described."

If only the local effects matter for medicine, tomorrow's versions of this ancient toxin molecule may be able to alleviate symptoms from wrinkles to severe muscle spasms without moving beyond the target neurons.

"I have a hard time imagining that any physician is going to want to inject something they know can move about when they have an option to use something that stays put," Chapman says. "It's an exciting prospect, supplanting a $2 billion drug with a safer drug."