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Why nicotine-mimicking molecules might make great anti-inflammatory drugs for MS, RA, gout and more

A set of structurally similar proteins can activate a receptor for nicotine on immune cells, resulting in a dialing down of inflammation.

Until the day that science identifies the precise genetic factors that allow some of us to live to be 100 despite the immensely damaging effects of inhaling the particulate byproducts of combusted plant biomaterials — also known as "smoking" — nobody should smoke. From any rational health care standpoint, it's a really bad idea.

But I'll let you in on one of the dirty little secrets of medical research: Nicotine — a highly addictive substance that keeps tobacco smokers hooked on the habit — has actually been shown to have therapeutic properties. Tobacco smoking has been demonstrated in numerous studies to have a negative association with, for example, Alzheimer's and Parkinson's diseases as well as with inflammatory bowel disease. The reason, it seems, is that nicotine — tobacco's pharmacologically active ingredient — is doing something right.

It's no secret that nicotine acts directly on receptors located on certain kinds of nerve cells. In fact, an entire class of cellular receptors for the important nerve-cell signaling substance acetylcholine is designated as "nicotinic" just because receptors of this type respond to nicotine pretty much as they do to acetylcholine. (The other broad class of acetylcholine receptors, designated as "muscarinic," ignore nicotine as you might shrug off a perfectly boring stranger.)

The nicotinic acetylcholine receptors themselves come in several varieties. One, designated the alpha-7 nicotinic acetylcholine receptor (or alpha-7 nAChR), abounds on nerve cells in many distinct regions of the brain; defects in its function have been fingered in both Alzheimer's disease and schizophrenia.

Here the plot thickens, quite literally.

In 2012, Stanford neuroimmunologist Larry Steinman, MD (whose groundbreaking multiple-sclerosis research led directly to the development and, in 2004, FDA approval of the widely used MS drug Tysabri), along with Jonathan Rothbard, PhD, a senior scientist in Steinman's lab, and their colleagues found, surprisingly, that a sawed-off little protein by the name of beta-amyloid — possibly the most reviled molecule in the history of medicine because its build-up in the brain is frequently (although perhaps wrongly) deemed the villain in Alzheimer's disease — had a therapeutic effect in a rodent model of MS. Supplying beta-amyloid to these animals actually reversed their paralysis, albeit only for the time during which it was being administered to them.

Beta-amyloid is one of numerous proteins known to have biochemical properties that make it possible for them to stack together to form so-called amyloid fibrils, potentially thickening into gummy plaques. Among these amyloid-forming proteins are some you've heard of, such as the life-critical hormone insulin, but also the notorious Alzheimer's disease-related proteins tau and beta-amyloid (which can form, respectively, neurofibrillary tangles and Alzheimer's plaques in the brain and are believed by many scientists to be culpable for the disorder), as well as the prion protein (infamous for mad cow disease and its rare but deadly equivalent in people).

In earlier studies, Steinman's lab had discovered that another amyloid-forming protein was therapeutic in an acute stroke model and that several additional amyloid-forming compounds could suppress immune hyperactivity.

But why?

It happens that the alpha-7 nicotinic receptor is also found on certain types of immune cells that can act as suppressors and regulators of the immune system. And, it turns out, a new study in Proceedings of the National Academy of Sciences, conducted by Steinman, Rothbard and their peers shows, that those very amyloid-forming proteins can activate this very receptor, on these very immune cells, resulting in a dialing down of inflammation.

Bottom line: alpha-7 nAChR-activating drugs might have therapeutic benefits in a variety of inflammatory diseases. Steinman and Rothbard are working to develop small-molecule therapeutics targeting this receptor and safe for human use against rheumatoid arthritis, gout, inflammatory bowel disease and multiple sclerosis.

"As a neurologist and immunologist, I view this work as a thrilling connection between my two favorite physiologic systems," Steinman says.

Image by Clker-Free-Vector-Images

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