Neuroinflammation: The Key Component in Targeting Neurological Disorders

The history of targeting neuroinflammation is a good example of the challenges to finding a treatment for Alzheimer disease.

The term “neuroinflammation” broadly identifies the response of the central nervous system (CNS) to injury, disease, and repair. Neuroinflammation is mediated by the production of cytokines, chemokines, reactive oxygen species, and secondary messengers.

This complex biologic response encompasses biochemical cascades initiated by the coordinated action of neural and non-neural cells. Some, but not all, are directed toward the ultimate goal of protecting the CNS and preserving its integrity.

In short, neuroinflammation can be defined as an inflammatory response within the brain. Because of its complexity and multifactorial nature, it is easy to understand why even a minimal unbalance in any of its components may result in unwanted consequences that promote CNS disease or hinder CNS recovery.

Because this maladaptive outcome often prevails, over time the term neuroinflammation has taken a negative connotation. However, in recent years, partly due to the failure of highly anticipated clinical trials targeting presumptive proinflammatory neurotoxic molecules and partly due to increased understanding of the science of inflammation in the brain, it has become apparent that this negative, one-sided view of neuroinflammation is rather restrictive, if not inaccurate.

Acute vs Chronic Inflammation

The saying "too much of a good thing" applies to much of life, but especially to inflammation. It is logical to think the inflammation needs to be stomped out at all times. In fact, inflammation can play an essential role in healing and injury repair to keep everything working normally.

Most are familiar with acute inflammation. An example is the redness, warmth, swelling, and pain around tissues and joints that occurs in response to an injury—like getting a splinter. Acute inflammation with the body trying to protect you from the bacteria in that splinter.

When the splinter is expelled, the inflammatory response resolves within hours. Acute inflammation is reparative—a return of homeostasis. Chronic inflammation, the polar opposite of acute inflammation, is associated with debilitating chronic diseases of the cardiovascular system, brain, liver, aging and more.

Chronic inflammation is destructive; it makes any organ system function worse. In the brain, we use the terms chronic neuroinflammation or acute neuroinflammation to signify destructive or reparative inflammation respectively. When we target neuroinflammation as a major contributor to neurologic disease, we are targeting chronic inflammation.

Targeting Chronic Inflammation: A Promising Shift in Treating Alzheimer Disease

Alzheimer disease (AD) is the most prevalent chronic, progressive neurodegenerative disease and cause of dementia. Experts predict the number of people affected by dementia will double every 20 years to 81.1 million by 2040. In an aging population, the number of people suffering from dementia increases every year, which poses significant health, social, and economic problems for society in the very near future.

Despite decades of research dedicated to the development of therapeutic strategies designed to slow down disease progression, no disease-modifying therapies exist to treat AD. The history of targeting neuroinflammation is a good example of the challenges to finding a treatment for AD.

Historically, scientists thought neuroinflammation was the biologic response to plaques and tangles; the hallmark pathology of AD. They assumed that getting rid of plaques and tangles would eliminate neuroinflammation. Then, they discovered that neuroinflammation precedes the appearance of plaques and tangles and is a common cause of nerve cell death and synaptic dysfunction—the hallmarks of cognitive decline.

Next, they determined that destructive chronic neuroinflammation is the problem. Now we understand that stopping destructive chronic inflammation is not enough to fix the problem.

The brain must go through a period of acute inflammation to repair the destruction. If you are confused, you are not alone. Think of a village on fire—the fire department puts out the fire, but the village is still damaged.

People must rebuild for there to be a normal functioning village. Targeting neuroinflammation for AD requires a “Goldilocks” anti-inflammatory therapy that must stop destructive chronic neuroinflammation but promote reparative inflammation, which is a tall order.

Currently, no drugs are approved to treat neuroinflammation, but there are several in development and undergoing clinical trials. One promising drug candidate is XPro1595, which targets chronic inflammation to treat AD and is currently undergoing phase 2 clinical trials. Other notable biomarkers in development to treat inflammation in AD are NP001 and GC021109, each carrying its own unique approach.

Moving Forward

Although our understanding of the neuroinflammatory mechanisms is in constant evolution and remodeling, there is little doubt that destructive neuroinflammation is a prominent feature of virtually every neurological/neurodegenerative disorder. Destructive chronic neuroinflammation is a common thread that connects traumatic, neurodegenerative, and psychiatric CNS pathologies.

Above all, neuroinflammation is a complex, multifaceted process accompanying neurological disease where destructive and reparative signals coexist. As a consequence, targeting destructive neuroinflammation for therapeutic purposes is attractive, particularly because of the potential efficacy across multiple disorders, but challenging because reparative neuroinflammation must be protected.

Ultimately, targeting destructive neuroinflammation is valuable, but how you target neuroinflammation is critical. Stopping all inflammation will not work. A targeted, precision medicine approach is essential and herein lies the challenge.

About the Author

RJ Tesi, MD, is the co-founder and CEO of INmune Bio (NASDAQ: INMB), a publicly traded, clinical-stage biotechnology company developing therapies that target the innate immune system to fight disease. INmune Bio has two product platforms that are both in clinical trials, the DN-TNF product platform, and the Natural Killer Cell Priming Platform, which includes INKmune.