A new study by researchers at the Albert Einstein School of Medicine dramatically underscores the potential role of the NF-kB protein in aging. NF-kB is a master protein which controls many inflammatory chemicals throughout the body. Researchers at the Roskamp Institute have studied NF-kB for many years as a potential way of controlling chronic inflammation which accompanies aging and underlies conditions such as Alzheimer’s disease. This new study points to a part of the brain as regulating the aging process. The current view of aging generally suggests that enzymes, DNA, proteins and other constituents of the body essentially “wear out” with age, accumulating damage due to environmental insults until they no longer function properly. This new study suggests something quite different, namely that a part of the brain called the Hypothalamus deliberately induces aging throughout the body. It has been suggested that one reason why the brain might take such drastic action is to inhibit reproduction past a certain age. This suggestion is highly speculative at this stage, but the data offered by the Albert Einstein researchers suggests that, with age, increased NF-kB activity triggers degeneration in both the brain and other areas of the body. The researchers showed that as mice aged, they increasingly expressed NF-kB in the part of the brain that is normally responsible for the production of reproductive and growth hormones. The researchers artificially manipulated NF-kB activity using genetic techniques and showed that reducing NF-kB activity was associated with better performance in cognitive tests, greater muscle strength and greater bone mass and skin thickness. Conversely, exacerbation of NF-kB activity increased all of these peripheral signs of aging, as well as reducing cognitive abilities. Furthermore the research suggested that microglia (the inflammatory cells resident in the brain) are the originators of the NF-kB activity and this spreads to nearby neurons, including those responsible for growth and reproductive hormones. These findings are of direct significance to work at the Roskamp Institute as researchers there have shown that increased NF-kB collates strongly with Alzheimer’s pathology and pathology of other central nervous system disorders. Moreover, they have worked extensively on ways to reduce NF-kB activation, particularly using the naturally occurring compound Anatabine.  Roskamp Institute researchers have shown in multiple preclinical studies of neuroinflammation (such as Alzheimer's, traumatic brain injury and Multiple Sclerosis) that Anatabine (supplied by RockCreek Pharmaceuticals) has potent anti-inflammatory properties. This new finding suggests that NFKB inhibitors might also have a role in decelerating aging. In fact,  preliminary studies at the Roskamp Institute suggest that mortality in mice with Alzheimer pathology is reduced by Anatabine treatment. Additional studies are needed to clarify whether Anatabine might reduce the Hypothalamic inflammation and increase the release of hormones that oppose aging.

Dr. Michael Mullan M.D., Ph.D
President & CEO
Roskamp Institute
 
 
Pro-inflammatory cytokine production can be beneficial to the human body, as it is part of the body’s biological response. However, overproduction of these proteins promotes the development of many deteriorating neurological diseases, such as Alzheimer’s disease (AD) and the neurological damages that are aftereffects of traumatic brain injury (TBI) and stroke. High levels of pro-inflammatory cytokines inhibit proper synaptic communication and function, which eventually leads to damages in the cortex and hippocampus of the brain.

In a study from Northwestern’s Feinberg School of Medicine and University of Kentucky, a new set of drugs have been developed that targets this issue by preventing the overproduction. These drugs target neuroinflammation, a type of brain inflammation that is believed to be a major factor in the injurious nature of diseases ranging from Alzheimer’s to Parkinson’s, as well as brain injuries. The drugs, currently represented by MW151 and MW189, have been tested in previous animal studies. MWI151 was given to a six-month old (the time at which the level of pro-inflammatory cytokines being to increase) mice that are genetically engineered to develop AD for three times a week; then, their brains were examined at eleven months of age, the time at which the conditions of AD are visible. The development of the full-blown AD was avoided as the level of cytokines had returned to normal levels and their synapses were working properly. Mice that were not given the drug still had high levels of pro-inflammatory cytokines and had synaptic malfunction.  In another cases, it has also helped decrease the nerve damage caused by TBI by preventing overproduction of pro-inflammatory cytokines and blocking the activation of glia cells. Success was also met when the drug was tested in mice to prevent the development of multiple sclerosis.

Phase one of the first human clinical trial has been completed, but these current studies have shown that the therapy time window is limited, so for future clinical trials, further studies involving models of other diseases and time windows will be conducted. With this new development, the future of early therapy to prevent the development of neurological diseases and the long-term complications of TBI and strokes seems promising.

Keywords: inflammation; pro-inflammatory cytokines; drug; Alzheimer’s disease; traumatic brain injury

Sources: http://www.northwestern.edu/newscenter/stories/2012/07/brain-inflamation-drug.html                   

             

               http://www.jneurosci.org/content/32/30.abstract.pdf (Early Stage Drug Treatment That Normalizes Proinflammatory Cytokine Production Attenuates Synaptic Dysfunction in a Mouse Model That Exhibits Age-Dependent Progression of Alzheimer’s Disease-Related Pathology)

Wendy Liu

July 25, 2012