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Neuroinflammation and Influenza

March 16, 2011

Over the last few weeks it has been somewhat like the clouds have parted and a new understanding of Parkinson’s Disease has emerged. While a great deal of research on the role of inflammation has long been available, it has been one of a number of possible explanations. It has now moved from the “possible” to the “probable” column and new avenues of treatment follow in its wake.

A few weeks ago a team from St. Jude’s led by Richard J. Smeyne published a report entitled,

“Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration”

This study provided a vivid confirmation of the work of earlier scientists and illustrated how a pathogen can enter the CNS and trigger an ongoing immune system response that ultimately becomes self-destructive.  Then, last week a report in London’s Telegraph provided graphic evidence of the destructive power of neuroinflammation in Alzheimer’s Disease. In both disorders a common mechanism is at work. This mechanism will be explored here and, most importantly, the avenues that it opens to possible treatments already on the shelf will be explored.

Research Background

While its relative importance in PD has been debated against the confusing backdrop presented by the disease, the recognition of a role for inflammation and microglial over-reaction is not new. For example:

  • “In many neurologic diseases, activated leukocytes enter the nervous system and initiate a chronic inflammatory process. Understanding how the cellular and humoral responses are associated with pathogenesis is essential for the formulation of a unifying model of central and peripheral nervous system inflammation.” (Diaz-Villoslada 1998)
  • “While different mechanisms including environmental toxins and genetic factors initiate neuronal damage in the substantia nigra and striatum in PD, there is unequivocal evidence that activation of neuroinflammatory cells aggravates this neurodegenerative process.” (Wilms 2007)
  • “The aging brain is characterized by a shift from the homeostatic balance of inflammatory mediators to a proinflammatory state. This increase in neuroinflammation is marked by increased numbers of activated and primed microglia, increased steady-state levels of inflammatory cytokines and decreases in anti-inflammatory molecules.” (Sparkman 2008)
  • “Microglia can respond to immunological stimuli and neuronal death to produce a host of toxic factors, including cytokines and ROS (reactive oxygen species). Microglia can also become persistently activated after a single stimulus and maintain the elevated production of both cytokines and ROS, long after the instigating stimulus is gone. Current reports suggest that this chronic microglial activation may be fuelled by either dying/damaged neurons or autocrine and paracrine signals from local glial cells, such as cytokines.” (Hong 2007)

While there may be a great deal of variety in response based on individual age, sensitivity, environmental exposures, genetics, and the usual list of  proposed causes, chronic microglial activaion is at the core.

The Common Element

The central feature of our drama is the response of the immune system within the brain and the failure of the activated microglia to revert to a dormant status at the appropriate time. This results in a decades-long degenerative process that ultimately leads to the group of disorders of which PD and AD are the best-known. For PWP, the option of anti-inflammatory treatment with either NSAIDs or traditional botanicals assumes new prominence.

Microglial over-reaction is essentially a hypersensitivity to the perceived presence of a pathogen. The pathogen may or may not be present, but the perception is enough to sustain the reaction for years. This hypersensitivity can arise in a number of ways.

  • As a normal part of aging. This accounts for the “classic” presentation of Senior Onset (SOPD).
  • As the result of exposure to viral and/or bacterial toxins at any point in life. This we may call Adult Onset (AOPD).
  • As the result of early life conditions including exposure to the bacterial toxin lipopolysaccharide (LPS) and a cascade of modifying factors. This leads to Young Onset (YOPD) and is by far the more complicated etiology.  It is this complexity that accounts for the bewildering nature of PD.

Senior Onset-

  • “Aging can impair functional interaction that occurs between the brain and the immune system. Recent findings indicate that microglia and astrocytes, innate immune cells of the brain, become more reactive during normal aging. This age-associated increase in innate immune reactivity sets the stage for an exaggerated inflammatory cytokine response in the brain after activation of the peripheral innate immune system.” (Godbout 2009)

As the years creep by, the odds in favor of the immune assault increase.If we accept the figure of twenty years for gestation, then about the 40 to 50 years of age window, an event occurs that initiates the cascade. As we saw with the St. Judes work, it can be a simple virus long since forgotten when the first tremor is noted.

Adult Onset-

This is a hybrid of the other two. Unlike YOPD, the cascade begins in the adult years and the environmental influences are lessened. The sequence of events is similar to SOPD but with a starting point earlier in life which negates the influence of aging. The trigger is typically exposure to pathogens such as influenza, nocardia, or salmonella. At least one case involving the lipopolysaccharide from the latter is on record in the form of the unfortunate Ines Niehaus, a young lab technician injured by broken glassware.

Young Onset

This is, by far, the most complicated etiology of PD, Its origins lie in the fetal environment if not even earlier. Most, if not all, of the various causes proposed for PD have an influence. Of particular importance is the exposure to the bacterial endotoxin lipopolysaccharide (LPS). If this occurs at a critical time of development, the child is born with a latent hypersenitivity to LPS. Because this endotoxin is ubiqutous, further exposure is inevitable.  Such is the complexity of this portion of our quest that it will be addressed in its own venue.

Addendum (10/18/09):

Medical News Today published an excellent report on the St. Judes work prompting these further comments:

It is getting more and more clear that the “multiple hit” promoters have been correct-

  • “This study also supports the theory that a hit-and-run mechanism is at work in Parkinson’s disease. The investigators believe the H5N1 infection sparks an immune response that persists long after the initial threat is gone, setting patients up for further devastating losses from a second hit, possibly from another infection, drug or environmental toxin. In this case, researchers believe the flu virus is the first hit that sets up development of Parkinson’s at a later time.”

It is curious that the work of German researcher Braak is not mentioned in any of this-

  • “Previous studies had isolated H5N1 in the nervous system. But this is the first to show the path the virus takes to enter the brain as well as the aftermath of the infection. Smeyne said the virus’ path from the stomach through the nervous system and into the brain is reminiscent of how Parkinson’s unfolds.”

The work also seems to go a long way toward answering questions regarding the role of alpha-synuclein-

  • “Researchers also found evidence that the avian flu infection led to over-production of a protein found in the brain cells of individuals with both Alzheimer’s and Parkinson’s diseases. The protein, alpha-synuclein, collected in H5N1-infected cells throughout the brain, including the midbrain where key dopamine-producing cells are located. There was little protein accumulation in the brain cells of uninfected mice.”

The article also reports that observations of a link between influenza and neurological problems go back to 1385.  It would be a mistake, however, to think of influenza as the only trigger.  Other viruses, polio for example, follow the same path from the stomach to brainstem. It is probably in error to even simply limit it to viral origins and exclude bacterial ones. In fact, once the hypersensitivity of the microglia is established any number of actors might claim the stage.

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