Suppression of Neuroinflammation as a Treatment for Neurodegenerative Disease

There is a growing focus on inflammation in the brain as an important factor in the progression of neurodegenerative disease. One result is greater thought given to therapeutic strategies involving the suppression of inflammatory signaling, akin to the approaches used to control inflammatory autoimmune conditions such as rheumatoid arthritis. I would wager that this is probably not as good a strategy as removing senescent glial cells in the brain, and thus removing their sizable contribution to inflammatory signaling, given the animal data in support of that approach, but it will certainly be attempted in the years ahead.

Inflammation is initiated as the body's immune cells activate inflammatory cascades to prevent tissue damage from injury or infiltrating antigens. Within the central nervous system, microglia, known as 'the brain's immune cells,' interact with astrocytes and neurons by assuming phagocytic phenotypes and releasing inflammatory cytokines. This can cause neurodegeneration, phagocytosis of synapses, diminished neural function, microglial activation, inflammatory cytokine release, and further microglial activation until threat to the neural environment abates. Activation of astrocytes, termed astrogliosis, also occurs as part of the inflammatory process.

When acute, this neuroinflammatory response is necessary and even beneficial to the neural environment in eliminating pathogens or aiding brain repair. However, when extreme threats to the neural environment such as protein aggregates (i.e., lewy bodies, neurofibrillary tangles) accumulate in the brain and protractedly sustain inflammation, continuous gliosis and apoptosis can occur as a result of unregulated inflammatory cytokine release. Continuity of this activated state results in chronic inflammation, which is implicated in virtually all neurological disorders, including Alzheimer's disease, Parkinson's disease, and ALS.

Overexpression of tumor necrosis factor-α (TNF-α), a proinflammatory cytokine with a central role in microglial activation, has been associated with neuronal excitotoxicity, synapse loss, and propagation of the inflammatory state. Thalidomide and its derivatives, termed immunomodulatory imide drugs (IMiDs), are a class of drugs that inhibit TNF-α production. Due to their multi-potent effects, several IMiDs, including thalidomide, lenalidomide, and pomalidomide, have been repurposed as drug treatments for diseases such as multiple myeloma and psoriatic arthritis. Preclinical studies of currently marketed IMiDs, as well as novel IMiDs, support the development of IMiDs as therapeutics for neurological disease. IMiDs have a competitive edge compared to similar anti-inflammatory drugs due to their blood-brain barrier permeability and high bioavailability, with the potential to alleviate symptoms of neurodegenerative disease and slow disease progression.



An analogy to free radicals seems apt here. For a long time it was believed that suppressing free radical activity with antioxidants would be helpful, but then we found out that free radicals are actually really important, and antioxidant supplementation can do more harm than good.

Likewise, recent research points to anti-inflammatory drugs interfering with healing of connective tissue injuries. The inflammatory response is important, and inhibiting it may do more harm than good, unless the inhibition is precisely targeted to harmful inflammation.

In fact, isn't inflammation involved in the signaling pathways promoting the destruction of senescent cells? We might even find that indiscriminate suppression of inflammation inhibits the clearance of senescent cells.

Posted by: Brandon Berg at January 8th, 2020 11:11 AM

What about using these drugs to treat psychiatric disorders, as well? My investigation has found that almost all psychiatric disorders are associated and may be caused by neuroinflammation, not just neurodegenerative disorders. For instance, autism, ADHD, schizophrenia, bipolar disorder, etc. have all been associated with neuroinflammation at some point in their etiology. Seizure and migraine disorders are also associated in both a cause and an effect manner with neuroinflammation! So it seems to me like drugs that reduce neuroinflammation would be highly valuable!

Posted by: Jen Markovics at December 30th, 2020 3:17 PM
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