A nonsteroidal antiinflammatory drug (NSAID) with nitric oxide-releasing capabilities dramatically reduced amyloid burden in a transgenic mouse model, according to a report in today's Journal of Neuroscience. More surprisingly, it did so while increasing the activity of microglia.
This study adds fuel to several debates, the first being whether NSAIDs should be used to help fight Alzheimer's disease. There is mounting evidence that NSAID use lowers the risk of AD, but that these drugs also can cause gastrointestinal bleeding and ulceration. Nitric oxide (NO)-donating NSAIDs have been developed in an attempt to circumvent this problem.
Marcia Gordon, Paul Jantzen, and colleagues at University of South Florida and elsewhere found that NCX-2216, an NO-releasing derivative of the NSAID flurbiprofen, dramatically reduced the heavy Aβ loads and Congo Red staining found in transgenic mice expressing both Swedish mutant AβPP and mutant presenilin-1. In contrast, ibuprofen produced only modest Aβ reduction and no reduction in staining, the latter result suggesting that ibuprofen only reduced non-fibrillar Aβ deposits but not plaques. A cyclooxygenase-2-selective NSAID reduced neither of these markers.
The study also speaks to the debate on whether the chronic inflammatory response seen in later stages of AD it a good or a bad thing. One side argues that microglia release reactive oxygen and nitrogen species, and other proinflammatory molecules that harm cells. The other side points to evidence that activated microglia can scavenge and clear potentially toxic Aβ deposits.
Jantzen et al. found that the NO-releasing NSAID dramatically increased the activation of microglia in the doubly transgenic mice. In normal mice, however, the drug did not generate activated microglia. Conversely, the same NSAID lacking the NO-releasing function did not activate microglia in the amyloid-burdened transgenic mice. "These data are consistent with the argument that activated microglia can clear Aβ deposits. We conclude that the NO-generating component of NCX-2216 confers biological actions that go beyond those of typical NSAIDs," the authors write.—Hakon Heimer
Q & A with co-author David Morgan, University of South Florida, Tampa:
Q: What is the status of the NO-donating NSAID used in this trial? Is it used in humans, experimental, or slated for clinical trials anywhere?
A: The drug is presently not being used in humans. A closely related compound, NO-naproxen is in clinical trials by AstraZeneca and Nicox for arthritis. Certainly these data encourage further investigation of its potential use in humans.
Q: Do you have any idea what sort of NO-linked mechanism might be at work?
A: It's too early to speculate. We need to identify which components of the molecule are responsible for which actions. We first thought it unlikely the NO at such a low molarity would have much effect on brain, but our data thus far suggest it is responsible for the microglial-activating effects.
Q: The paper appears to suggest that, initially, microglial activation is good, but becomes detrimental when chronic. Given that the Elan trial of an AD vaccine was aborted due to cerebral inflammation, is this question testable in humans?
A: There are many scenarios where activation of microglia is thought to be beneficial. The facial nerve transection model is perhaps best studied in this regard. However, clearly when associated with an inflammatory reaction, microglial activation is believed detrimental (Patrick McGeer refers to this action as "autotoxicity".) My guess is the Aristotelian mean applies here as to almost everything else; a little is good (or can be), too much is bad. The inverted U shaped function is hard to avoid in biology. The question is how to titrate microglia activation.
I think it best to await the longer-term outcomes in the Elan vaccine trial before concluding what the problems are. I have yet to read precisely what the conditions exhibited by the patients were, and have heard rumors ranging from latent herpes virus eruptions to multiple sclerosis caused by the adjuvant, not the Aβ vaccine. Elan has released two somewhat cryptic descriptions. I have every confidence they will provide us with more details once they have fully characterized the problem (reported so far in less than five percent of the patients).
I believe work from other groups and our own lab demonstrating exaggerated astrocyte and microglia activation in aged brain following injury, implies the aged brain is in a proinflammatory state. Bob Floyd has taken to calling this "smoldering inflammation." Hence, I think any agent that might provoke the eruption of a CNS conflagration needs to be evaluated carefully, and prior knowledge of counteragents demonstrated to quell such activation should be available, before administration to humans.
- Jantzen PT, Connor KE, DiCarlo G, Wenk GL, Wallace JL, Rojiani AM, Coppola D, Morgan D, Gordon MN. Microglial activation and beta -amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J Neurosci. 2002 Mar 15;22(6):2246-54. PubMed.