NSI-189's Mechanism of Action: Theories About How It Works

NSI-189's Mechanism Of Action

The mechanism of action of NSI-189 phosphate remains a trade secret. It has been speculated that NSI-189 binds to the glucocorticoid receptor in the brain. Glucocorticoid receptor binding could be form of negative feedback that decreases circulating cortisol. Cortisol is a stress hormone implicated in depression and other stress-related neuropsychiatric disorders.

Neuralstem screened a library of over ten thousand compounds searching for neurogenic drug candidates, eventually settling on NSI-189. It’s possible that Neuralstem has suppressed information about the mechanism of action of NSI-189 to further protect their intellectual property.

Once NSI-189’s actual target in the brain has been revealed, it is much easier to develop copycat drugs that hit the same receptors. A competing pharmaceutical company could then essentially scoop all of Neuralstem’s preclinical work on neurogenic drugs. This may be one reason Neuralstem hasn’t disclosed NSI-189s mechanism of action.

Healthy individuals are unlikely to realize any benefit from NSI-189. Though Neuralstem is not transparent about NSI-189’s underlying mechanism of action, there are good reasons to think that NSI-189 only normalizes hippocampal neurogenesis in depressed patients whose baseline rate of neurogenesis is suppressed. Chronically stressed individuals with depression stand to gain the most.

If you have a lot of time on your hands, Neuralstem’s patent submission for NSI-189 is an excellent read.

What is NSI-189 Phosphate?

NSI-189 is an antidepressant drug under clinical development by Neuralstem. NSI-189 was identified by screening for compounds that increase neurogenesis. Neurogenesis refers to the process by which new neurons are generated from neural stems cells and progenitors and proliferate in the central nervous system (CNS).

The idea is that depression can be alleviated by enhancing neurogenesis in the hippocampus–a brain structure implicated in learning, mood, and memory.

To be crass, Neuralstem wants to improve your mood by repopulating your brain with newly minted neurons. This sounds pretty crazy, but NSI-189 isn’t particularly novel in this respect. Almost all antidepressants – independent of class or mechanism (SSRI, tricyclic, etc.) – seem to increase neurogenesis, at least in rodents.

Why would increasing neurogenesis bring someone out of a major depression? It is well-documented that chronic elevation of the stress hormone cortisol can damage neurons in the hippocampus. In addition, severely depressed patients seem to suffer from hippocampal atrophy. Hence, repopulating a damaged hippocampus with nascent neurons may be a viable strategy to restore synaptic plasticity.

The depression-neurogenesis link is actually more complicated (and controversial) than it sounds. For example, causality is blurred. Does impaired neurogenesis cause depression, or vice-versa? Some scientists are skeptical neurogenesis has any functional significance at all in adulthood, because it’s restricted to very specific brain regions, and the turnover of neurons is very low.

Speculation About NSI-189’s Mechanism

A few hypotheses have been developed about NSI-189’s MOA. One speculation is that NSI-189 is a selective glucocorticoid receptor agonist in the brain. Since glucocorticoids are regulated by a negative feedback system, NSI-189 induced stimulation of the glucocorticoid receptor would result in a decrease in circulating cortisol (the stress hormone implicated in depression and other stress-related affective disorders). The glucocorticoid receptor is thought be one mechanism by which depression would suppress neurogenesis.

Some circumstantial evidence supports this view. For example, the side effect profile of NSI-189 seems to be similar to the glucocorticoid agonist, dexamethasone. Some of the side effects of NSI-189 include fatigue or mild sedation, difficulty waking in the morning and increased appetite, which is consistent with the notion that NSI-189 may be a glucocorticoid receptor agonist.

Another idea that has been proposed is that NSI-189 may be a very selective serotonergic drug. It is already well-doucmentated that most (if not all) SSRIs dose-dependently increase neurogenesis in rodents and humans alike. NSI-189’s side effect profile also roughly overlaps with the SSRIs.

Why Healthy Individuals Should Avoid Experimenting With NSI-189

It is tempting to think that if drug X enhances biological process Y in a certain disease context, that X would also enhance Y in a disease-free individual. For example, cortisol administration improves cognitive function in patients with Addison’s disease (a disease of impaired cortisol secretion), but giving cortisol to a healthy subject would only be harmful.

Another fallacy is that supra-normal activity of a biological process are favorable.

For example, could too much neurogenesis be deleterious? Some evidence suggests that while SSRIs increase the rate of neurogenesis, they don’t affect the rate of integration of new neurons. This suggests that SSRIs are just stirring the pot and possibility depleting neural stem cell precursors without affecting functional intgregration of new neurons.

Trade-Offs Between Neuroplasticity and Neural Network Stability

“Enhanced Neuroplasticity” has become a buzzphrase that is assumed at the outset to be beneficial.

These assumptions stem from the observation that impaired neuroplasticity underlies many disease states, e.g., depression and Alzheimer’s disease.

What is often overlooked is that neuroplasticity is actually finely tuned by the brain at the local level of individual synopsis (connections between neurons).

You may think your brain needs to be moar plastic, but actually too much neuroplasticity will destabilize neural circuits. Destabilization of neural networks results in mental illness, e.g., bipolar disorder which is in part caused by instability of neural circuits in the amygdala (the part of the brain that appraises fear and emotion).

The fact that the brain is highly malleable during childhood and adolescence but more static in adulthood is by design. This is not a bug, but a feature.

  • Neuralstem Press Release: Phase 1b Biomarker Data
  • Results of Phase 1b Trial (Poster as a PDF)
  • Neuralstem Press Release: NSI-189 Shows Benefits in Major Depressive Disorder
  • QEEG Effects of NSI-189 (Poster as PDF)
  • Published papers about NSI-189
  • Method for screening neurogenic agents (Neuralstem patent) 
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Xavier Kent

I'm interested in nutrition, nootropics, and javascript. I'm a firm believer in getting really good at one thing.


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