Pipeline-in-a-drug, page-230

I came across an interesting article today on the "Interesting Engineering" website - Alzheimer’s enzyme reveals how inflammation contributes to cognitive decline.

Gemini summarises the article as follows:

Scientists identified a key enzyme, SIRT2, involved in memory loss associated with Alzheimer's disease. The research highlights how brain cells called astrocytes, when they become reactive in Alzheimer's (for example, in response to amyloid-beta plaques), contribute to cognitive decline by overproducing an inhibitory neurotransmitter called **A. This excessive **A production dampens brain activity and impairs memory. The study also identified another enzyme, ALDH1A1, working alongside SIRT2 in this **A overproduction pathway. The researchers suggest that understanding these enzymes could lead to more targeted therapeutic approaches, potentially allowing scientists to selectively inhibit harmful **A production without affecting other cellular processes, which would help in studying the individual roles of different molecules in the progression of Alzheimer's disease.

The article concludes with the following "Although SIRT2 itself may not be an ideal drug target given its limited influence on neurodegeneration, the findings lay critical groundwork for developing more targeted therapies to regulate astrocytic reactivity in Alzheimer’s disease."

I found that last part interesting as I sat in on a webinar on Friday that discussed concussion in sport. The presenter talked through a range of topics and covered some of the neurological 'sciency' information about what happens in the brain with concussions.

I got bored during a follow up speakers Type 1 Diabetes discussion so I asked Gemini to review all available literature and studies online, to determine whether NNZ 2591 could be applied as a treatment for Concussion/TBI - as you do

It provided the following response - The mechanism of NNZ-2591 is related to regulating the IGF-1 pathway and normalizing the function of glial cells (astrocytes and microglia), which play roles in brain development, communication, and inflammation.
I then asked whether the mechanism of action applies? Does the research show it is likely applicable based on what happens in the brain following a concussion/TBI and what NNZ 2591 does?

It provided the following response - Based on its known mechanism of action and the pathophysiology of concussion/TBI, there is a plausible scientific rationale to suggest that NNZ-2591 could potentially have beneficial effects. Here's why:

1. Targeting Glial Cell Function (Astrocytes and Microglia):
Concussion Pathophysiology: Following a concussion, glial cells (microglia and astrocytes) become activated. This activation is crucial for the initial cleanup of debris and initiating repair, but prolonged or excessive activation contributes significantly to persistent neuroinflammation, synaptic dysfunction, and potentially chronic symptoms. This neuroinflammatory response is a key target for TBI therapies.NNZ-2591 Mechanism: The drug aims to normalize glial cell function. This is potentially more sophisticated than simply blocking inflammation. If it can temper the excessive, detrimental activation while allowing for the beneficial, protective functions of these cells, it could help resolve inflammation more effectively and support a healthier brain environment for recovery.
2. Modulating the IGF-1 Pathway:
Concussion Pathophysiology: Insulin-like Growth Factor 1 (IGF-1) is vital for normal brain development, plasticity, and survival. Levels and signaling pathways involving IGF-1 can be disrupted after TBI. IGF-1 has known neuroprotective roles and is involved in repair processes, including neurogenesis and synaptic remodeling. Dysregulation after injury could impair recovery.NNZ-2591 Mechanism: NNZ-2591, as a cGP analogue, interacts with the IGF-1 pathway. By modulating this pathway, it might help restore balance, enhance the brain's natural protective and repair mechanisms, support neuronal health, and improve synaptic function post-injury.

3. Supporting Synaptic Function:
Concussion Pathophysiology: Concussions disrupt neuronal function and communication, leading to synaptic dysfunction, which underlies many cognitive, emotional, and physical symptoms. Problems with synaptic plasticity can hinder recovery.NNZ-2591 Mechanism: By influencing IGF-1 and potentially normalizing the glial environment that supports neurons, NNZ-2591 may help stabilize or restore synaptic function, which could translate to improved neurological recovery.
Conclusion on Applicability:
Yes, the core mechanisms of NNZ-2591 – regulating glial cell function/neuroinflammation and modulating the IGF-1 pathway to support neuronal health and synaptic function – directly address key pathological processes known to occur following a concussion or TBI.


Given Gemini's reference to Astrocytes when exploring Concussion/TBI, I wanted to know what it thought of the Interesting Engineering article's reference to Astrocytes and whether NNZ 2591 could conceivably regulate Astrocytic activity. This is what it responded with:

NNZ-2591, a synthetic analog of cyclic glycine-proline (cGP), which is a metabolite of insulin-like growth factor 1 (IGF-1), has shown effects on glial cells, including astrocytes, primarily in preclinical models of acute brain injury and neurodevelopmental disorders.

Key Findings Regarding NNZ-2591 and Astrocytic Reactivity:

• Enhanced Astrocytic Reactivity in Acute Injury: A significant preclinical study on rats with hypoxic-ischemic brain injury found that NNZ-2591 treatment "not only reduced both caspase-3 mediated apoptosis and microglial activation but also enhanced astrocytic reactivity, which may mediate its protective effect." This suggests that in the context of acute injury, NNZ-2591 promotes a form of astrocytic response that is considered beneficial for neuroprotection.
  • Source:Peripheral administration of a novel diketopiperazine, NNZ 2591, prevents brain injury and improves somatosensory-motor function following hypoxia-ischemia in adult rats - PubMed
• Modulation of Neuroinflammation: Neuren Pharmaceuticals states that NNZ-2591's mechanism of action is related to the IGF-1 pathway, which plays a critical role in brain development, maintenance, and repair. Their research indicates that NNZ-2591 can help address neuroinflammation, over-activation of microglia, and dysfunction of synapses. While not always detailing the specific effects on astrocyte reactivity in chronic conditions, the general mechanism involves regulating cellular responses to disease, stress, and injury.
  • Source:Science Behind Neuren's Products - Neuren Pharmaceuticals, Neuren Non-Confidential Presentation - Neuren Pharmaceuticals
• Related Compounds and Astrogliosis: Research on compounds related to NNZ-2591, such as GPE (glycine-proline-glutamate), from which cGP can be derived, also indicates that they may "promote astrocytosis" or "induce astrogliosis." Astrogliosis is a form of reactive astrocytosis, often occurring in response to brain injury or disease.
  • Source:Publications - Neuren Pharmaceuticals, NNZ-2591 - Drug Targets, Indications, Patents - Patsnap Synapse

Considerations:

It's important to note that "astrocytic reactivity" is a complex process. In some situations, like acute brain injury, enhanced astrocytic reactivity (astrogliosis) can be part of a protective and repair mechanism (e.g., forming a glial scar, releasing neurotrophic factors). However, in chronic neurodegenerative diseases like Alzheimer's, sustained or specific types of astrocytic reactivity can contribute to detrimental neuroinflammation and disease progression, as highlighted in the article you initially mentioned.

The current literature indicates that NNZ-2591 enhances astrocytic reactivity in a manner considered neuroprotective in acute injury models. Whether NNZ-2591 could specifically "regulate" the detrimental type of astrocytic reactivity seen in Alzheimer's disease by, for example, dampening chronic inflammatory responses from astrocytes, is not explicitly detailed in the provided search results. However, its general mechanism through the IGF-1 pathway aims to restore normal cellular functioning and modulate neuroinflammation, suggesting a potential to influence astrocyte behavior in various pathological states. Neuren indicates NNZ-2591's effects are "state-dependent," meaning it aims to correct impairment without impacting normal cells.

In summary, while NNZ-2591 has been shown to enhance astrocytic reactivity in a beneficial way in certain preclinical injury models and is known to modulate neuroinflammation, its specific role in regulating the type of astrocytic reactivity implicated in Alzheimer's disease would require further targeted research.

I know that this is not definitive and trials are needed but I thought it was interesting and worth sharing, if for no other reason than to highlight the possible potential that NNZ 2591 has a primary or adjunct therapy.

If the medically minded/trained among us have any views on Gemini's assessment, would love to hear them.