Potential New Treatment for Alzheimer’s Disease, Other Neurodegenerative Conditions
Drug developed by Case Western Reserve University researchers found to protect ‘guardian of the brain’
The BBB acts as a “guardian of the brain” by allowing key molecules to enter and leave the brain, while blocking dangerous substances from the blood, including bacteria and virus. Notably, the researcher said, deterioration of the BBB is an early indicator of many forms of neurodegenerative disease, including AD and traumatic brain injury (TBI).
More specifically, the researchers targeted an enzyme in the immune system—known as 15-PGDH (15-hydroxyprostaglandin dehydrogenase)—that they discovered to be especially highly enriched in the BBB. They found that this enzyme is even further elevated in AD, traumatic brain injury and aging in both mice and humans, and that this change harms the BBB.
New drug
With 15-PGDH in the BBB as the focus, the team used a drug (SW033291) they developed at Case Western Reserve School of Medicine and University Hospitals to block the enzyme.
This enzyme-blocking drug was originally developed in the Markowitz lab with support from the Harrington Discovery Institute and the Case Western Reserve School of Medicine for an entirely different purpose. Specifically, it was first shown by Markowitz and School of Medicine Dean Stan Gerson to activate stem cells to repair tissue damage in mouse models of colitis and bone-marrow transplants.
“Finding together that blocking 15-PGDH also blocks brain inflammation and protects the BBB was an exciting new discovery,” Markowitz said. “Notably, SW033291 didn’t change how much amyloid—a sticky protein that accumulates in Alzheimer’s—was in the brain. This is important because the most recently approved AD drugs focus only on removing amyloid and, unfortunately, don’t work very well and have risky side effects. Inhibiting 15-PGDH thus offers a completely new approach for AD treatment.”
Read the full story:
The Research Paper (Open Access)
Inhibiting 15-PGDH blocks blood–brain barrier deterioration and protects mice from Alzheimer’s disease and traumatic brain injury
Significance
Koh et al. show that 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is pathologically elevated in human and mouse Alzheimer’s disease (AD), traumatic brain injury (TBI), and aging, with 15-PGDH localized to myeloid cells of the blood–brain barrier (BBB). They further show that pharmacologic and genetic inhibition of 15-PGDH protects the BBB, blocks production of reactive oxygen species, prevents downstream neurodegeneration, and preserves cognition in mouse models of AD and TBI. Thus, 15-PGDH inhibition represents a therapeutic approach for AD and TBI by protecting the BBB.
There is a lot of research on this drug / chemical SW033291 I can see, and it’s been patented in 2021. But it’s not gone through any phase 1 clinical trials that I can find…
Here is the patent:
WO2021252936 - REJUVENATION OF AGED TISSUES AND ORGANS BY INHIBITION OF THE PGE2 DEGRADING ENZYME, 15-PGDH
Abstract
(EN) The present disclosure provides compositions and methods based on the use of 15-PGDH as a therapeutic target in rejuvenation of aging non-skeletal muscle tissues and/or organs. The 15-PGDH inhibitor SW033291 administered intraperitoneally for 4 weeks resulted in restoration of follicular structure and re-establishment of the marginal zone in spleens of 25 month old mice. Treatment of 25 month old mice with SW033291 also reduced the levels of IL10, IL6, BTC, GM-CSF, IL 13 back to levels similar to 4 month old mice.
As a note, the Empirium drug has apparently begun phase 1 trials. Unfortunately, I haven’t found any reliable source for its structure. It’s the only drug in the class to have made it to trials?
I’m very interested in these compounds. If anyone can come up with a convincing safety story for one I would investigate getting it manufactured.
Essentially, a single injection of PGE2 brokers the exchange in muscle stem cells of a lifetime’s worth of genetic bookmarks and dog-eared pages for a crisp new set of instructions that not only enhances the function of individual muscle stem cells but is also passed down to their descendants.
A single dose of a molecule that dwindles in aging restores long-term strength to old mice
This had fallen off my radar. It looks incredibly promising. It looks as Empirium are moving ahead with human trials. Crossing fingers it’s successful.
Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength
Highlights
EP4 expression and phosphorylated CREB are decreased in aged MuSCs
PGE2 reverses epigenetic and transcriptional changes in aged MuSCs
AI identification of AP1 and grammar responsible for epigenetic rejuvenation
PGE2 treatment increases aged MuSC function and strength after injury and with exercise
Summary
Repair of muscle damage declines with age due to the accumulation of dysfunctional muscle stem cells (MuSCs). Here, we uncover that aged MuSCs have blunted prostaglandin E2 (PGE2)-EP4 receptor signaling, which causes precocious commitment and mitotic catastrophe. Treatment with PGE2 alters chromatin accessibility and overcomes the dysfunctional aged MuSC fate trajectory, increasing viability and triggering cell cycle re-entry. We employ neural network models to learn the complex logic of transcription factors driving the change in accessibility. After PGE2 treatment, we detect increased transcription factor binding at sites with CRE and E-box motifs and reduced binding at sites with AP1 motifs, overcoming the changes that occur with age. We find that short-term exposure of aged MuSCs to PGE2 augments their long-term regenerative capacity upon transplantation. Strikingly, PGE2 injections following myotoxin- or exercise-induced injury overcome the aged niche, leading to enhanced regenerative function of endogenous tissue-resident MuSCs and an increase in strength.
I wonder if Prostaglandin E1 has a similar effect?
AI Overview
PGE1 and PGE2 are both types of prostaglandins, which are hormone-like substances that play various roles in the body. They differ in their chemical structure and have distinct, though sometimes overlapping, biological effects. PGE1 is known to have anti-inflammatory properties, while PGE2 is often associated with inflammation.
Here’s a more detailed breakdown:
PGE1 (Prostaglandin E1):
Anti-inflammatory: PGE1 is known to inhibit certain inflammatory processes.
Platelet inhibition: It can inhibit platelet aggregation, meaning it can help prevent blood clots from forming.
Muscle relaxation: PGE1 can relax smooth muscle in various tissues, including the gut and the lower esophageal sphincter.
Gastric protection: It can reduce gastric secretion, which may help prevent ulcers.
Examples in medicine: PGE1, in the form of misoprostol, is used for cervical ripening and labor induction.
PGE2 (Prostaglandin E2):
Pro-inflammatory: PGE2 is often involved in inflammatory responses.
Pain and fever: It can contribute to pain and fever sensations.
Bone metabolism: PGE2 can influence bone formation and resorption.
Examples in medicine: PGE2, in the form of dinoprostone, is also used for cervical ripening and labor induction.
Key Differences and Similarities:
Receptors:
Both PGE1 and PGE2 bind to different subtypes of prostaglandin E receptors (EP receptors), which are linked to various cellular responses.
Platelet function:
While both affect platelet function, PGE1 is generally a stronger inhibitor than PGE2, which can have both stimulatory and inhibitory effects depending on the concentration and conditions.
Anti-inflammatory vs. pro-inflammatory:
PGE1 is generally considered anti-inflammatory, while PGE2 is often associated with inflammation. However, both can have roles in both processes depending on the specific context.
Clinical applications:
Both PGE1 and PGE2 have clinical uses, including labor induction and cervical ripening, though they may be used in different formulations and routes of administration
There is an approved drug, “Iloprost”, that allegedly has beneficial effects on circulation long after a treatment (IV infusion of 4 sequential days). It acts on various prostanoid receptors but is alleged less active at EP4 than PGE2 is.
