Hi Reddit, I’m Susanna Rosi and I’m interested in understanding why our brain loses the ability to learn and form new memories. One of the models we investigate is physical trauma, such as concussions, that can lead to long-term and sometimes permanent changes in memory. Recently, my team has been working with a drug-like compound called ISRIB, which has been shown to have protective and restorative effects on cognition. In our recent studies of mice that received a traumatic brain injury, a dose of ISRIB administered even weeks after trauma was able to restore the mouse’s ability to perform memory-related tasks.
Here’s an article UCSF produced about my latest research: https://www.ucsf.edu/news/2017/07/407656/drug-reverses-memory-failure-caused-traumatic-brain-injury
I’m interested in the molecular basis of injury-induced dementia, the contributions of different cell types (neurons, microglia, astrocytes, infiltrating leucocytes) to cognitive deficits, and compounds that could protect or even enhance cognition. I will be back at 1 pm ET to answer your questions, Ask me anything!
EDIT: Hello everybody, I am here to answer your questions, and surprise! I also have Austin Chou and Karen Krukowski, the authors on the paper, here with me. Looking forward to answering your questions!
EDIT: Thank you, everyone, for your thoughtful questions! We will be signing off now, but we had a lot of fun responding.
Hi Susanna, and thank you for doing this AMA. This is obviously an important area of research.
I have to be honest, I struggled when reading your article because ISRIB looks like such a sketchy molecule. I struggle to call it "drug-like". Before even considering off target effects, the solubility of the molecule scares me. From your paper:
Drug Administration. ISRIB solution was made by dissolving 5 mg ISRIB in 1 mL dimethyl sulfoxide (DMSO) (Fisher Scientific, D128-500) and 1 mL polyethylene glycol 400 (PEG400) (EMD Millipore, PX1286B-2). The solution was gently heated in a 40 °C waterbath and vortexed every 30 s until the solution became clear. The solution was kept in a warm environment throughout the experiment. Each solution was used for injections up to 4 d maximum. If the solution became visibly cloudy or precipitated, a new solution was prepared. ISRIB was delivered at 2.5 mg/kg dosage through i.p. injections. The vehicle solution consisted of 1 mL DMSO and 1 mL PEG400.
A couple of questions:
What sort of pharmacokinetic experiments did you with ISRIB? If I understand your dosing scheme, it looks like you gave the drug once, the day before the trauma, and then again 29 days later before the memory/cognition test. But previous studies suggest that the half-life of ISRIB is incredibly short. How do you imagine the drug is working in your models given this half-life?
Are there genetic experiments that support your proposed mechanism of action for ISRIB? My understanding is that these results are somewhat contrary to what might be expected from genetic studies.
Do TBI-treated mice in these models exhibit some biomarker that can be used to quantify damage (i.e. a tau related marker as is used in CTE)? If so, is there any evidence that ISRIB reduces this biomarker in TBI mice?
Thank you for your thoughtful post!
To clarify, we gave the drug starting at 29 days later, the day before behavior tests. The drug was then given with 1 injection per day for the duration of our behavior test (which at most was 4 days). The half-life of ISRIB is indeed 8-12 hours. Our collaborators on the paper, Peter Walter and his lab, have tested the pharmacokinetics of ISRIB. The drug is also currently licensed to Calico for further studies.
An important nuance of our experiments is that ISRIB is given only in a short treatment window at a time long after injury. This would be markedly different from a genetic experiment. However, our collaborator Mauro Costa-Mattioli has extensively worked on this pathway from a genetic perspective to confirm that ISRIB acts upon eIF2 and ATF4 pathway.
To clarify, a biomarker is a molecule that is easily measurable to predict the outcome of an injury. However, such a molecule has not yet been identified in animal models or human patients.
How do you induce a traumatic brain injury in mice? What's the next step in this research?
Hi, thank you for your question.
Rosi and her team first used mechanical pistons to hit anesthetized mice in precise parts of their surgically exposed brains, resulting in contusive injuries, focused blows that can also result from car accidents or being hit with a heavy object.
Hello susanna, would this be a treatment to ptsd?
Great question! PTSD is certainly comorbid with TBIs. ISRIB could treat TBI injuries, but whether it would have an effect on PTSD-specific pathways is outside our expertise.
Do you think athletes (Boxers specifically) could take this drug while remaining active in the sport? If the drug were to work, would the affected athlete still be able to play while taking the drug?
If the sports results in a TBI, the athlete should not return to play until cleared by a medical doctor. But to answer your question about ISRIB, we have not seen any side effects in our rodents that alters their physical activity.
Hello! 2nd year Med student interested in Neurology/AD here curious to hear your perspective on the neurological basis of memory loss in AD. When we start to see loss of semantic memory through word finding difficulties early on, are the neurons responsible for holding the memories or retrieving them damaged? Would this drug you are studying have the potential to target specific areas of the brain if distinct, disturbed cognitive processes were discernible based on functional differences observed via fMRI/PET/etc?
Thanks so much for doing this! I always learn a lot from these science based AMA's!!
That's a million dollar question (which neurons are damaged). I believe it is not clear yet in the AD field whether the neurons are directly damaged or if the circuit is malfunctioning during early stage AD.
We have not observed region-specificity to drug delivery, but that is not to say there isn't cell-specificity.
So, I've got a colleague that survived a terrible accident falling more than 60 ft in the mountains, entering a coma and showing in the mri diffuse axonal damage. Few people thought she was going to survive, let alone well.
A year after that she was perfect, physically and mentally. My question is just... How??? What happened?? What's the difference between her and someone who doesn't recover?
Wow, your colleague is a great example of extreme human resilience! Certainly one that we can not medically explain yet.
Concussions and brain trauma has been a hot topic in regard to American Football lately. Do you believe there is a significant link between football and brain trauma? If so could the compound be used to potentially treat sport's related brain trauma?
Hi, thanks for the topical question. The link between football and TBI is hotly debated. As you can see, there is growing evidence that repeated head trauma can lead to CTE: https://www.nytimes.com/interactive/2017/07/25/sports/football/nfl-cte.html
We are certainly looking into repeated-injury models and are hopeful that ISRIB could have a positive effect.
Thanks for taking the time for an AMA, Dr. Rosi. The latest research you linked to is fascinating! As a prospective graduate student applying for programs this year, in your opinion, what university programs, including UCSF's, would you recommend that have strong focuses in traumatic brain injury? Additionally, would you have any recommendations of programs or specific faculty that currently have strong focuses in neuro-cognitive investigations (especially those with a more behavior, neuroanatomy and cell-centric approach, rather than a overwhelmingly molecular approach)?
Thank you for your inquiry. I enthusiastically support UCSF's graduate programs. We rank highly every year and have lots of top labs in neuro-cognitive fields. As you can see from our study, this was a collaboration between two UCSF labs with very different backgrounds.
Any chance of a clinical trial you would take someone for?
Unfortunately, ISRIB is still far from being used to treat humans. Our lab only focuses on preclinical models and more research really needs to be done.
Hi Ms (Dr?) Rosi. Do you think that this research/drug will be beneficial for patients who have suffered from hypoxic brain injuries? How old would an injury have to be before you'd deem it too old to be able to be helped, do you think?
So hypoxia and TBIs share some similarities, and as long as the integrated stress response is chronically activated, we would be able to speculate that ISRIB can be beneficial.
If you need another lab rat, I'll volunteer, because I've had quite a lot of traumatic brain injury from getting hit by a car, and had most of my RTL resectioned about 15 years later. I figure that I owe it to humanity to let science learn all it can from what happened to me so it can help others.
I really appreciate your enthusiasm. However, ISRIB is still far from human trials.
Hi Dr Rosi! Does the same drug help with lost past memories, or only the creation of new memories/learning?
It's a great question about past memories. While our work shows that ISRIB is effective for new memories, we have not investigated whether existing memories are affected. Importantly, TBI patients as a population tend to have more problems with memory formation rather than retrograde amnesia.
What types of brain injuries do you hope to target in humans? You mention concussions, so presumably that would mean mTBI, which generally have much milder lasting impairments, if any. Do you hope your drug will also help alleviate cognitive impairment from moderate and severe TBIs?
To note, even a mild TBI can have profound long term effects. Our work shows that ISRIB is effective in both a mild, concussive model as well as a focal contusion model, which is a moderate TBI model. We are hopeful that ISRIB will be beneficial across a spectrum of TBIs that have activated integrated stress response.
Hi Susanna, very interesting research. I'm a psychology grad student who works with brain injury, but I don't focus on the molecular side of things. Could you explain your theory of how ISRIB produces these effects, and how likely the effects are to translate to humans?
Thank you for your interest! So after a TBI, the integrated stress response pathway is activated, which is a universal response for damaged cells. This results in decrease of protein translation, including those involved in memory formation (as our collaborator Mauro Costa-Mattioli has shown in other published work). ISRIB targets this pathway and removes the block on translation.
The integrated stress response is a highly conserved pathway between rodents and humans, so if we also see activation in human patients, there is hope that ISRIB can be equally beneficial.
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