mTOR inhibitors and the Blood Brain Barrier

[John_Hemming]

We already have a thread on Rapamycin

Rapamycin and the Issue of Getting Through the Blood Brain Barrier

[csf_Blood_brain] Over the past year or so I’ve head many times that Blagosklonny takes a higher dose of rapamycin (20mg+) every two weeks because (he’s suggested) it helps increase the passage of the rapamycin through the blood brain barrier (and therefore increased mTOR inhibition in the brain), and I’ve asked him what research he based this on, but never got a response. Today I just found what may be the information / conjecture that this belief is based on. Here is the quote and paper below: The focus of this research study is in part to see the effect of rapamycin on the mouse model of Leigh Syndrome (LS), which has a significant impact on the brain, as specified below: Leigh Syndrome (LS) is a severe mitochondrial disease that occurs in about 1:40,000 newborns and is associated with retarded growth, muscular deficits including myopathy and dyspnea, lactic acidosis, and a characteristic progressive necrotizing encephalopathy of the vestibular nuclei, cerebellum, and olfacto…

I think the essential conclusion on Rapamycin is that any that gets through the BBB is pumped out pretty quickly via transport proteins.

The same appears to be the situation with Everolimus although the reported levels in CSF are 5% of serum.

Hence one might conclude that the situation is similar with Rapamycin.

However, I think it is worth getting together a list of mTOR inhibitors that have no difficulty with the Blood Brain Barrier.

Which are people’s preferred molecules?

[adssx]

Monepantel: Monepantel: a brain-penetrant mTOR inhibitor

And SGLT2 inhibitors: Canagliflozin - Another Top Longevity Drug - #1724 by Davin8r

[adssx]

We really need a brain penetrant rapalog: Rapamycin exerts geroprotective effects in the ageing human immune system by enhancing resilience against DNA damage (BioRxiv)

[John_Hemming]

That’s true. I think the difficulty lies in there being pumps to pump out things that do this.

There are other routes to neurons. PEMF may be an option. HIF obviously is. I wonder to what extent melatonin actually reverses mitochondrial damage rather than preventing it.

All the AMPK activators are worth looking at, but it would be nice to have a rapalog.

[John_Hemming]

A suggestion from twitter. Co-dose with verapramil.

[CronosTempi]

Telmisartan crosses the BBB, and is neuroprotective in certain contexts (I posted studies in the telmisartan thread).