Anavex Life Sciences Corp (AVXL)

[Biostockclub]

Re: Lower dose in PD

“It was recently shown that motor neurons have the highest levels of Sig-1Rs in the central nervous system (CNS), and that Sig-1Rs may help direct the flow of ions through potassium channels [5]. This would be a way of reducing the excitability of motor neurons, therefore slowing the progression of ALS.”

From article by an author who co-authored the paper cited on slide 7 of our CTAD presentation. This was published in 2017 1 year after the one cited in the slide which was published in 2016.

The motor neurons also would apply to Parkinson’s as well as ALS, and dystonia as someone posted.

Here’s the 2017 article that states the above quote.
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-017-0380-6


Here’s the original article link quoted and cited on slide 7 of the presentation
https://www.ncbi.nlm.nih.gov/m/pubmed/26869505/

This is the section quoted on the slide:
“The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum (ER) protein that resides specifically in the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), an interface between ER and mitochondria. In addition to being able to translocate to the plasma membrane (PM) to interact with ion channels and other receptors, Sig-1R also occurs at the nuclear envelope, where it recruits chromatin-remodeling factors to affect the transcription of genes. Sig-1Rs have also been reported to interact with other membranous or soluble proteins at other loci, including the cytosol, and to be involved in several central nervous system (CNS) diseases. Here, we propose that Sig-1R is a pluripotent modulator with resultant multiple functional manifestations in living systems.”
Cite
https://www.ncbi.nlm.nih.gov/m/pubmed/26869505/

My narrative, not a quote, based on above:
The S1r is able to translocate (move) to the plasma membrane (PM) to interact with ion channels in order to “go to where problems in the mitochondria are” - specifically, they reside on the MAM (see above), but move around to problem areas (like a fire truck!) to address the problems (put them out).

So, if there are more S1r’s on motor neurons than other types of neurons (such as ones which control mood - affect depression, ones which affect memory and cognition - cause Alzheimer’s), less of the drug is needed to affect this highly populated area. Tons of receptors (entryways or binding sites) are going to receive the drug, as opposed to fewer open pathways in the memory and cognitive neurons which would need more drug to get in (fewer doors).

Further reason for lower dose necessary (from the transgenic mouse model research):

“Humans are very sensitive to most inflammatory stimuli, whereas mice are highly resistant to the very same stimuli. Indeed, mice are about 10,000-fold more resistant than humans to endotoxin, which is one of the most common pro-inflammatory bacterial toxins used to study inflammation. Unlike humans, mice tolerate millions of live bacteria in their blood before the induction of severe inflammation or shock.”
Cite
https://www.wired.co.uk/article/testing-drugs-on-mice

My narrative, not quote, based on above:
Therefore, due to much higher resistance to inflammation in mice than humans, much higher doses of inflammatory agents are necessary to get the same level of disease or infection and therefore higher doses of meds may be necessary to neutralize the stimuli.
In humans, it is not a 1 to 1 association of dose (based solely on weight).


Btw, outside the scope of this particular topic, but having to do with our drug’s superior performance in apoe gene AD participants, read the second article (2016 - the one used in the presentation on slide 7) to learn how S1r recruits chromatin remodeling factors at the nuclear envelope which affect the TRANSCRIPTION OF GENES.

Note: much more is actually known and understood about the S1r’s mechanism of action in the CNS than we give credit for. Certainly these disease states are complex, however, we have some powerful tools in our kit which we have been studying and understanding as well.

Finally, adding to our understanding in this complex but unraveling field:

An obligatory plug for the “home team” Pittsburgh Supercomputing Center:

“New imaging tools and technologies, like large-volume confocal fluorescence microscopy, have greatly accelerated neuroscience research in the past five years by allowing researchers to image large regions of the brain at such a high level of resolution that they can zoom in to the level of a single neuron or synapse, or zoom out to the level of the whole brain. These images, however, contain such a large amount of data that only a small part of one brain’s worth of data can be accessed at a time using a standard desktop computer. Additionally, images are often collected in different ways — at different resolutions, using different methodologies and different orientations. Comparing and combining data from multiple whole brains and datasets requires the power of supercomputing.”

Note: A SINGLE NEURON can be viewed! And we are establishing a data repository. Please read! Exciting news.
https://www.psc.edu/news-publications/2662-cmu-psc-pitt-building-brain-data-repository

GL to CNS scientists, patients, and investors,
Biostock