Anavex Life Sciences Corp (AVXL)

[apostrophe]

Unlike all the other current approaches to treating Alzheimers, Anavex 2-73 targets the sigma1 receptor (Sig1R)

Read about the sigma 1 receptor (it's an odd little cancer research article but within it they do provide an interesting description of S1 (slightly editted for readability):

"... Sig1Rs have been associated with many diseases including stroke, cocaine addiction, Alzheimer's disease, amnesia, amyotrophic lateral sclerosis, retinal degeneration, and cancer. Nonetheless, the way Sig1R operates in such diseases is still poorly understood. Su and colleagues'work on neurons and CHO cells have shed light on the molecular mechanisms underlying Sig1R functions. Sig1R is mainly located at the E[ndoplasmic] R[eticulum], in close contact with the mitochondria, in the so-called mitochondria-associated-ER membrane domains (MAM). In resting condition, Sig1R resides in ceramide- and cholesterol-rich lipid microdomains associated with the ER-resident chaperone GRP78 (BiP) Under cellular stress leading to ER injury, Sig1R dissociates from BiP and binds IP3 receptors, enhancing in turn cell survival through the control of calcium signaling between the ER and mitochondria. In addition, Sig1R translocates to other cell compartments and binds to different membrane proteins. The stimulation with sigma “agonists” mimicks stress-induced Sig1R dissociation from BiP and Sig1R delocalization, while sigma ligands classified as “antagonists” impede this process. Altogether, these results have led to a model in which Sig1R is [(relatively?)] “silent” in normal physiological conditions, whereas in case of a disease, Sig1R behaves as a chaperone that binds client protein to the benefit of cell survival . This exciting hypothesis has been validated by recent studies demonstrating that Sig1R molecular silencing reduces brain recovery after experimental stroke and promotes retina degeneration after acute damage to the optic nerve. ..."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712323/

The researchers in the article think it's "exciting" because they seem to assume that it only mainly benefits cancer cells. They seem focused on blocking S1 to fight cancer cells so they may be a little off assuming it is "silent" in normal cells. I don't know, smart as they are, researchers sometimes seem prone to tunnel vision. It may not be as silent as they thought. It seems more like a "dead man's switch". Take your foot all the way off the pedal and it becomes literal. Is that it. They do say "poorly understood", so I guess shouldn't be too critical. No question though that it is a very important receptor.

The reason I suggested "relatively silent" is that totally silencing the S1R results in programmed cell death. This has been proven experimentally.

"Silencing of sigma-1 receptor induces cell death in human lens cells"

http://www.ncbi.nlm.nih.gov/pubmed/16472803

Programmed cell death of certain cells is also a natural process of growth during reproduction. For example, when the fingers form, they are initially joined and pcd allows them to seperate. So, it looks like if S1 shuts down, the cell sickens and dies. Conversely, if it is switched on, it helps the cell make the right proteins. Switching on strongly yields a kind of enhanced survival mode which seems to relate to a kind of downstream repair that I was envisioning in a previous post.

Somehow I can't envision blocking s1 becoming much of a viable cancer therapy. They would have the same problem as with poisons causing collateral damage to surrounding tissues.

OTOH Anavex 2-73 promoting sustained S1 activation, would seem to be just the right thing to do to help stressed-out brain cells suffering from injury to their ER .

May we also recall that 2-73 binds (agonist) to muscarinic receptors M1 and M4 while avoiding M2 amd M3 activation. Current SOC side-effects suggest errant activation of M2/M3 by Aricept.

M1 - The M1 muscarinic acetylcholine receptors facilitate cue detection behaviors and are necessary and for most direct effects of ACh on pyramidal neuron excitability. Pyramidal cells are principal cells, as opposed to interneurons, that are connecting one brain region or subregion to another. - ok, good to keep that working

M2 - M2 muscarinic receptors are located in the heart, where they act to slow the heart rate down to normal sinus rhythm after positive stimulatory actions of the sympathetic nervous system, by slowing the speed of depolarization - good thing to avoid (too slow of a heart rate) as a side effect. [Also (see below) if Aricept/donepezil (as it appears to do) errantly binds to M2 in the brain, this throttles down new acetylcholine release, which is self-defeating to its purpose of increasing acetylcholine by slowing down the breakdown of existing acetylcholine. Eventually the existing acetylcholine is going to dissipate anyway, but now we are left with even less acetylcholine than before. Probably why it stops working/becomes counter-productive after a while. ]

M3 -smooth muscle contraction, bronchoconstriction, Increase intracellular calcium in vascular endothelium, increased endocrine and exocrine gland secretions, e.g. salivary glands and stomach, In CNS Eye accommodation, vasodilation, induce emesis (vomitting) - good thing to avoid as a side effect

M4 - M4 muscarinic receptors are coupled to Gi/o heterotrimeric proteins.[5]

It function as inhibitory autoreceptors for acetylcholine. Activation of M4 receptors inhibits acetylcholine release in the striatum. The M2 subtype of acetylcholine receptor functions similarly as an inhibitory autoreceptor to acetylcholine release, albeit functioning actively primarily in the hippocampus and cerebral cortex.

Muscarinic acetylcholine receptors possess a regulatory effect on dopaminergic neurotransmission. Activation of M4 receptors in the striatum inhibit D1-induced locomotor stimulation in mice. M4 receptor-deficient mice exhibit increased locomotor simulation in response to D1 agonists, amphetamine and cocaine.[6][7][8] Neurotransmission in the striatum influences extrapyramidal motor control, thus alterations in M4 activity may contribute to conditions such as Parkinson's Disease.[9][10][11]

[I.e.. Probably why Anavex 2-73 is helpful in inhibiting seizures, spasms and inflammation.

With M2, we don't want to inhibit the hippocampus and cerebral cortex. but with M4 in the in the striatum (a different part of the brain that Parkinson's afflicts), we do because it regulates/inhibits uncontrolled movement e.g.Parkinson's Disease. I recall reading about another experimental drug that is intended to help with Parkinson's but it screws up M4 and they were looking for something to ameliorate this. Could be that 2-73 fits the bill right now... ]

"A balanced interaction between dopaminergic and cholinergic signaling in the striatum is critical to goal-directed behavior. But how this interaction modulates corticostriatal synaptic plasticity underlying learned actions remains unclear—particularly in direct-pathway spiny projection neurons (dSPNs). Our studies show that in dSPNs, endogenous cholinergic signaling through M4 muscarinic receptors (M4Rs) promoted long-term depression of corticostriatal glutamatergic synapses, by suppressing regulator of G protein signaling type 4 (RGS4) activity, and blocked D1 dopamine receptor dependent long-term potentiation (LTP). Furthermore, in a mouse model of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson’s disease (PD), boosting M4R signaling with positive allosteric modulator (PAM) blocked aberrant LTP in dSPNs, enabled LTP reversal, and attenuated dyskinetic behaviors. An M4R PAM also was effective in a primate LID model. Taken together, these studies identify an important signaling pathway controlling striatal synaptic plasticity and point to a novel pharmacological strategy for alleviating LID in PD patients.
"
http://www.cell.com/neuron/fulltext/S0896-6273(15)00933-2