Replies to Post #161600 onAnavex Life Sciences Corp (AVXL)

Replies to #161600 on Anavex Life Sciences Corp (AVXL)

08/05/18 4:33 PM

#161603 RE: Investor2014 #161600

In other word you want a drug to ineffective at producing ROS under normal conditions.

This view is NOT held by the authors of the paper nor the scientific community in general. One area I did not disagree with Sokol was the idea of hormesis given in the Wikipedia reference he quoted which, when referring to hormesis stated "The accumulation of transient low doses of ROS either through chronic physical activity or caloric restriction influences signaling from the mitochondrial compartment to the cell, reduces glucose metabolism, induces mitochondrial metabolism, increases stress resistance and ultimately, increases lifespan. "

The authors of the Goguadze study say much of the same but in more detail and technical terms.

Such ROS increase,
generated by inducing s1R activity in normal conditions,
could constitute a physiological signal. Indeed, ROS function
as mediators of signal transduction by triggering redox regulation
of proteins, enzymes, and ion channels (Angelova and
Abramov 2016) and may constitute a method of communication
between mitochondrial function and other cellular processes
to maintain cell homeostasis and promote cell adaptation
to stress (Sena and Chandel 2012). Different sites of mitochondrial
ROS production have distinct signaling roles and
the primary production sites likely change under different
physiological conditions (Sena and Chandel 2012). For instance,
ROS phosphorylated epidermal growth factor (EGF)
and platelet-derived growth factor (PDGF) receptors, thus
mimicking growth factor-induced signaling (Miller et al.
1994; Gamou and Shimizu, 1995). H2O2 activated phospholipases,
including cytosolic PLA2, which has been shown to
be translocated to the membrane fraction in a calciumindependent
fashion and concomitantly activated (van
Rossum et al. 2004). ROS signaling modulates ion channel
function, including BK, KCN, ERG, or TRP channels, and
consequently regulates neuronal excitability (Angelova and
Abramov 2017). ROS induction also triggers cytoprotective
pathways and, for instance, ROS are potent regulators of the
Bcl-2 expression via both transcription and protein degradation
(Hildeman et al. 2003; Li et al. 2004). ROS decrease the
expression of Bcl-2 mRNA by promoting CRE-binding protein
or NF-?B to CRE and ?B sequences on the Bcl-2 promoter
or by facilitating protein degradation (Sohur et al. 1999;
Pugazhenthi et al. 2003; Li et al. 2004). Interestingly, s1Rs
have previously been shown to promote cell survival in part
by transcriptionally regulating Bcl-2 expression via the ROS/
NF-?B pathway, since knockdown of s1Rs potentiated H2O2-
induced apoptosis in CHO cells (Meunier and Hayashi 2010).
It therefore appears that oxidative stress is a major component
of physiological s1R activity.
Mitochondrial ROS can be generated through different
mechanisms and the beneficial or damaging effects of ROS
are initiated when they target distinct molecules and consequently
begin functioning as part of complex signal transduction
pathways. Various ROS have different physical and
chemical properties that allow them to modify distinct target
molecules. The reduction-oxidation-dependent signaling system
is highly conserved and based on the oxidation and
reduction of cysteine residues. Experimental evidence suggests
that ROS generation causes reversible posttranslational
modification, not only of cysteine residues but
also of selenocysteine, methionine, and histidine residues
(Johnson 2011). Although the mechanisms underlying ROS
signaling are not fully understood, at individual mitochondria
level, ROS may trigger opening of mitochondrial permeability
transition pore (mPTP) in intact cell systems. The phenomenon
of ROS-triggered mPTP opening associated with further
stimulation of ROS formation has been termed ROS-induced
ROS release (Zorov et al. 2000). Sources of mitochondrial
ROS include ETC, the mitochondrial matrix and enzymes of
the tricarboxylic acid cycle (TCA), or, for instance, the outer
membrane enzyme monoamine oxidase (for reviews, Tahara
et al. 2009; Angelova and Abramov 2016).

As for your points about A2-73 showing some positive effects in mitigating oxidative stress, I did not go over them closely but I expect you've faithfully reproduced parts of the text. My point has always been that overall it underperforms. I never said that it had no effects whatsoever...that was someone else falsely ascribing that view to me.