Replies to post #158855 on Anavex Life Sciences Corp (AVXL)

[nidan7500]

F1ash, thanks for the great effort and for this information. w/any luck this week could include the most important 3-5 days in many, many lives.

At least validation of the sigma1 approach if not A2-73 in particular.

“We therefore evaluated the effect of ANAVEX2-73 and PRE-084, a reference s1R agonist, on preservation of mitochondrial integrity in Aß25-35-injected mice. In isolated mitochondria from hippocampus preparations of Aß25-35 injected animals, we measured respiration rates, complex activities, lipid peroxidation, Bax/Bcl-2 ratios and cytochrome c release into the cytosol. Five days after Aß25-35 injection, mitochondrial respiration in mouse hippocampus was altered. ANAVEX2-73 (0.01-1 mg/kg IP) restored normal respiration and PRE-084 (0.5-1 mg/kg IP) increased respiration rates. Both compounds prevented Aß25-35-induced increases in lipid peroxidation levels, Bax/Bcl-2 ratio and cytochrome c release into the cytosol, all indicators of increased toxicity. ANAVEX2-73 and PRE-084 efficiently prevented the mitochondrial respiratory dysfunction and resulting oxidative stress and apoptosis. The s1R, targeted selectively or non-selectively, therefore appears as a valuable target for protection against mitochondrial damages in AD.”

https://bscb.org/learning-resources/softcell-e-learning/mitochondrion-much-more-than-an-energy-converter/

“Mitochondria: determinators
Recent research indicates that in addition to converting energy mitochondria play quite a large part in determining when a cell will die by ordinary cell death (necrosis) or programmed cell death (apoptosis). In apoptosis the mitochondrion releases a chemical, cytochrome c, and this can trigger programmed cell death (apoptosis).

[Investor2014]

Thanks F1ash.

Please read below in the context that I am not trained in biology or medicine.

Related to this in a recent thread a poster quoted excerpts from this paper:
Sigma-1 Receptor Agonists Induce Oxidative Stress in Mitochondria and Enhance Complex I Activity in Physiological Condition but Protect Against Pathological Oxidative Stress

It is important to note the title of the paper and the difference between Physiological (naturally occurring conditions in biology) and Pathological (abnormal objectively or subjectively occurring in disease) conditions.

In other words if a compound is ineffective or only slightly attenuates in Physiological conditions, in layman terms it doesn't mess up something that is working ok. Whereas, the right kind of activity is desired in Pathological conditions.

Having reviewed the complete paper it appears those excerpts were picked mainly from the section of the paper that discuss activity in Physiological conditions. (It of course helps to have full access to research papers if you want to get the full context and not rely on potentially misunderstood excerpts).

We analyzed their impact on mitochondrial ROS production and oxidative respiration, in physiological and pathological conditions induced by direct application of Aß peptides.

We probably all recall Missling's firetruck analogy of SR1 being inactive in Physiological conditions and becoming active to put out the fire in Pathological condition. It looks like those critical posts forgot to mention that only A2-73 remained inactive in Physiological conditions and had superior activity in Pathological conditions exactly as one would want.

In fact in Physiological conditions only the

ANAVEX compounds also increased markedly complex I activity (Fig. 4b).

Now this is a good thing since Mitochondrial function, in particular complex 1 of the electron transport chain (ETC), has been shown to decrease during normal ageing and in neurodegenerative disease.
Mitochondrial Complex 1 Activity Measured by Spectrophotometry Is Reduced across All Brain Regions in Ageing and More Specifically in Neurodegeneration

The first mentioned paper concludes:

The s1R agonists (PRE-084, AN1-41, and to a lesser extent AN3-71) decreased Aß1–42-induced increase in mitochondrial ROS. s1R antagonists did not affect Aß1–42-induced increase in mitochondrial ROS. This observation confirmed that, in pathological conditions, s1R agonists have direct anti-oxidant potential in mitochondria. In order to determine whether this effect was due to a restoration of ETC, we analyzed the oxidative respiration and observed that PRE-084, AN1-41, and AN2-73 attenuated or significantly prevented the Aß1–42-induced decrease in RCR, indicating that the ETC worked more efficiently. Indeed, Aß1–42 altered in the same concentration range, both complex I and complex IV activities. These effects were significantly prevented by PRE-084 for complex I and IV activities and the ANAVEX compounds for complex IV activity. The s1R antagonists remained without effect. These data confirmed the direct mitochondria protective effect of s1R agonists. The mechanism of action may combine a general effect on TCA cycle efficacy and up-regulation of cellular anti-oxidant pathways. First, amyloid toxicity decrease TCA cycle enzymes, including isocitrate dehydrogenase and a-ketoglutarate dehydrogenase (Mastrogiacomo et al. 1993, 1996; Ko et al. 2001). Therefore, by chaperoning Ca2+ flow, thus balancing Ca2+-dependent TCA cycle enzymes, s1R agonists may be able to maintain NADH pool inside the matrix. Direct measures of s1R ligands effects on TCA enzymes must now be performed to confirm this hypothesis. Second, s1R agonists have been shown to modulate cellular anti-oxidants, including for instance the NF-?B pathway (Meunier and Hayashi 2010). For instance in a neurodegenerative condition, Hyrskyluoto et al. (2013) reported that PRE084 is able to decrease the levels of ROS and oxidative stress in neuronal PC6.3 cells expressing mutant huntingtin proteins via the up-regulation of NF-?B.

The present study therefore confirmed that s1R activity is closely related to mitochondrial physiopathology. In physiological conditions, s1R agonists are able to generate a moderate oxidative stress, through ROS production involving complex I activity. In pathological conditions, such as Aß-induced stress, s1R activity may help to contribute to a rapid restoration of mitochondrial physiology. Detailed analyses on other mitochondrial functional responses and morphological changes by s1R ligands must now be performed.