Replies to post #382138 on Anavex Life Sciences Corp (AVXL)

[frrol]

"...small molecules specific to Ca2+ channels or handling proteins on the plasma membrane and membranes of intracellular organelles to correct neuronal Ca2+ dysregulation..."

That's an element of our MOA as an S1 agonist.

[nidan7500]

So, something ..."“An increasing body of evidence suggests that age-related dysregulation of neuronal Ca2+ homeostasis may play a proximal role in the pathogenesis of AD as disrupted Ca2+ could induce synaptic deficits and promote the accumulation of Aß plaques and neurofibrillary tangles. Given that Ca2+ disruption is ubiquitously involved in all AD pathologies, it is likely that using chemical agents or small molecules specific to Ca2+ channels or handling proteins on the plasma membrane and membranes of intracellular organelles to correct neuronal Ca2+ dysregulation could open up a new approach to AD prevention and treatment.”

So maybe adding one of these small molecules to the Anavex treatment would improve results with more advanced AD patients!

< "we know, we know..." (Senge). Getting closer to "CAVU" ... "Ceiling and visibility unlimited on top".

[abew4me]

"The many functions of Sigma1R that are related to the pathology of DEEs and to central nervous system (CNS) physiology suggest a potential role for Sigma1R in the DEE pathophysiology of seizures and in aspects of higher cognitive function.

For example, ANAVEX 2-73 (blarcamesine), which has agonist activity both at the Sigma1R and at muscarinic receptors, is currently in clinical trials for neurodegenerative diseases (NCT03774459, NCT03790709; Alzheimer's disease, Parkinson's disease dementia, and Rett syndrome (which manifests with seizures in most patients)) and was granted FDA's Orphan Drug Designation for infantile spasms in 2016 [41,42,[54][55][56][57]. ...

... In mouse models, Sigma1R agonists are neuroprotective and have improved motor neuron function in neurodegenerative conditions [50]. The Sigma1R agonist ANAVEX 2-73 (blarcamesine) has demonstrated disease-modifying improvements in preclinical models of the neurodegenerative disorder Rett syndrome, and is currently in phase 2b/3 clinical trials for Alzheimer's disease (NCT03790709) and Parkinson's disease dementia (NCT03774459) ( Table 3) [41,[54][55][56][57]. Together, these data show that Sigma1R activity is required for normal motor neuron function. ...

... Sig-1R usually binds to the endoplasmic reticulum molecular chaperone BIP to control the stability and function of specific signaling molecules at the ER and regulate Ca 2+ signaling, intracellular energy supply, and ER stress [13]. When Ca 2+ is depleted, Sig-1R dissociates from GRP78/BIP, resulting in prolonged Ca 2+ transfer to the mitochondria through IP3R [14]. The Sig-1R antagonist RC-106 can also trigger ER stress and enhance GRP78/BIP, ATF4, and CHOP expression, promoting the clearance of unfolded proteins [15]. ...
... RTT is a severe neurodevelopmental disorder associated with mutations in the transcriptional regulator MECP2. The motor, sensory, and autonomic phenotypes of RTT model mice were improved by a Sig-1R agonist [14]. ...

https://www.researchgate.net/publication/337168416_ANAVEXR2-73_blarcamesine_a_Sigma-1_receptor_agonist_ameliorates_neurologic_impairments_in_a_mouse_model_of_Rett_syndrome