Anavex Life Sciences Corp (AVXL)

[dia76ca]

Alzheimer's, Parkinsons and Retts are only the beginning. Have look at "Sigma-1 receptor as a Pluripotent Modulator in the Living system." Su et al, Trends Pharmacol sci. 2016 Apr:37(4):262-278.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771390/ including,

"CNS diseases reported to associate with the Sig-1R: speculation on the role of the Sig-1R in complex with respective interacting protein partner

The Sig-1R has been reported to be involved with certain CNS diseases (Table 1). Although the exact Sig-1R-interacting protein(s) which may relate to each disease is not totally clear at present, we tentatively place those proteins in the table simply to indicate the possibility as such. Nevertheless, the potential roles of the Sig-1R in interaction with its respective partners in some CNS diseases are speculated as follows.

Amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease)

The loss of function of Sig-1Rs in the motor neuron disrupted the ER-mitochondrion contact, caused a reduction of Ca2+ signaling, and stunned the axon extension, leading to amyotrophic lateral sclerosis in animals [65]. Thus, the action of Sig-1R–IP3R–VDAC in maintaining an intact contact between ER and mitochondria may play an important role in this disease. Further, the close proximity of the Sig-1R to the muscarinic acetylcholine receptor at the plasma membrane [21] may also be involved in this disease. In addition, the Sig-1R-Insig interaction may participate in the etiology of this disease because Insig was reported to be important in this disease by reducing the glutamate-induced excitotoxicity [66].

Alzheimers’ disease

The Sig-1R plays an important role in maintaining the structural integrity of the MAM presumably through the tethering of the Sig-1R with IP3R and VDAC. The ER-mitochondrion cross-talk via the Sig-1R-IP3R-VDAC linkage at the MAM has recently been implicated to play an important role in the pathogenesis of Alzheimer’s disease [57]. Knockdown of Sig-1R caused neurodegeneration. The level of Sig-1Rs is reduced in the brain of human Alzheimer’s patients [57]. In addition, the Sig-1R-Insig interaction may play a role in this disease because Insig has been shown to be involved in the progress of the disease as it affects the cholesterol synthesis [67].

Huntington’s disease

The “dopamine system stabilizer” class of drugs [68] have been suggested as potential agents to treat Huntington’s disease as the drug can act as either a functional agonist or a functional antagonist depending on the initial levels of dopamine. One of those drugs is 4- [3-(methylsulfonyl)phenyl]-1-propylpiperidine (pridopidine) . Pridopidine, in addition to binding to dopamine D2R, binds the Sig-1R with an affinity 20 times higher than that at D2R in a PET imaging study [69], suggesting that pridopidine may work through its duel actions at D2R and Sig-1R [69]. As the Sig-1R has been shown to interact directly with D2R [20], it is tempting to speculate that the Sig-1R-D2R interaction may play an important role in the action of pridopidine. The effect of pridopidine against Huntington’s disease may involve the drug’s ability, like cocaine does [15], to translocate Sig-1Rs to the nuclear envelope to recruit chromatin-remodeling factors to suppress the gene expression of MAOB, thus increasing dopamine level in the brain. This possibility remains to be tested in the future.

Pain or neuropathic pain

The Sig-1R per se or its agonists was demonstrated to be involved in the attenuation of morphine-induced analgesia [25–27]. These results suggest the Sig-1R as an endogenous pain modulator in the CNS. Although the exact molecular mechanism remains to be totally clarified, the Sig-1R was shown to co-immunoprecipitate with the MOR in HEK cells [27]. Further, as stated above, the Sig-1R also co-immunoprecipitates with the NMDA receptor subunit GluN2 [32] as well as with CB1R [33], both of which are known to be involved in pain perception. Thus, the Sig-1R antagonists combined with morphine are being developed as an analgesic agent to reduce the dose of morphine while still maintaining effective analgesia.

Parkinson’s disease

A Sig-1R agonist PRE-084 was found to induce functional neurorestoration in experimental Parkinsonism in that density of dopaminergic fibres is increased and a modest recovery of dopamine level is seen [70]. Further, this agonist treatment also causes a wider intracellular distribution of Sig-1Rs [70], presumably due to the agonist-induced Sig-1R translocation. As such, although the Sig-1R-interacting partner protein was not identified in this report, it is tempting to speculate that the Sig-1R agonist PRE-084 may cause the translocation of Sig-1Rs to the nuclear envelope to bind emerin which in turn recruits chromatin-remodeling factors to suppress the gene expression of MAOB [64], thus reducing the dopamine degradation and causing an increase of dopamine in the brain. However, another possibility for the involvement of the Sig-1R in this disease is that the Sig-1R can interact directly with TrKB [36] to enhance the receptor binding and/or signaling of the BDNF that is known to promote the survival of neurons.

Depression

BDNF, a neurotrophic factor, is known to play an important role in the action against depression because BDNF causes increases of dendritic spines and axon elongation for enhanced communications between neurons [71, 72]. BDNF does so via its receptor TrkB at the plasma membrane. The Sig-1R has been shown to be involved in depression partly through the Sig-1R’s action in stabilizing the post-translational processing of mature BDNF [35]. Interestingly, the Sig-1Rwas also shown to co-immunoprecipitate with TrkB [36], suggesting that one of the antidepressive actions of the Sig-1R may be due to its ability to bind the BDNF receptor TrKB and enhance thereof the downstream signaling of TrkB.

Cocaine addiction

The Sig-1R-Kv1.2 interaction has been shown to shape neuronal and behavioral responses to cocaine [41]. This study demonstrated that cocaine “hijacks” Sig-1R to increase the interaction between Sig-1R and Kv1.2 potassium channel to decrease the intrinsic excitability of GABAergic neurons, thus leading to cocaine-induced behavioral sensitization. In addition, cocaine also causes the translocation of Sig-1R from the ER to the nuclear envelope to interact with emerin to suppress the gene transcription of dopamine-metabolizing enzyme MAOB to facilitate the action of cocaine [64]."