Wednesday, July 08, 2020 3:06:35 PM
1. This is from the recent Seeking Alpha article: Anavex Is Likely To Report Positive Parkinson's Disease Trial Results For A2-73, Increasing Share Value https://seekingalpha.com/article/4357368
"PD is characterized by abnormal dopamine signaling due to the loss of dopamine producing neurons....cocaine, and perhaps A2-73 ... enhance D1R and D2R signaling.
PD patients have sworn that cocaine relieves their dyskinesia during "off" episodes." (Dyskinesia is abnormality or impairment of voluntary movement.)
"Sig1R agonists increase Sig1R monomer binding to DAT, stabilizing DAT, and increasing extracellular dopamine. In several different mouse models of PD, treatment with the SigR1 agonist PRE084 significantly attenuated motor impairment. Increased dopamine signaling relieves PD motor symptoms, but there is also evidence that patients with higher Levodopa dosages (dopamine) maintain their cognitive ability."
2. This is from the Fox Foundation: https://www.michaeljfox.org/grant/neurorestorative-effects-sigma-1-receptor-agonist-model-parkinsons-disease:
"In a previous MJFF-sponsored project, we evaluated PRE-084 (an experimental compound binding to the sigma-1 receptor) in pre-clinical models of Parkinson’s disease. Chronic treatment with PRE-084 produced a gradual improvement of motor deficits and activated molecules involved in brain repair. In this project, we will evaluate a sigma-1 receptor agonist (ANAVEX2-73) produced by Anavex, which is now being evaluated in patients with Alzheimer’s disease. In our experimental study, the efficacy of ANAVEX2-73 on Parkinson’s biology will be compared to that of PRE-084 and other Sig-1R ligands. "
3. This from: Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases (Under the heading "Role of S1R in Parkinson's Disease (PD). https://www.frontiersin.org/articles/10.3389/fnins.2019.00862/full
Role of S1R in Parkinson’s Disease (PD)
Dopamine receptors play important roles in learning and memory, motivation and movement and S1R agonists modulate dopaminergic signaling through multiple mechanisms. This has primarily been studied in the context of psychostimulant research, but these results may be important for understanding regulation of dopamine neurotransmission and its dysregulation in HD and PD. S1R appears to differentially regulate dopamine D1 and D2 receptors, as S1R activation by cocaine inhibits D2R (Navarro et al., 2013) and prevents histamine H3 receptor-dependent inhibition of the dopamine D1 receptor, stimulating Gs, recruitment of ß-arrestin and phosphorylation of ERK1/2 (Moreno et al., 2014). Although S1R activation does not affect basal dopamine neurotransmission, it attenuates methamphetamine-induced and DAT-dependent increases in firing of dopamine neurons (Sambo et al., 2017). It also interacts directly with the DAT and attenuates calcium signals evoked by methamphetamine (Sambo et al., 2017). As a result, S1R limits hyperactivity, motivated behavior and reinforcement from methamphetamine (Sambo et al., 2017).
Abnormalities in movement and cognition in PD result from degeneration of dopaminergic neurons projecting from the substantia nigra to the striatum. S1R is expressed in these neurons (Hong W.C. et al., 2017) and it can bidirectionally modulate NMDAR-dependent release of dopamine in striatal brain slice experiments (Gonzalez-Alvear and Werling, 1994). S1R may be decreased in striatal regions that are preferentially affected in PD (Mishina et al., 2005), which could contribute to neuropathology as indicated by studies with S1R KO mice. Similar to PD patients, S1R KO mice have age-related deficits in motor behavior and degeneration of dopaminergic neurons (Hong W.C. et al., 2017). This appears to be related to aggregation and phosphorylation of a-synuclein which may be driven by phosphorylation of eIF2a from ER stress and proteasomal dysfunction (Hong W.C. et al., 2017). Pharmacological inhibition of ER stress prevented oligomerization of a-synuclein, dopaminergic neuron loss and motor impairments in S1R KO mice (Hong W.C. et al., 2017).
Recent studies found that S1R agonists are protective in PD models. For example, chronic treatment with PRE-084 gradually improves PD-like motor deficits from unilateral intrastriatal 6-hydroxydopamine (6-OHDA) lesions (hemiparkinsonian model) when treatment onset was prompt (Francardo et al., 2014). This treatment suppressed neuroinflammation while increasing levels of neurotrophic factors, monoamines (e.g., dopamine and serotonin), dopaminergic innervation of the striatum, and nigral neuron survival (Francardo et al., 2014). Low dose pridopidine treatment (0.3 mg/kg) of unilaterally 6-OHDA-lesioned mice partially protected nigral dopaminergic cell bodies and increased dopaminergic fiber density in the motor striatum (Francardo et al., 2019). This was associated with a gradual restoration of forelimb use (cylinder test, stepping test) and prevention of rotational bias toward the ipsilateral side (Francardo et al., 2019). The delayed recovery of motor function corresponds roughly with the expected timeline of pridopidine-dependent dopaminergic axon sprouting (Francardo et al., 2019). Treatment efficacy was absent in S1R KO mice, which had reduced loss of dopaminergic neurons in the substantia nigra pars compacta, but a greater loss of dopaminergic fibers in the striatum compared to wild-type mice (Francardo et al., 2019). The increased vulnerability of S1R knockout mice to axonal degeneration in the nigrostriatal pathway could relate S1R’s ability to promote growth and repair of neurites (Francardo et al., 2019). The neuroresorative effects of pridopidine were associated with upregulation of neurotrophic factors (BDNF, GDNF, pERK1/2) and associated signaling in the striatum and substantia nigra as well as reduced microglial activation (Francardo et al., 2019).
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