Novel Therapeutic Target for Prevention of Neurodegenerative Diseases: Modulation of Neuroinflammation with Sig-1R Ligands

Abstract

Neurodegenerative diseases (NDDs) are characterized by progressive deterioration of the structure and function of cells and their networks in the nervous system. There are currently no drugs or other treatments that can stop the progression of NDDs. NDDs have many similarities and common pathways, e.g., formation of misfolded amyloid proteins, intra- and extracellular amyloid deposits, and chronic inflammation. Initially, the inflammation process has a cytoprotective function; however, an elevated and prolonged immune response has damaging effects and causes cell death. Neuroinflammation has been a target of drug development for treating and curing NDDs. Treatment of different NDDs with non-steroid anti-inflammatory drugs (NSAIDs) has failed or has given inconsistent results. The use of NSAIDs in diagnosed Alzheimer’s disease is currently not recommended. Sigma-1 receptor (Sig-1R) is a novel target for NDD drug development. Sig-1R plays a key role in cellular stress signaling, and it regulates endoplasmic reticulum stress and unfolded protein response. Activation of Sig-1R provides neuroprotection in cell cultures and animal studies. Clinical trials demonstrated that several Sig-1R agonists (pridopidine, ANAVEX3-71, fluvoxamine, dextrometorphan) and their combinations have a neuroprotective effect and slow down the progression of distinct NDDs.

Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice

“…Importantly, thioredoxin-interacting protein has been recently identified as a link between redox state and metabolism where it plays an essential role in normal glucose homeostasis [51]. Furthermore, consistent with our observations of increased MERCS in APP/PS1 mice compared to NTG mice, we observed significant upregulation of RIPK1, RRBP1, SIGMAR1 and TGM2, which play important roles at MERCS [52][53][54][55]. CP2 treatment reversed trends in the expression of these genes (Supplementary Table 1).…”

The Chemotype of Chromanones as a Privileged Scaffold for Multineurotarget Anti-Alzheimer Agents

“…All these ligands exhibited strong and preferred σ 1 affinity in the nanomolar range (Table 1) with the azepane 19 (K i = 42.8 nM) being the most potent σ 1 ligand. The selectivity in favor of σ 1 (ratio σ 2 /σ 1 ) was between 4.5 (19) and 321 (12).…”

“…Upon σ 1 receptor stimulation, signalization pathways leading to ER stress, inflammation, or oxidative damage can be modulated. Since ER stress is associated with the aging process, targeting the σ 1 receptor represents an approach toward the treatment of AD. , First investigated as a drug against Huntington’s disease, the σ 1 receptor agonist pridopidine (Figure ) also featured neuroprotective properties in cellular and animal models of AD due to the stabilization of mushroom-shaped memory spines . Antagonism at the σ 1 receptor has been associated with cell death promoting effects, whereas agonism preserved cell survival …”

“…19,20 First investigated as a drug against Huntington's disease, the σ 1 receptor agonist pridopidine (Figure 1) also featured neuroprotective properties in cellular and animal models of AD due to the stabilization of mushroom-shaped memory spines. 19 Antagonism at the σ 1 receptor has been associated with cell death promoting effects, whereas agonism preserved cell survival. 21 The sigma-2 (σ 2 ) receptor also constitutes a therapeutic target for neurocognitive disorders including AD.…”

Oxidative Stress as a Potential Mechanism Underlying Membrane Hyperexcitability in Neurodegenerative Diseases

“…Thus, a common feature of these CNS diseases is a chronic immune activation, affecting innate and adaptative immune responses. In addition, microglia, astrocytes, endothelial cells, and peripheral immune cells release inflammatory cytokines and chemokines, causing a prolonged proinflammatory state of microglia, increasing the permeability of the BBB and facilitating the infiltration of immune cells into the CNS [ 13 , 14 ].…”