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.

Keywords: Alzheimer’s disease; ER-stress; astrocytes; cytokines; microglia; neurodegenerative diseases; neuroinflammation; non-steroid anti-inflammatory drugs; sigma-1 receptor ligands.

Figure 1

Different types of microglial cells, their characteristic cytokines, and their roles in cellular processes. The imbalance of pro- and anti-inflammatory microglia leads to the progression of NDDs. (See Ref. [31]).

Figure 2

Activation of microglia and astrocytes (e.g., by aggregated pathogenic proteins) and their cross-talk. Pro-inflammatory microglial cells are neurotoxic. Reactive astrocytes can be both beneficial and harmful to surrounding neurons. Microglia–astrocyte cross-talk is maintained by secreted canonical cytokines, growth factors, neurotransmitters, glia-transmitters, and chemokines. M: resting microglia, A: naive astrocyte. (Based on Kwon et al. 2020, Ref. [36]. Cell images from the Servier Medical Art repository were used).

Figure 3

Two signals are involved in the formation of the NLRP3 inflammasome: activation of toll-like receptors (TLR) and TREM2 by toxic amyloid aggregates. Biosynthesis of the NLRP3 protein after NF-κB induced gene expression results in oligomerization of the protein. Recruitment of caspase-1 and ASC generates the NLRP3 inflammasome, and caspase-1 cleaves the IL-precursor proteins leading to the release of mature cytokines IL-1β and IL-18. These cytokines activate the cells of the immune system and trigger the inflammatory response, including the opening of the BBB. TREM2: triggering receptor expressed on myeloid cells 2; ASC: adapter apoptosis-associated speck-like protein containing CARD. (Based on the work of Oliveira et al. 2021, Ref. [43]).

Figure 4

Sig-1R regulation of the three main signaling pathways of ER stress-activated unfolded protein response (UPR) focusing on the central role of the transcription factor NF-κB. Sig-1R activation increases cell survival by the attenuation of the activity of the three sensors (PERK, IRE-1α, and ATF6) and decreasing the pro-apoptotic responses, as well as increasing the anti-apoptotic Bcl-2 activity. (Abbreviations: PERK: protein kinase RNA-like ER-kinase; IRE1α: inositol requiring enzyme 1α; ATF6: activating transcription factor 6; eIF2α: eukaryotic translation initiation factor 2α; XBP1: X-box binding protein 1 (spliced form); TRAF2: TNF-associated factor-2; ATF4: transcriptional activator factor-4; MT: mitochondrion; CHOP: c/EBF homologous protein; Bcl-2: B-cell lymphoma 2; Bax: Bcl-2 like protein 2; Bak: Bcl-2 homologous antagonist killer; JNK: c-Jun terminal amino kinase; ASK1: apoptosis signal-regulating kinase).