Sigma-1 Receptor Agonists Acting on Aquaporin-Mediated H2O2 Permeability: New Tools for Counteracting Oxidative Stress

Abstract

Sigma1 Receptor (S1R) is involved in oxidative stress, since its activation is triggered by oxidative or endoplasmic reticulum stress. Since specific aquaporins (AQP), called peroxiporins, play a relevant role in controlling H2O2 permeability and ensure reactive oxygen species wasted during oxidative stress, we studied the effect of S1R modulators on AQP-dependent water and hydrogen peroxide permeability in the presence and in the absence of oxidative stress. Applying stopped-flow light scattering and fluorescent probe methods, water and hydrogen peroxide permeability in HeLa cells have been studied. Results evidenced that S1R agonists can restore water permeability in heat-stressed cells and the co-administration with a S1R antagonist totally counteracted the ability to restore the water permeability. Moreover, compounds were able to counteract the oxidative stress of HeLa cells specifically knocked down for S1R. Taken together these results support the hypothesis that the antioxidant mechanism is mediated by both S1R and AQP-mediated H2O2 permeability. The finding that small molecules can act on both S1R and AQP-mediated H2O2 permeability opens a new direction toward the identification of innovative drugs able to regulate cell survival during oxidative stress in pathologic conditions, such as cancer and degenerative diseases.

Discovery of RC-752, a Novel Sigma-1 Receptor Antagonist with Antinociceptive Activity: A Promising Tool for Fighting Neuropathic Pain

“…Then, water permeability was measured for the cells pre-incubated with known S1R modulators (i.e., the agonists PRE-084 and RC-33 and the antagonist NE-100) [ 66 , 67 ] and the novel compounds ( R / S )- 1a , ( R / S )- 1c , ( R / S )- 1d , and ( R / S )- 2d . As reported in Figure 5 A, the activity of known S1R modulators is consistent with our previous findings [ 65 ]. Briefly, the osmotic water permeability of HeLa cells was measured by a stopped-flow light scattering method and expressed as a percentage of k relative.…”

Repurposing the Antiplatelet Agent Ticlopidine to Counteract the Acute Phase of ER Stress Condition: An Opportunity for Fighting Coronavirus Infections and Cancer

“…Under prolonged ER stress, ATF4 triggers pro-apoptotic signals through induction of CHOP, which is responsible for initiation of the apoptotic cascade [ 37 ]. This evidence highlights once again the crucial role of the S1R in controlling ER stress and the activity of ticlopidine as an ER stressor [ 14 , 38 ].…”

Aquaporins and Neuropathic Pain

“…In addition, trifluoperazine has been confirmed to play a therapeutic role in CNS edema by regulating the expression and localization of AQP4 [167,168]. The interaction between AQPs, NLRP3 inflammasome and Sigma1 receptor points out the way to develop new drugs targeting oxidative stress [169,170]. These pieces of evidence suggest that the direct or indirect interactions between AQPs and intermediate proteins and ion channels will be the focus of future drug development.…”