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. 2022 Nov 15;11(22):3608.
doi: 10.3390/cells11223608.

α-Lipoic Acid Derivatives as Allosteric Modulators for Targeting AMPA-Type Glutamate Receptors' Gating Modules

Mohammad Qneibi  1 , Safa' Nassar  2 , Sosana Bdir  1 , Adel Hidmi  2
Affiliations

α-Lipoic Acid Derivatives as Allosteric Modulators for Targeting AMPA-Type Glutamate Receptors' Gating Modules

Mohammad Qneibi et al. Cells. .

Abstract

The ionotropic glutamate receptor subtype α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) is responsible for most excitatory transmission in the brain. AMPA receptor function is altered in numerous neurological illnesses, making AMPA receptors appealing therapeutic targets for clinical intervention. Alpha-Lipoic acid (α-LA) is a naturally occurring compound, which functions as a co-factor in metabolism and energy production. α-LA is an antioxidant with various benefits in treating diabetes, including managing symptomatic diabetic neuropathy. This study will test a novel and innovative strategy to synthesize a new isomer of lipoic acid (R-LA) derivatives (bifunctional NO-donor/antioxidant) in one chemical on homomeric and heteromeric AMPA receptor subunits. We used patch-clamp electrophysiology to examine LA derivatives expressed in human embryonic kidney 293 cells (HEK293) for inhibition and changes in desensitization or deactivation rates. LA derivatives were shown to be potent antagonists of AMPA receptors, with an 8-11-fold reduction in AMPA receptor currents seen following the delivery of the compounds. Furthermore, the LA derivatives influenced the rates of desensitization and deactivation of AMPA receptors. Based on our results, especially given that α-LA is closely connected to the nervous system, we may better understand using AMPA receptors and innovative drugs to treat neurological diseases associated with excessive activation of AMPA receptors.

Keywords: AMPA receptor; desensitization; inhibition; neuroprotective; α-Lipoic acid.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structure of α-Lipoic acid and its derivatives.
Scheme 1
Scheme 1
Synthesis of compounds (LA1 and LA4).
Scheme 2
Scheme 2
Synthesis of compounds (LA2 and LA3).
Figure 2
Figure 2
Suppression of AMPA receptor currents by α-LA compounds. Graphs (a,c,e,g) present AMPA receptor currents (pA) before and after the administration of α-LA derivatives on GluA1, GluA1/2, GluA2, and GluA2/3 subunits. While (b,d,f,h) present the ratio A/AI, where A represents the current caused by 10 mM glutamate alone and AI represents the current induced by glutamate + α-LA (12 µM). The whole-cell current was measured at −60 mV, pH 7.4, and 22 °C. A one way analysis of variance (ANOVA) was performed for comparison: *** p < 0.001; ns, not significant. Ten cells were investigated for each LA compound. All values are shown as mean SEM.
Figure 3
Figure 3
The potency of LA compounds against AMPA receptor subunits. The IC50 values for LA derivatives on whole-cell normalized peak amplitude in HEK293 cells are shown in (a–d). IC50 values were calculated using GraphPad Prism version 6.01 (GraphPad Software, San Diego, CA, USA), and concentration-response relationships were fitted as composite curves to the Hill equation. The whole-cell current was measured at −60 mV, pH 7.4, and 22 °C. Each concentration was applied to the cell for 500 ms before rinsing out for 20 ms. Following many washout periods, glutamate (10 mM) was supplied alone, and the instantaneous evoked current was measured. Each data point is the average of three to four different trials.
Figure 4
Figure 4
The effects of α-LA and its derivatives on AMPA receptor deactivation rate. As shown in the graphs, each subunit was influenced by the α-LA derivatives, with (a) representing the effect of α-LA derivatives on GluA1 deactivation rate, (c) representing the impacts of α-LA derivatives on GluA1/2, (e) representing the effects of α-LA derivatives on GluA2, and (g) demonstrating the effect of α-LA derivatives on the deactivation rate of GluA2/3. α-LA derivatives significantly affected AMPA receptor subunits, as seen by the traces in (b,d,f,h). The whole-cell current was measured at −60 mV, pH 7.4, and 22 °C. A one way analysis of variance (ANOVA) was performed for comparison: *** p < 0.001; ns, not significant. Ten cells were investigated for each LA compound. As stated in the supplementary material tables, the cells were washed for 20 s between α-LA compounds, and a 10 mM glutamate was supplied alone after each α-LA compound (12µM) to ensure cell health. All values are shown as mean SEM.
Figure 5
Figure 5
The effects of α-LA derivatives on AMPA receptor desensitization rate. As shown in the graphs, each subunit was influenced by the α-LA derivatives, with (a) representing the effect of α-LA derivatives on GluA1 desensitization rate, (c) representing the impacts of α-LA derivatives on GluA1/2, (e) representing the effects of α-LA derivatives on GluA2, and (g) demonstrating the effect of α-LA derivatives on the desensitization rate of GluA2/3. The traces in (b,d,f,h) show that α-LA derivatives substantially impacted AMPA receptor subunits. The whole-cell current was measured at −60 mV, pH 7.4, and 22 °C. A one way analysis of variance (ANOVA) was performed for comparison: * p < 0.05; ** p < 0.01; *** p < 0.001; ns, not significant. Ten cells were investigated for each LA derivative. The cells were rinsed for 20 s between α-LA compounds, and a 10 mM glutamate was administered alone after each α-LA compound (12 µM) to guarantee cell health, as shown in the supplementary material tables. All values are shown as mean SEM.
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