Underlying mechanism for NMDA receptor antagonism by the anti-inflammatory drug, sulfasalazine, in mouse cortical neurons

Noh, Joseph J.; Gwag, Byoung Joo; Chung, Jun Mo

doi:10.1016/j.neuropharm.2005.07.020

Cited by 8 publications

(11 citation statements)

References 39 publications

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“…We did not observe a significant change in AMPA receptor–mediated eEPSCs (control: 101.16 ± 9.63 pA; SAS 89.98 ± 21.48 pA, P = 0.23, Figure E,F). These results indicate that SAS attenuates eEPSCs primarily via a reduction in NMDA receptor–mediated currents, supporting previous in vitro studies describing the NMDA antagonistic properties of SAS…”

Section: Resultssupporting

confidence: 90%

“…Because SAS can act as a noncompetitive NMDA receptor antagonist and the Mg 2+ ‐free solution induces epileptiform activity by removing the Mg 2+ block from NMDA receptors, we wanted to evaluate the efficacy of SAS on other models of hyperexcitability. To test this, GABA A receptor–mediated inhibition was blocked by the addition of bic to the perfusate, greatly enhancing the duration and lateral spread of the VSD signals, which is reflective of network hyperexcitability.…”

Section: Resultsmentioning

confidence: 99%

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Sulfasalazine decreases mouse cortical hyperexcitability

et al. 2019

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Objective Currently prescribed antiepileptic drugs (AEDs) are ineffective in treating approximately 30% of epilepsy patients. Sulfasalazine (SAS) is an US Food and Drug Administration (FDA)–approved drug for the treatment of Crohn disease that has been shown to inhibit the cystine/glutamate antiporter system xc‐ (SXC) and decrease tumor‐associated seizures. This study evaluates the effect of SAS on distinct pharmacologically induced network excitability and determines whether it can further decrease hyperexcitability when administered with currently prescribed AEDs. Methods Using in vitro cortical mouse brain slices, whole‐cell patch‐clamp recordings were made from layer 2/3 pyramidal neurons. Epileptiform activity was induced with bicuculline (bic), 4‐aminopyridine (4‐AP) and magnesium‐free (Mg2+‐free) solution to determine the effect of SAS on epileptiform events. In addition, voltage‐sensitive dye (VSD) recordings were performed to characterize the effect of SAS on the spatiotemporal spread of hyperexcitable network activity and compared to currently prescribed AEDs. Results SAS decreased evoked excitatory postsynaptic currents (eEPSCs) and increased the decay kinetics of evoked inhibitory postsynaptic currents (eIPSCs) in layer 2/3 pyramidal neurons. Although application of SAS to bic and Mg2+‐free–induced epileptiform activity caused a decrease in the duration of epileptiform events, SAS completely blocked 4‐AP–induced epileptiform events. In VSD recordings, SAS decreased VSD optical signals induced by 4‐AP. Co‐application of SAS with the AED topiramate (TPM) caused a significantly further decrease in the spatiotemporal spread of VSD optical signals. Significance Taken together this study provides evidence that inhibition of SXC by SAS can decrease network hyperexcitability induced by three distinct pharmacologic agents in the superficial layers of the cortex. Furthermore, SAS provided additional suppression of 4‐AP–induced network activity when administered with the currently prescribed AED TPM. These findings may serve as a foundation to assess the potential for SAS or other compounds that selectively target SXC as an adjuvant treatment for epilepsy.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Sulfasalazine decreases mouse cortical hyperexcitability

et al. 2019

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“…Finally, in some reports, SAS was used as a pharmacological tool to evaluate the potential of system

x_{normalc}^{-}

inhibition to decrease hyperexcitability . Although SAS is not a selective system

x_{normalc}^{-}

inhibitor, it is currently the only clinically approved drug acting on this target . More selective inhibitors with improved bioavailability are currently under development .…”

Section: Discussionmentioning

confidence: 99%

Anticonvulsant and antiepileptogenic effects of system xc− inactivation in chronic epilepsy models

et al. 2019

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Objective The cystine/glutamate antiporter system xnormalc− could represent a new target for antiepileptogenic treatments due to its crucial roles in glutamate homeostasis and neuroinflammation. To demonstrate this, we compared epilepsy development and seizure susceptibility in xCT knockout mice (xCT−/−) and in littermate controls (xCT+/+) in different chronic models of epilepsy. Methods Mice were surgically implanted with electrodes in the basolateral amygdala and chronically stimulated to develop self‐sustained status epilepticus (SSSE); continuous video‐electroencephalography monitoring was performed for 28 days after SE and hippocampal histopathology was assessed. Corneal kindling was induced by twice daily electrical stimulation at 6 Hz and maintenance of the fully kindled state was evaluated. Next, messenger RNA (mRNA) and protein levels of xCT and of the proteins involved in the phosphoinositide 3‐kinase (PI3K)/Akt/glycogen synthase kinase 3β (GSK‐3β)/eukaryotic initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4) signaling pathway were measured at different time points during epileptogenesis in NMRI mice treated with pilocarpine. Finally, the anticonvulsant effect of sulfasalazine (SAS), a nonselective system xnormalc− inhibitor, was assessed against 6 Hz‐evoked seizures in pilocarpine‐treated mice. Results In the SSSE model, xCT−/− mice displayed a significant delayed epileptogenesis, a reduced number of spontaneous recurrent seizures, and less pronounced astrocytic and microglial activation. Moreover, xCT−/− mice showed reduced seizure severity during 6 Hz kindling development and a lower incidence of generalized seizures during the maintenance of the fully kindled state. In pilocarpine‐treated mice, protein levels of the PI3K/Akt/GSK‐3β/eIF2α/ATF4 pathway were increased during the chronic phase of the model, consistent with previous findings in the hippocampus of patients with epilepsy. Finally, repeated administration of SAS protected pilocarpine‐treated mice against acute 6 Hz seizure induction, in contrast to sham controls, in which system xnormalc− is not activated. Significance Inhibition of system xnormalc− could be an attractive target for the development of new therapies with a potential for disease modification in epilepsy.

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“…Sulfasalazine is widely used as an antagonist of system x c -; however, it also blocks parallel mechanisms of inflammation and neuron pathology including NMDA receptor activation and NFκB signaling (Gan, et al, 2005, Noh, et al, 2006). Similarly, other drugs, including the phenylcycline derivatives 4-CPG and LY367385, act as system x c - antagonists but they also are competitive antagonists of metabotropic glutamate receptors (mGluRs) (Baker, et al, 2003, Fogal, et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

System xc− regulates microglia and macrophage glutamate excitotoxicity in vivo

Kigerl

Ankeny

Garg

et al. 2012

Experimental Neurology

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It is widely believed that microglia and monocyte-derived macrophages (collectively referred to as central nervous system (CNS) macrophages) cause excitotoxicity in the diseased or injured CNS. This view has evolved mostly from in vitro studies showing that neurotoxic concentrations of glutamate are released from CNS macrophages stimulated with lipopolysaccharide (LPS), a potent inflammogen. We hypothesized that excitotoxic killing by CNS macrophages is more rigorously controlled in vivo, requiring both the activation of the glutamate/cystine antiporter (system xc-) and an increase in extracellular cystine, the substrate that drives glutamate release. Here, we show that non-traumatic microinjection of low-dose LPS into spinal cord gray matter activates CNS macrophages but without causing overt neuropathology. In contrast, neurotoxic inflammation occurs when LPS and cystine are co-injected. Simultaneous injection of NBQX, an antagonist of AMPA glutamate receptors, reduces the neurotoxic effects of LPS+cystine, implicating glutamate as a mediator of neuronal cell death in this model. Surprisingly, neither LPS nor LPS+cystine adversely affects survival of oligodendrocytes or oligodendrocyte progenitor cells. Ex vivo analyses show that redox balance in microglia and macrophages is controlled by induction of system xc- and that high GSH:GSSG ratios predict the neurotoxic potential of these cells. Together, these data indicate that modulation of redox balance in CNS macrophages, perhaps through regulating system xc-, could be a novel approach for attenuating injurious neuroinflammatory cascades.

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Underlying mechanism for NMDA receptor antagonism by the anti-inflammatory drug, sulfasalazine, in mouse cortical neurons

Cited by 8 publications

References 39 publications

Sulfasalazine decreases mouse cortical hyperexcitability

Sulfasalazine decreases mouse cortical hyperexcitability

Anticonvulsant and antiepileptogenic effects of system xc− inactivation in chronic epilepsy models

System xc− regulates microglia and macrophage glutamate excitotoxicity in vivo

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