Article
Inhibition of SLC7A11 reduces excitatory synaptic input of peritumoral neurons in glioma patients
Search Medline for
Authors
Published: | June 18, 2018 |
---|
Outline
Text
Objective: Malignant glioma is frequently associated with drug-resistant epilepsy which limits quality-of-life. Expression of SLC7A11, a cysteine-glutamate antiporter, in gliomas has been shown to be associated with poor survival and an increased rate of glioma induced epilepsy. However, the mediators of the effect of glioma cells on neurons in the glioma infiltrated cortex are not well known and new therapeutic targets for seizure treatment are needed. Therefore, in this study, we examined synaptic events in the human peritumoral brain during inhibition of SLC7A11.
Methods: We recorded intracellular neuronal activity in acute brain slices of tumor infiltrated cortex of patients who underwent a neurosurgical glioma resection. Postsynaptic currents were recorded in whole-cell voltage-clamp configuration in an artificial cerebrospinal fluid. SLC7A11 was inhibited using sulfasalazine (SAS). The data was analyzed using either a one-way ANOVA or a paired t-test in SPSS v23.0.
Results: In total, we analyzed 12355 excitatory postsynaptic events in 12 neurons in the peritumoral cortex of seven patients with an astrocytic glioma. Five patients (71%) suffered from glioma induced epilepsy. After administration of SAS we observed a significantly lower rate of excitatory synaptic events compared to the baseline condition (2.7Hz; vs. 3.9Hz, p=0.03). Moreover, we found a reduction of the events’ peak-amplitude and area under the curve (22.95pA vs. 29.93pA; p<0.001 and 58.49pA*ms vs. 109.9pA*ms; p<0.001). The interevent interval was prolonged under SAS-conditions (264.3ms vs. 214.5ms; p<0.001).
Conclusion: Inhibition of SLC7A11 leads to a significant reduction of excitatory synaptic input in neurons in the glioma infiltrated human cortex. Our data suggest that specific inhibition of glutamate driven neuronal hyperexcitability may be a putative target for treatment of glioma associated epilepsy.