Low-concentration sevoflurane inhalation in treating MK801-induced schizophrenia like disease in mice and a feasibility study of schizophrenia patients

Abstract GABAergic deficits have been considered to associate with the pathophysiology of schizophrenia and hence GABA receptor subtype A (GABAARs) modulators may have therapeutic values for schizophrenia. Sevoflurane, a commonly used volatile anesthetic, enhances GABAergic neurotransmission through the GABAAR. The present study aims to investigate the therapeutic effectiveness of low-concentration sevoflurane in MK801-induced schizophrenia-like mice and amongst schizophrenia patients in a single arm trial. Three weeks after administration of MK801 (0.5 mg/kg, i.p. twice a day) for five days, mice were exposed to 1% sevoflurane for 1 hr/day for 5 days. One week after treatment, they were subjected to behavioral tests, and then sacrificed for immunohistochemical stain, western blot assay and electrophysiology recordings in the prefrontal cortex. Ten schizophrenia patients received 5-hr sevoflurane (0.5–1.2%) for 6 days, and were assessed with the PANSS and the BPRS-18 in the 1st and 2nd week after the treatments. MK801 induced hypolocomotion and social deficits, downregulated the expression of NMDARs subunits, and postsynaptic density protein 95 (PSD95), reduced parvalbumin- and GAD67-positive neurons, and changed the amplitude and frequency of mEPSC and mIPSC and evenly increased the excitation/inhibition (E/I) ratio. All these changes induced by MK-801 were attenuated by sevoflurane administration. Schizophrenia symptoms assessed with the scales were significantly improved in the 1st and 2nd week after treatments. Low-concentration sevoflurane inhalation effectively reversed MK801-induced schizophrenia-like disease in mice and alleviated schizophrenia patients’ symptoms. Our work suggested that sevoflurane may be a valuable therapeutic strategy for treating schizophrenia patients.