The effect of lansoprazole on MK-801-induced schizophrenia-like behaviors in mice.

As a heterogeneous disorder, schizophrenia is known to be associated with neuroinflammation. A recent study showed that several cytokines are higher in the plasma and cerebrospinal fluid of schizophrenia patients. Lansoprazole, a proton pump inhibitor used for treating erosive esophagitis, has been reported to reduce INF-γ-induced neurotoxicity and decrease inflammatory cytokines including IL-1ß, IL-6, and TNF-α. These findings persuaded us to examine whether lansoprazole ameliorates schizophrenia-like symptoms. The schizophrenia mouse model was induced by the acute administration of MK-801, an NMDA receptor antagonist. Sensorimotor gating, Barnes maze, and social novelty preference tests were conducted to evaluate schizophrenia-like behaviors. We found that lansoprazole (0.3, 1, or 3 mg/kg) ameliorated sensorimotor gating deficits, spatial learning, and social deficits caused by MK-801 treatment (0.2 mg/kg). The catalepsy test, balance beam test, and rotarod test were performed to reveal the adverse effects of lansoprazole on motor coordination. The behavioral results indicated that lansoprazole did not result in any motor function deficits. Moreover, lansoprazole decreased inflammatory cytokines including IL-6 and TNF-α only in the cortex, but not in the hippocampus. Collectively, these results suggest that lansoprazole could be a potential candidate for treating schizophrenia patients who suffer from sensorimotor gating deficits or social disability without any motor-related adverse effects.

4-Methoxycinnamic acid attenuates schizophrenia-like behaviors induced by MK-801 in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Scrophularia buergeriana has been used for traditional medicine as an agent for reducing heat in the blood and for nourishing kidney 'Yin'. Therefore, S. buergeriana might be a potential treatment for mental illness, especially schizophrenia, which may be attenuated by supplying kidney Yin and reducing blood heat. In a pilot study, we found that S. buergeriana alleviated sensorimotor gating dysfunction induced by MK-801. AIM OF THE STUDY: In the present study, we attempted to reveal the active component(s) of S. buergeriana as a candidate for treating sensorimotor gating dysfunction, and we identified 4-methoxycinnamic acid. We explored whether 4-methoxycinnamic acid could affect schizophrenia-like behaviors induced by hypofunction of the glutamatergic neurotransmitter system. MATERIALS AND METHODS: Mice were treated with 4-methoxycinnamic acid (3, 10, or 30 mg/kg, i.g.) under MK-801-induced schizophrenia-like conditions. The effect of 4-methoxycinnamic acid on schizophrenia-like behaviors were explored using several behavioral tasks. We also used Western blotting to investigate which signaling pathway(s) is involved in the pharmacological activities of 4-methoxycinnamic acid. RESULTS: 4-Methoxycinnamic acid ameliorated MK-801-induced prepulse inhibition deficits, social interaction disorders and cognitive impairment by regulating the phosphorylation levels of PI3K, Akt and GSK-3ß signaling in the prefrontal cortex. And there were no adverse effects in terms of catalepsy and motor coordination impairments. CONCLUSION: Collectively, 4-methoxycinnamic acid would be a potential candidate for treating schizophrenia with fewer adverse effects, especially the negative symptoms and cognitive dysfunctions.