YGS is a traditional herbal medicine and consists of seven different extracts, namely, Atractylodes lancea rhizome, Poria sclerotium, Cnidium rhizome, Uncaria thorn, Japanese Angelica root (Angelica radix), Bupleurum root and Glycyrrhiza in the proportions of 4:4:3:3:3:2:1.5.16
Liao et al. reported Angelicae radix exerts effects on γ-aminobutyric acid receptors and serotonin receptors.17
YGS is likely to have effects on not only BPSD of dementia, but also undesirable symptoms of borderline personality disorder and schizophrenia. Therefore, in the present study, we analyzed the effects on a mouse model of schizophrenia, that is poly I:C-mice.
Poly I:C-mice shows schizophrenia-like symptoms, decreased PPI and increased sensitivity to methamphetamine,10,12,13
but the basal locomotor activity is comparable to PBS-mice.11
In the present study, the locomotor activity of poly I:C-mice was also comparable to PBS-mice and YGS did not influence the activities of poly I:C-mice (). This data is intriguing because the sedative effect of antipsychotics causes some clinical problems. The decreased PPI, increased sensitivity to methamphetamine and cognitive deficits in poly I:C-mice reverted to control levels after the administration of YGS (, , ). These results suggest that YGS could have therapeutic effects equivalent to established antipsychotics without unwanted sedation in humans, as is the case with poly I:C-mice, although we have not examined whether YGS had sedative effect on PBS mice (control mice) in the present study. This point should be clarified before YGS is brought to clinical trial on schizophrenic patients.
Previous studies have shown that YGS attenuated 5-HT2A
receptor agonist-induced behavior18
and that dopamine receptors and serotonin receptors were involved in PPI.19–22
And, in the present study, YGS also improved cognitive deficits in NORT. Previously, Hashimoto et al. reported that phencyclidine-induced cognitive deficits in NORT were improved by subchronic administration of either clozapine or α7 nicotinic receptor agonist, but not of haloperidol.23,24
Although the mechanisms of the deficit and the improvement of cognitive functions in NORT are not known, it might be related to the function of NMDA receptor because the modulation of NMDA receptor functions could be involved in behavioral alterations of phencyclidine-injected mice and poly I:C-mice25
and the action mechanism of clozapine and α7 nicotinic receptor agonist.24,26,27
Additionally, a component of YGS, Uncaria rhynchophylla, has protective effect against apoptosis induced by N-methyl-D-aspartate in rat hippocampal slice.28
Therefore, the therapeutic effects of YGS on the abnormal behavior of poly I:C-mice could be achieved in part by modulating dopamine, serotonin or glutamate signaling pathways. Since YGS consists of multiple herbal extracts, further studies are required to clarify which compound(s) have therapeutic activities.
Glutathione levels were decreased in the medial prefrontal cortex and cerebrospinal fluid in schizophrenic patients15
and gene expression of glutathione-synthesizing enzymes and glutathione component in fibroblasts from schizophrenic patients was also decreased.14
In red blood cells from schizophrenic patients, antioxidant enzyme activities were decreased compared with the control group.29
Consistent with human studies mentioned above, we also found decreased glutathione levels in the whole brain of poly I:C-mice. YGS significantly restored the decreased total glutathione level (). As a glutathione precursor, N-acetyl-cysteine, improved mismatch negativity in schizophrenic patients30
and reversed working memory deficits caused by phencyclidine.31
The therapeutic effects of YGS observed in the present study may be, at least partly, attributed to recovered glutathione synthesis. It remains to be investigated whether upregulation of glutathione levels by a glutathione precursor could restore abnormal behaviors in poly I:C-mice.
The present study showed for the first time that Chinese herbal medicine, YGS, restores behavioral alterations and a decrease of brain glutathione level in schizophrenic model mice. These results suggest that YGS could be a novel remedy for the symptoms of schizophrenia.