Yokukansan promotes hippocampal neurogenesis associated with the suppression of activated microglia in Gunn rat

Abstract

BackgroundThe pathophysiology of schizophrenia (SCZ) remains unclear, and its treatment is far from ideal. We have previously reported that yokukansan (YKS), which is a traditional Japanese medicine, is effective as an adjunctive therapy for SCZ. However, the mechanisms underlying the action of YKS have not yet been completely elucidated. A recent meta-analysis study has shown that adjuvant anti-inflammatory drugs are effective for SCZ treatment, and it has been proposed that some of the cognitive deficits associated with inflammation may in part be related to inflammation-induced reductions in adult hippocampal neurogenesis. Although certain ingredients of YKS have potent anti-inflammatory activity, no study has determined if YKS has anti-inflammatory properties.MethodsUsing the Gunn rat, which has been reported as a possible animal model of SCZ, we investigated whether YKS affects cognitive dysfunction in an object-location test and the suppression of microglial activation and neurogenesis in the hippocampus.ResultsWe found that YKS ameliorated spatial working memory in the Gunn rats. Furthermore, YKS inhibited microglial activation and promoted neurogenesis in the hippocampal dentate gyrus of these rats. These results suggest that the ameliorative effects of YKS on cognitive deficits may be mediated in part by the suppression of the inflammatory activation of microglia.ConclusionsThese findings shed light on the possible mechanism underlying the efficacy of YKS in treating SCZ.

Electroconvulsive shock attenuated microgliosis and astrogliosis in the hippocampus and ameliorated schizophrenia-like behavior of Gunn rat

“…The finding that microglia in the hippocampus of Gunn rats are activated is in line with our previous studies [28, 66]. Gunn rats have high levels of unconjugated bilirubin (UCB) in their blood [23].…”

Gunn rats with glial activation in the hippocampus show prolonged immobility time in the forced swimming test and tail suspension test

“…The results of this study indicating that both microglia and astrocytes are significantly activated in the hippocampus of Gunn rats as shown by immunohistochemistry using Iba1 and S100B are consistent with our previous studies which demonstrated increased immunoreactivity for another microglial marker CD11b (Furuya et al., 2013; Liaury et al., 2012, 2014) and for another astrocytic marker GFAP (Limoa et al., 2016) in the hippocampal DG, CA1, and CA3. These observations of the increased immunoreactivity using two distinct markers for each glial cell substantiate both microglial activation and astrocytic activation in the hippocampus of Gunn rats.…”

“…Therefore, Gunn rats have been used as an experimental model of kernicterus (bilirubin encephalopathy), which can be considered as an organic brain disorder. As patients with organic brain disorder often present symptoms of schizophrenia and affective disorder (Hamilton, Frick, Takahashi, & Hopping, 1983), it is not unexpected that Gunn rats show depression‐like behavior as demonstrated by this study and schizophrenia‐like behavior as shown by our previous studies (Furuya et al., 2013; Liaury et al., 2012, 2014; Limoa et al., 2016). It has been shown that a neuronal damage in the hippocampus is caused by unconjugated bilirubin in growing Gunn rats (Ohno, 1981).…”

“…However, the numbers of established models which show signs or symptoms relevant to the diseases are limited. We previously demonstrated that Gunn rats with hyperbilirubinemia showed the activation of both microglia stained with CD11b (Furuya et al., 2013; Liaury et al., 2012, 2014; Limoa et al., 2016) and astrocytes stained with glial fibrillar acidic protein (GFAP) (Limoa et al., 2016) in the hippocampus and exhibited schizophrenia‐like behavior in the prepulse inhibition test (Liaury et al., 2014; Limoa et al., 2016), the object‐location test (Furuya et al., 2013), and the novel object recognition test (Liaury et al., 2014). …”

Fluoride-Induced Neuron Apoptosis and Expressions of Inflammatory Factors by Activating Microglia in Rat Brain

“…The developmental neurotoxicity of fluoride may be closely associated with neurodegenerative changes [17]. The suppression of the inflammatory activation of microglia might play a part in ameliorated cognitive deficits [48]. Microglia activation is a key causative factor in neurodegeneration [49].…”