Hispidulin attenuates the social withdrawal in isolated disrupted‐in‐schizophrenia‐1 mutant and chronic phencyclidine‐treated mice

Abstract

Background and Purpose: Hispidulin is a flavonoid isolated from Clerodendrum inerme that was found to inhibit intractable motor tics. Previously, we found that hispidulin attenuates hyperlocomotion and the disrupted prepulse inhibition induced by methamphetamine and N-methyl-D-aspartate (NMDA) receptor antagonists, two phenotypes of schizophrenia resembling positive symptoms. Hispidulin can inhibit COMT, a dopamine-metabolizing enzyme in the prefrontal cortex (PFC) that is important for social interaction. Here, we investigated whether hispidulin would affect social withdrawal, one of the negative symptoms of schizophrenia. Experimental Approach: We examined whether acute administration of hispidulin would attenuate social withdrawal in two mice models, juvenile isolated disrupted-inschizophrenia-1 mutant (mutDISC1) mice and chronic phencyclidine (PCP)-treated naïve mice. Key Results: In chronic PCP-treated mice, hispidulin (10 mgÁkg −1 , i.p.) attenuated social withdrawal similar to that observed with dopamine D 1 receptor antagonist (SCH-23390, 0.02 mgÁkg −1 , i.p.) and was mimicked by the selective COMT inhibitor, OR-486 (10 mgÁkg −1 , i.p.). Hispidulin increased extracellular dopamine levels in the PFC of chronic PCP-treated mice. In isolated mutDISC1 mice, hispidulin also reversed social withdrawal. In both models, intra-PFC microinjection of a D 1 agonist (SKF-81297: 10 nmol/mouse/bilateral) reversed the impairment of Ser 897 phosphorylation at the GluN1 subunit of NMDA receptors, suggesting the association between GluN1 Ser 897-phosphorylation and D 1 activation in the PFC exits in both models. Conclusions and Implications: Hispidulin attenuated social withdrawal by activating D 1 receptors indirectly through elevated dopamine levels in the PFC by COMT inhibition. This nature of hispidulin suggests that it a potential novel therapeutic candidate for the treatment of negative symptoms in schizophrenia.

Mitotic Abnormality Inducing Effects of Leaf Aqueous Extract of <i>Clerodendrum inerme</i> Gaertn. on <i>Allium cepa</i> Root Apical Meristem Cells

“…Several known flavonoids, like hispidulin, apigenin, acacetin, and diosmetin have been isolated from the aerial parts of C. inerme (Nan et al 2005a, b, Chen et al 2012, Huang et al 2015, Srisook et al 2015. Among them, hispidulin was found to be one of the active chemical constituents having various pharmacological activities including neuropsychiatric disorders (Huang et al 2015, Liao et al 2016, Chiou et al 2018, Mouri et al 2020, anti-inflammatory activity (Srisook et al 2015), anticancer activity (Gao et al 2014), and anti-osteoporotic_activity (Zhou et al 2014). Several glycosides, such as 2-(3-methoxy-4-hydroxylphenyl) ethyl-O-2″ ,3″-diacetyl-α-L-rhamnopyranosyl-(1 3)-4-O-(E) feruloyl-β-D glucopyranoside, melittoside, inerminoside, isoverbascoside, monomelittoside, in addition to stigmasta 5,22,25-trien-3-β-ol, betulinic acid, B-friedoolean-5-ene-3-β-ol, and β-sitosterol were isolated from the aerial part of the C. inerme (Nan et al 2005a, b, Ibrahim et al 2014.…”

α6-Containing GABAAReceptors: Functional Roles and Therapeutic Potentials

“…In addition, a breakdown of connectivity in a specific dorsolateral prefrontal cortexto-cerebellum network directly corresponded to negative symptom severity in schizophrenia, and restoration of network connectivity with transcranial magnetic stimulation corresponded to amelioration of negative symptoms (Brady et al, 2019). In mouse models mimicking schizophrenia, a6GABA A R PAMs not only rescued PPI deficits (Chiou et al, 2018) but also reduced social withdrawal and cognitive deficits (Mouri et al, 2020) (Chiou et al, 2019, Abstract and Poster No. 645.14/B55 at the Soc Neurosci Meeting 2019, Chicago, IL, USA).…”

“…# Compound 6, DK-I-56-1, and hispidulin rescued social withdrawal and cognitive deficits (Chiou et al, 2019;Mouri et al, 2020) in mouse models mimicking schizophrenia.…”

“…Interestingly, maternal separation stress in mice carrying the mutated schizophrenia risk gene, DISC1 (Disrupted in Schizophrenia 1), can induce PPI impairment and social withdrawal, mimicking positive and negative symptoms, respectively, in schizophrenia (Niwa et al, 2013). Hispidulin reduced both behavioral phenotypes in these mice and in chronic PCP-treated mice (Mouri et al, 2020). The a6GABA A R-selective PAMs Compound 6 and DK-I-56-1 also reduced PPI impairment, social withdrawal, and cognitive impairment in chronic PCPtreated mice (Chiou et al, 2019, poster at the Soc Neurosci 2019, No.…”

Insights into the Promising Prospect of G Protein and GPCR-Mediated Signaling in Neuropathophysiology and Its Therapeutic Regulation

“…This is an unusual expression profile (Figures 2 and 3 ). As a result of this, GPR52 activation may promote good effects of schizophrenia by antagonizing Gi/o-coupled D2 receptor action in striatopallidal MSNs, while also reducing schizophrenic adverse effects and cognitive disability by upgrading NMDA receptor movement in prefrontal cortical neurons via protein kinase A (PKA), as can be seen in D1 receptor-NMDA signal transduction [ 181 , 182 ].…”