Background and Purpose: The pathophysiological role of α₆‐subunit‐containing GABA_Areceptors, which are mainly expressed in cerebellar granule cells, remains unclear. Recently, we demonstrated that hispidulin, a flavonoid isolated from a local herb that remitted a patient's intractable motor tics, attenuated methamphetamine‐induced hyperlocomotion in mice as a positive allosteric modulator (PAM) of cerebellar α₆GABA_Areceptors. Here, using hispidulin and a selective α₆GABA_Areceptor PAM, the pyrazoloquinolinone Compound6, we revealed an unprecedented role of cerebellar α₆GABA_Areceptors in disrupted prepulse inhibition of the startle response (PPI), which reflects sensorimotor gating deficits manifested in several neuropsychiatric disorders.Experimental Approach: PPI disruptions were induced by methamphetamine and NMDA receptor antagonists in mice. Effects of the tested compounds were measured inXenopusoocytes expressing recombinant α₆β₃γ_2SGABA_Areceptors.Key Results: Hispidulin given i.p. or by bilateral intracerebellar (i.cb.) injection rescued PPI disruptions induced by methamphetamine, ketamine, MK‐801 and phencyclidine. Intracerebellar effects of hispidulin were mimicked by Ro15‐4513 and loreclezole (two α₆GABA_Areceptor PAMs), but not by diazepam (an α₆GABA_Areceptor‐inactive benzodiazepine) and were antagonized by furosemide (i.cb.), an α₆GABA_Areceptor antagonist. Importantly, Compound6(i.p.) also rescued methamphetamine‐induced PPI disruption, an effect prevented by furosemide (i.cb.). Both hispidulin and Compound6potentiated α₆β₃γ_2SGABA_Areceptor‐mediated GABA currents.Conclusions and Implications: Positive allosteric modulation of cerebellar α₆GABA_Areceptors rescued disrupted PPI by attenuating granule cell activity. α₆GABA_Areceptor‐selective PAMs are potential medicines for treating sensorimotor gating deficits in neuropsychiatric disorders. A mechanistic hypothesis is based on evidence for cerebellar contributions to cognitive functioning including sensorimotor gating.

Currently, no drug is effective in delaying the cognitive impairment of Alzheimer’s disease, which ranks as one of the top 10 causes of death worldwide. Hydroxylated stilbenes are active compounds that exist in fruit and herbal plants. Piceatannol (PIC) and gnetol (GNT), which have one extra hydroxyl group in comparison to resveratrol (RSV), and rhapontigenin (RHA) and isorhapontigenin (isoRHA), which were metabolized from PIC in vivo and contain the same number of hydroxyl groups as RSV, were evaluated for their effects on Alzheimer’s disease-associated factors in vitro and in animal experiments. Among the five hydroxylated stilbenes, PIC was shown to be the most active in DPPH radical scavenging and in inhibitory activities against acetylcholinesterase and amyloid-β peptide aggregations, with concentrations for half-maximal inhibitions of 40.2, 271.74, and 0.48 μM. The different interactions of the five hydroxylated stilbenes with acetylcholinesterase or amyloid-β were obtained by molecular docking. The scopolamine-induced ICR mice fed with PIC (50 mg/kg) showed an improved learning behavior in the passive avoidance tests and had significant differences (p < 0.05) compared with those in the control group. The RHA and isoRHA at 10 μM were proven to stimulate neurite outgrowths in the SH-SY5Y cell models. These results reveal that nutraceuticals or functional foods containing PIC have the potential for use in the treatment of neurodegenerative disorders.

Acute leukemia is a highly heterogeneous disease; therefore, combination therapy is commonly used for patient treatment. Drug–drug interaction is a major concern of combined therapy; hence, dual/multi-target inhibitors have become a dominant approach for cancer drug development. HDACs and HSP90 are involved in the activation of various oncogenic signaling pathways, including PI3K/AKT/mTOR, JAK/STAT, and RAF/MEK/ERK, which are also highly enriched in acute leukemia gene expression profiles. Therefore, we suggest that dual HDAC and HSP90 inhibitors could represent a novel therapeutic approach for acute leukemia. MPT0G449 is a dual effect inhibitor, and it showed cytotoxic effectiveness in acute leukemia cells. Molecular docking analysis indicated that MPT0G449 possessed dual HDAC and HSP90 inhibitory abilities. Furthermore, MPT0G449 induced G₂ arrest and caspase-mediated cell apoptosis in acute leukemia cells. The oncogenic signaling molecules AKT, mTOR, STAT3, STAT5, MEK, and ERK were significantly downregulated after MPT0G449 treatment in HL-60 and MOLT-4 cells. In vivo xenograft models confirmed the antitumor activity and showed the upregulation of acetyl-histone H3 and HSP70, biomarkers of pan-HDAC and HSP90 inhibition, with MPT0G449 treatment. These findings suggest that the dual inhibition of HDAC and HSP90 can suppress the expression of oncogenic pathways in acute leukemia, and MPT0G449 represents a novel therapeutic for anticancer treatment.