Author: Kato, Tomoko ; Tooyama, Ikuo ; Tomiyama, Takami ; Kitada, Masaaki ; Gamo, Keizo ; Yanagisawa, Daijiro ; Shirai, Nobuaki ; Taguchi, Hiroyasu ; Sogabe, Takayuki ; Hirao, Koichi ; Hirahara, Yukie

The accumulation of β-amyloid (Aβ) aggregates in the brain occurs early in the progression of Alzheimer's disease (AD), and non-fibrillar soluble Aβ oligomers are particularly neurotoxic. During binding to Aβ fibrils, curcumin, which can exist in an equilibrium state between its keto and enol tautomers, exists predominantly in the enol form, and binding activity of the keto form to Aβ fibrils is much weaker. Here we described the strong binding activity the keto form of curcumin derivative Shiga-Y51 shows for Aβ oligomers and its scant affinity for Aβ fibrils. Furthermore, with imaging mass spectrometry we revealed the blood-brain barrier permeability of Shiga-Y51 and its accumulation in the cerebral cortex and the hippocampus, where Aβ oligomers were mainly localized, in a mouse model of AD. The keto form of curcumin derivatives like Shiga-Y51 could be promising seed compounds to develop imaging probes and therapeutic agents targeting Aβ oligomers in the brain.

06 May 2020·ChemMedChem

Enhanced Efficacy of Gefitinib in Drug‐Sensitive and Drug‐Resistant Cancer Cell Lines after Arming with a Singlet Oxygen Releasing Moiety

Article

Author: Xue, Jinping ; Chen, Juanjuan ; Li, Dongyao ; Huang, Kunshan ; Huo, Beibei

AbstractAttractive results have been achieved with small‐molecule target‐based drugs in the anticancer field; however, enhancing their treatment effect and solving the problem of drug resistance remain key concerns worldwide. Inspired by the specific affinity of gefitinib for tumour cells and the strong oxidation capacity of singlet oxygen, we combined a chemically generated singlet oxygen moiety with the small‐molecule targeted drug gefitinib to improve its anticancer effect. We designed and synthesised a novel compound (Y5‐1), in which a small‐molecule targeted therapy agent (gefitinib) and a singlet oxygen (provided by an in vitro photodynamic reaction) thermally controlled releasing moiety are covalently conjugated. We demonstrated that the introduction of the singlet oxygen thermally controlled releasing moiety enhanced the anticancer activities of gefitinib. The results of this study are expected to provide a novel strategy to enhance the effect of chemotherapy drugs on drug‐resistant cell lines.

01 Mar 2015·PsychopharmacologyQ3 · MEDICINE

Enhanced inhibitory control by neuropeptide Y Y5 receptor blockade in rats

Q3 · MEDICINE

Article

Author: J. Peterson ; B. Campbell ; A. W. Lee ; X. Huang ; A. Dec ; J. Lee ; S. Zorn ; E. Dale ; A. R. West ; A. Bari ; T. W. Robbins ; D. Song

RATIONALEThe neuropeptide Y (NPY) system acts in synergy with the classic neurotransmitters to regulate a large variety of functions including autonomic, affective, and cognitive processes. Research on the effects of NPY in the central nervous system has focused on food intake control and affective processes, but growing evidence of NPY involvement in attention-deficit/hyperactivity disorder (ADHD) and other psychiatric conditions motivated the present study.OBJECTIVESWe tested the effects of the novel and highly selective NPY Y5 receptor antagonist Lu AE00654 on impulsivity and the underlying cortico-striatal circuitry in rats to further explore the possible involvement of the NPY system in pathologies characterized by inattention and impulsive behavior.RESULTSA low dose of Lu AE00654 (0.03 mg/kg) selectively facilitated response inhibition as measured by the stop-signal task, whereas no effects were found at higher doses (0.3 and 3 mg/kg). Systemic administration of Lu AE00654 also enhanced the inhibitory influence of the dorsal frontal cortex on neurons in the caudate-putamen, this fronto-striatal circuitry being implicated in the executive control of behavior. Finally, by locally injecting a Y5 agonist, we observed reciprocal activation between dorsal frontal cortex and caudate-putamen neurons. Importantly, the effects of the Y5 agonist were attenuated by pretreatment with Lu AE00654, confirming the presence of Y5 binding sites modulating functional interactions within frontal-subcortical circuits.CONCLUSIONSThese results suggest that the NPY system modulates inhibitory neurotransmission in brain areas important for impulse control, and may be relevant for the treatment of pathologies such as ADHD and drug abuse.

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Discovery	JP	Shiga University of Medical Science	-

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