Abstract
Traditional Chinese medicines (TCMs) have been a rich source of novel drug discovery, and Cassia seed is one of the common TCMs with numerous biological effects. Based on the existing reports on neuroprotection by Cassia seed extract, the present study aims to search possible pharmacological targets behind the neuroprotective effects of the Cassia seeds by evaluating the functional effect of specific Cassia compounds on various G-protein-coupled receptors. Among the four test compounds (cassiaside, rubrofusarin gentiobioside, aurantio-obtusin, and 2-hydroxyemodin 1-methylether), only aurantio-obtusin demonstrated a specific V1AR antagonist effect (71.80 ± 6.0% inhibition at 100 µM) and yielded an IC50 value of 67.70 ± 2.41 μM. A molecular docking study predicted an additional interaction of the hydroxyl group at C6 and a methoxy group at C7 of aurantio-obtusin with the Ser341 residue as functional for the observed antagonist effect. In the transient brain ischemia/reperfusion injury C57BL/6 mice model, aurantio-obtusin attenuated the latency time that was reduced in the bilateral common carotid artery occlusion (BCCAO) groups. Likewise, compared to neuronal damage in the BCCAO groups, treatment with aurantio-obtusin (10 mg/kg, p.o.) significantly reduced the severity of damage in medial cornu ammonis 1 (mCA1), dorsal CA1, and cortex regions. Overall, the findings of this study highlight V1AR as a possible target of aurantio-obtusin for neuroprotection.
Highlights
We evaluated the functional effect of cassiaside, rubrofusarin gentiobioside, and aurantio-obtusin (Figure 1) on vasopressin
The functional role of test compounds (Figure 1) on dopamine receptors was assessed by measuring their effect on cAMP modulation in transfected Chinese hamster ovary (CHO) cells using homogeneous time-resolved fluorescence (HTRF) detection
We tested functional effect of cassiaside, rubrofusarin gentiobioside, and aurantio-obtusin on vasopressin 1A receptor (V1A R), D3 R, NK1 R, and 5-HT1A R which were the top protein targets for Cassia compounds in neurodegenerative diseases predicted via proteocheminformatics modeling [45]
Summary
Vasopressin (AVP) and oxytocin have been implicated in the etiology of psychiatric disorders, such as schizophrenia [1], autism [2,3,4], and depression [5]. AVP acts centrally within the central nervous system (CNS) where it modulates a range of behaviors from learning and memory and responses to stressors to social behaviors [6]. The vasopressin 1A receptor (V1A R) has been contemplated to play the dominant role in regulating behavior and until recently, among vasopressin subtypes (V1A , V1B and V2 ); the V1A R is thought to be the only subtype expressed widely in the brain [6,7,8]. A recent study showed a marked reduction in anxiety-like behavior and a profound impairment in social recognition in
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