Identification of Marine Neuroactive Molecules in Behaviour-Based Screens in the Larval Zebrafish

Abstract

High-throughput behavior-based screen in zebrafish is a powerful approach for the discovery of novel neuroactive small molecules for treatment of nervous system diseases such as epilepsy. To identify neuroactive small molecules, we first screened 36 compounds (1–36) derived from marine natural products xyloketals and marine isoprenyl phenyl ether obtained from the mangrove fungus. Compound 1 demonstrated the most potent inhibition on the locomotor activity in larval zebrafish. Compounds 37–42 were further synthesized and their potential anti-epilepsy action was then examined in a PTZ-induced epilepsy model in zebrafish. Compound 1 and compounds 39, 40 and 41 could significantly attenuate PTZ-induced locomotor hyperactivity and elevation of c-fos mRNA in larval zebrafish. Compound 40 showed the most potent inhibitory action against PTZ-induced hyperactivity. The structure-activity analysis showed that the OH group at 12-position played a critical role and the substituents at the 13-position were well tolerated in the inhibitory activity of xyloketal derivatives. Thus, these derivatives may provide some novel drug candidates for the treatment of epilepsy.

Xyloketal-derived small molecules show protective effect by decreasing mutant Huntingtin protein aggregates in Caenorhabditis elegans model of Huntington’s disease

“…Xyloketal B, an extract from marine mangrove fungi, 9 has exhibited potent neuroprotection in different models of neurological diseases, including Parkinson’s disease and epilepsy. 10 – 13 Xyloketal B has unique bicyclic acetal moieties fused to its aromatic core structure ( Figure 1 ), which can be easily modified to improve and expand its activity. 5 , 14 Given that some xyloketal derivatives have the ability to hydrogen bond, xyloketal may have the potential to bind to mHtt proteins and disrupt the process of Htt aggregation, thereby attenuating the pathological progression of HD.…”

From the North Sea to Drug Repurposing, the Antiseizure Activity of Halimide and Plinabulin

“…This is a key advantage for (marine) natural product discovery and research, where material is often scarce [62,63] and was, therefore, used by PharmaSea for neuroactive drug discovery [1][2][3]. Other examples of zebrafish-based screening for active marine natural products can be found in [64,65].…”

Building a zebrafish toolkit for investigating the pathobiology of epilepsy and identifying new treatments for epileptic seizures

“…Accordingly, PTZ has been used in medium-throughput screens of bioactive chemical libraries to identify many new potential anti-epileptic treatments (Baxendale et al, 2012). Indeed, zebrafish treated with PTZ or other convulsants have been used to identify novel anticonvulsants from a wide variety of sources, including marine-derived natural products (Challal et al, 2014;Long et al, 2014), the terrestrial plant derivative Tanshinone IIa (Buenafe et al, 2013), a putative glutamate receptor ligand present in extracts from Citrus aurantium (Rosa-Falero et al, 2015), ar-turmerone from turmeric (Orellana-Paucar et al, 2013) and Vitamin K analogues (Rahn et al, 2014).…”