Melatonin receptor agonist Piper betle L. ameliorates dexamethasone-induced early life stress in adult zebrafish

Early life exposure to stress has been suggested to be a crucial factor for the development of the brain and its functions. It is well documented that childhood stress is a risk factor for sleep problems in adulthood. Piper betle L. leaf extract (PB) has been used in several traditional medicines to cure various ailments. Recently, PB has been proved to have antidepressant activity. The literature suggests that antidepressants affect the synthesis and release of melatonin through several mechanisms. Thus, this study investigated the potential role of PB for the treatment of sleep disruption after early life stress exposure. Firstly, dexamethasone (DEX) (2 and 20 mg/l for 24 h) was administered to zebrafish larvae on the 4th day post-fertilization (dpf) to induce early life stress. The effects of stress on behaviour during adulthood, melatonin level and stress-related gene expression (nfkb) in the brain were then studied. Next, the possible role of PB (10 and 30 mg/Kg) was studied by measuring its effect on behaviour and by quantifying the expression levels of several melatonin-related (MT1, MT2, aanat1, aanat2) and stress-related (nfkb) genes by qPCR. DEX-treated zebrafish exhibited anxious behaviour, along with a lower level of melatonin and a higher mRNA expression of nfkb. After treatment with PB, a similar effect on behaviour and gene expression levels as the melatonin treatment group (10 mg/kg; positive control) was seen in adult zebrafish. These molecular confirmations of the observed behavioural effects of the PB indicate a possible role in the treatment of early life stress-induced sleep disruption.