Protective effects of phenformin on zebrafish embryonic neurodevelopmental toxicity induced by X-ray radiation

Abstract

Radiotherapy (RT) is a common treatment for head and neck cancers, but central nervous system function can be impaired by clinical radiation doses. This experimental study evaluated the protective efficacy of the anti-hyperglycaemic/anti-neoplastic agent phenformin against radiation-induced developmental toxicity in zebrafish embryos. Zebrafish embryos pre-treated with 25 lM phenformin 1 h before x-ray irradiation were compared to irradiation-only embryos for mortality, hatching rate, morphology, spontaneous movement, heart beat, larval swimming, activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), malondialdehyde content (MDA, a by-product of membrane lipid oxidation), and acetylcholinesterase (AChE) activity. In addition, expression levels of multiple genes related to neural development and apoptosis (sod2, bdnf, ache, p53, bax, and bcl-2) were compared by RT-PCR and associated protein expression levels by western blotting. Pre-treatment with phenformin increased hatching rate, spontaneous movement, heart beat, and larval motor activity, decreased mortality and malformation rate, increased SOD, CAT, and AChE activities, and reduced MDA compared to irradiation-only embryos. The mRNA expression levels of anti-apoptotic sod2, bdnf, ache, and bcl-2 were enhanced while mRNA expression of p53 and pro-apoptotic bax were reduced in the phenformin pre-treatment group. Further, p53, Bax, and c-H2AX (a biomarker of DNA damage) were downregulated while Bcl-2 and BDNF were upregulated by phenformin pre-treatment. Taken together, this study supports the protective efficacy of phenformin against radiation toxicity in zebrafish embryos by suppressing oxidative stress and ensuing apoptosis.

Embryonic Exposure to UV-328 Impairs the Cell Cycle in Zebrafish (Danio rerio) by Inhibiting the p38 MAPK/p53/Gadd45a Signaling Pathway

“…The difference between UV-234 and UV-328 may be due to the variations in their chemical structures. Previous studies have also suggested that different BUVs elicit unique responses in zebrafish or cells. , Moreover, the downregulation of p53 may lead to increased hatching and heart rates in zebrafish by inhibiting apoptosis . However, further investigations are necessary to fully elucidate the sequence of these cascading effects.…”

“…32,51 Moreover, the downregulation of p53 may lead to increased hatching and heart rates in zebrafish by inhibiting apoptosis. 52 However, further investigations are necessary to fully elucidate the sequence of these cascading effects.…”

Synthesis and Structure of Novel Phenothiazine Derivatives, and Compound Prioritization via In Silico Target Search and Screening for Cytotoxic and Cholinesterase Modulatory Activities in Liver Cancer Cells and In Vivo in Zebrafish

“…In addition, ACh synthesis and degradation has to be in balance because sudden inhibition of AChE leads to paralysis and death. 38 Previous studies have established the presence of a feedback between AChE activity and ACHE transcription 39 − 41 as well as other feedback mechanisms involving changes in the BCHE expression and activity of BChE 42 − 44 and acetycholine receptors 40 , 45 acting as modulators of cholinergic signaling. 46 However, to our knowledge, there is no study in the literature testing the association between the enzyme activity and transcription levels of cholinesterases in response to the PTZ exposure in cancer cells.…”

High-throughput preparation of radioprotective polymers via Hantzsch’s reaction for in vivo X-ray damage determination

“…Zebrafish embryos have been used as a unique vertebrate model to quickly screen therapeutic agents 46,47 . Zebrafish embryos are small, optically transparent and easily available, and have short embryonal development, which are conducive to quick and direct observation of radiation-induced damage to animals (death, deformation, abnormal organs and damaged DNA); thus, zebrafish embryos have also been used to study radiation-induced mutation and evaluate radioprotective agents including amifostine [48][49][50][51][52][53] . Here we used zebrafish embryos as the model to study the in vivo protection by P(2)(1) against a high dose (80 Gy) of X-ray radiation.…”

“…Decreased activity of superoxide dismutase (SOD, a radical scavenger) and generation of malondialdehyde (MDA, a lipid peroxidation end product) in organisms are biomarkers of radiation-induced damage [53][54][55] . Thus, the levels of SOD and MDA in the embryos were measured ( Fig.…”