Theaflavin-3,3′-digallate prevents radiofrequency radiation-induced learning and memory impairment in mice via regulating GSK-3α/GRα/RORα/BMAL1 expression

Abstract

Radiofrequency (RF) electromagnetic radiation is an environmental hazard that causes neurobehavioral disorders and leads to learning and memory decline. In addition, theaflavin-3,3′-digallate (TFDG) is the most effective antioxidant and bioactive compound among the theaflavins in black tea, and theaflavins have been proven to provide protection against neuronal cell injury. Herein, we aimed to explore the salutary effects and relevant molecular mechanisms of TFDG on RF radiation-induced learning and memory damage in mice. Our results showed that oral administration of TFDG effectively relieved learning and memory impairment in mice caused by RF radiation (1.8 GHz, 240 μW cm⁻²), including decreasing the number of learning attempts and increasing the memory rate in a Y-maze test, and raising the novel object recognition rate in a novel object recognition test. TFDG also reduced the pathological damage of the hippocampal pyramidal and granular neurons in RF-radiated mice, for neurotransmitters in the hippocampus, decreased the levels of glutamate (GLU), nitric oxide (NO) and acetylcholinesterase (AchE) activity and increased the acetylcholine (Ach), dopamine (DA) and dopamine transporter (DAT) levels. The decrease in the antioxidant ability in the hippocampus of RF-radiated mice was reversed by TFDG treatment by enhancing the levels of total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities and lowering the malondialdehyde (MDA) content. Furthermore, RF radiation induced the accumulation of glycogen synthase kinase-3α/glucocorticoid receptor alpha (GSK-3α/GRα) proteins and mRNA expression in the hippocampus of mice and the downregulation of retinoid-related orphan nuclear receptor alpha/brain and muscle ARNT-like 1/dopamine receptor D5 (RORα/BMAL1/DRD5) genes/protein expression. Conclusively, TFDG can improve RF radiation-induced learning and memory impairment, which may be related to the reduction of RF radiation-induced hippocampal neuron injury, the regulation of neurotransmitter disorders and antioxidant capacity reduction via the regulation of GSK-3α/GRα/RORα/BMAL1 pathway abnormalities.