Melatonin attenuates D-galactose-induced memory impairment, neuroinflammation and neurodegeneration via RAGE/NF-B-K/JNK signaling pathway in aging mouse model

Abstract

Melatonin acts as a pleiotropic agent in various age-related neurodegenerative diseases. In this study, we examined the underlying neuroprotective mechanism of melatonin against D-galactose-induced memory and synaptic dysfunction, elevated reactive oxygen species (ROS), neuroinflammation and neurodegeneration. D-galactose was administered (100mg/kg intraperitoneally (i.p.)) for 60days. After 30days of D-galactose administration, vehicle (same volume) or melatonin (10mg/kg, i.p.) was administered for 30days. Our behavioral (Morris water maze and Y-maze test) results revealed that chronic melatonin treatment alleviated D-galactose-induced memory impairment. Additionally, melatonin treatment reversed D-galactose-induced synaptic disorder via increasing the level of memory-related pre-and postsynaptic protein markers. We also determined that melatonin enhances memory function in the D-galactose-treated mice possibly via reduction of elevated ROS and receptor for advanced glycation end products (RAGE). Furthermore, Western blot and morphological results showed that melatonin treatment significantly reduced D-galactose-induced neuroinflammation through inhibition of microgliosis (Iba-1) and astrocytosis (GFAP), and downregulating other inflammatory mediators such as p-IKK, p-NF-(K)B65, COX2, NOS2, IL-1, and TNF. Moreover, melatonin lowered the oxidative stress kinase p-JNK which suppressed various apoptotic markers, that is, cytochrome C, caspase-9, caspase-3 and PARP-1, and prevent neurodegeneration. Hence, melatonin attenuated the D-galactose-induced memory impairment, neuroinflammation and neurodegeneration possibly through RAGE/NF-B-K/JNK pathway. Taken together, our data suggest that melatonin could be a promising, safe and endogenous compatible antioxidant candidate for age-related neurodegenerative diseases such as Alzheimer's disease (AD).