Melatonin attenuates D‐galactose‐induced memory impairment, neuroinflammation and neurodegeneration via RAGE/NF‐KB/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 (100 mg/kg intraperitoneally (i.p.)) for 60 days. After 30 days of D‐galactose administration, vehicle (same volume) or melatonin (10 mg/kg, i.p.) was administered for 30 days. 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 β , p‐ NF ‐ K B 65, COX 2, NOS 2, IL ‐1 β , and TNF α . 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 ‐ K B / 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 ).