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-IKKβ, p-NF-K B65, COX2, NOS2, IL-1β, and TNFα. 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).

Chronic Melatonin Treatment Prevents Memory Impairment Induced by Chronic Sleep Deprivation

“…Previous studies have documented the protective effect of melatonin on learning and memory deficits induced by a number of pathological or physiological conditions such as Alzheimer's disease [57,58], aging [59], diabetes [60], and head trauma [61]. Additionally, melatonin was shown to prevent cognitive deficits in memory due to administration/ingestion of chemicals and medications such as aromatic thinner solvents [62], pesticides [63], D-galactose [59], and dexamethasone [64].…”

Inhibition of ERK1/2 Signaling Pathway is Involved in Melatonin's Antiproliferative Effect on Human MG-63 Osteosarcoma Cells

“…Melatonin plays key roles in the biologic regulation of circadian rhythms [27,28], sleep [29,30], antioxidant protection [31][32][33][34][35], cell aging [36], tumor growth [12,37], reproduction [31,38], and bone physiology [39,40]. A growing amount of data indicates that the age-related decline in the level of melatonin is closely associated with bone diseases: osteosarcoma, adolescent idiopathic scoliosis and osteoporosis [1,39].…”

Protective Effect of Lupeol Against Lipopolysaccharide-Induced Neuroinflammation via the p38/c-Jun N-Terminal Kinase Pathway in the Adult Mouse Brain

“…Cresyl violet staining was performed according to a previously described procedure (Ali et al 2015). Following overnight drying, the tissue slides were washed three times with 0.01 M PBS for 5 min.…”