Melatonin Attenuates Scopolamine-Induced Memory/Synaptic Disorder by Rescuing EPACs/miR-124/Egr1 Pathway

Abstract

Alzheimer's disease (AD) is the most prevalent type of dementia in elderly people. There are decreased melatonin levels in the serum of AD patients, and melatonin supplements are able to reverse AD pathology and memory deficits in many animal experiments and clinical trials. However, the underlying mechanism regarding how melatonin rescues the AD-like memory/synaptic disorder remains unknown. Here, we use the Morris water maze, step-down inhibitory avoidance task, in vivo long-term potentiation recording, and Golgi staining and report that intraperitoneal injection of melatonin (1 mg/kg/day) for 14 days in rats effectively reverses the memory and synaptic impairment in scopolamine-induced amnesia, a well-recognized dementia animal model. Using real-time polymerase chain reaction and western blotting experiments, we further determined that melatonin rescues the EPACs/miR-124/Egr1 signal pathway, which is important in learning and memory, as reported recently. Our studies provide a novel underlying epigenetic mechanism for melatonin to attenuate the synaptic disorder and could benefit drug discovery in neurodegenerative diseases.

Effects of Chronic Scopolamine Treatment on Cognitive Impairments and Myelin Basic Protein Expression in the Mouse Hippocampus

“…Dose of SCO was selected based on previous studies (Wang et al 2013;Yan et al 2014). The control mice (n = 14 at each point in time) were injected with the same volume of saline (pH 7.4).…”

Epac activation initiates associative odor preference memories in the rat pup

“…Suppression of miR-124 restored normality in all measures. A study of memory amelioration by melatonin also found Epac and miR-124 modulation associated with improvement (Wang et al 2013). In contrast, another recent study reported Epac activation in the nucleus accumbens interfered with conditioned place preference learning (Park et al 2014).…”

Melatonin, Noncoding RNAs, Messenger RNA Stability and Epigenetics—Evidence, Hints, Gaps and Perspectives

“…AD-like memory deficits were investigated in a rat model using scopolamine toxicity [190]. The toxin caused decreases in EPAC1, EPAC2 (cAMP-regulated guanine nucleotide exchange factor-1, -2) and RagA (Ras-related GTP-binding protein), changes that led to an increase in miR-124 and a decline of its target, Egr1 mRNA (early growth response protein 1, alias NGFI-A, nerve growth factor-induced protein A).…”

“…The toxin caused decreases in EPAC1, EPAC2 (cAMP-regulated guanine nucleotide exchange factor-1, -2) and RagA (Ras-related GTP-binding protein), changes that led to an increase in miR-124 and a decline of its target, Egr1 mRNA (early growth response protein 1, alias NGFI-A, nerve growth factor-induced protein A). Melatonin reversed all these changes and attenuated memory and synaptic deficits [190]. …”