ABSTRACT
Melatonin is involved in the control of various physiological functions, such as sleep, cell growth and free radical scavenging. The ability of melatonin to behave as an antioxidant, together with the fact that the Alzheimer-related amyloid ß-peptide (Aß) triggers oxidative stress through hydroxyl radical-induced cell death, suggests that melatonin could reduce Alzheimer's pathology. Although the exact etiology of Alzheimer's disease (AD) remains to be established, excess Aß is believed to be the primary contributor to the dysfunction and degeneration of neurons that occurs in AD. Aß peptides are produced via the sequential cleavage of ß-secretase ß-site APP-cleaving enzyme 1 (BACE1) and γ-secretase (PS1/PS2), while α-secretase (ADAM10) prevents the production of Aß peptides. We hypothesized that melatonin could inhibit BACE1 and PS1/PS2 and enhance ADAM10 expression. Using the human neuronal SH-SY5Y cell line, we found that melatonin inhibited BACE1 and PS1 and activated ADAM10 mRNA level and protein expression in a concentration-dependent manner and mediated via melatonin G protein-coupled receptors. Melatonin inhibits BACE1 and PS1 protein expressions through the attenuation of nuclear factor-κB phosphorylation (pNF-κB). Moreover, melatonin reduced BACE1 promoter transactivation and consequently downregulated ß-secretase catalytic activity. The present data show that melatonin is not only a potential regulator of ß/γ-secretase but also an activator of α-secretase expression through the activation of protein kinase C, thereby favoring the nonamyloidogenic pathway over the amyloidogenic pathway. Altogether, our findings suggest that melatonin may be a potential therapeutic agent for reducing the risk of AD in humans.
Subject(s)
ADAM Proteins/metabolism , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Aspartic Acid Endopeptidases/metabolism , Melatonin/pharmacology , Membrane Proteins/metabolism , Neuroblastoma/metabolism , Receptors, Melatonin/metabolism , ADAM Proteins/genetics , ADAM10 Protein , Amyloid Precursor Protein Secretases/genetics , Aspartic Acid Endopeptidases/genetics , Cell Line, Tumor , Gene Expression/drug effects , Gene Expression/genetics , Humans , Membrane Proteins/genetics , Neuroblastoma/genetics , Presenilins/genetics , Presenilins/metabolism , Receptors, Melatonin/geneticsABSTRACT
OBJECTIVE: The aim of this study was to evaluate the effectiveness of Cognitive Sensory Motor Training Therapy (Perfetti's method) vis-à-vis conventional occupational therapy in the recovery of arm function after acute stroke. DESIGN: Prospective randomized controlled trial. SETTING: Two rehabilitation centers in Bangkok, Thailand. SUBJECTS: Forty first-time acute stroke patients without severe cognitive or language impairment. INTERVENTION: All subjects were randomly divided into two groups; one was treated using Perfetti's method and the other using conventional occupational therapy. Each group underwent therapy for 30 minutes, five times a week for four weeks. MAIN MEASURES: The primary variable was arm function as assessed by the Action Research Arm Test; secondary variables were the extended Barthel Index and the box and block test score. RESULTS: The intention-to-treat analysis revealed no statistically significant differences between the two groups at the end of treatment for any variable. CONCLUSIONS: There was no evidence of a difference between Cognitive Sensory Motor Training Therapy of Perfetti's method and conventional occupational therapy with respect to the restoration of hand and arm function after a stroke.