Caffeine Neuroprotective Mechanism Against β-Amyloid Neurotoxicity in SHSY5Y Cell Line: Involvement of Adenosine, Ryanodine, and N-Methyl-D-Aspartate Receptors.

Mojtaba Keshavarz,Atena Amiri,Majid Reza Farrokhi

doi:10.15171/apb.2017.069

Mojtaba Keshavarz, Atena Amiri + Show 1 more

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https://doi.org/10.15171/apb.2017.069

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Abstract

Purpose: Some reports have shown neuroprotective effects of caffeine in several neurodegenerative disorders. However, its mechanism of action is not completely clear. Therefore, the aim of this study was to explore the interference of ryanodine, N-methyl-D-aspartate (NMDA) and adenosine modulators with the neuroprotective effects of caffeine against β-amyloid (Aβ) neurotoxicity in the SHSY5Y cells.Methods: The SHSY5Y cells were treated with Aβ23-35 (20µM) and/or caffeine (0.6 and 1mM), or both for 24 hours. Adenosine (20, 40, 60, 80, 100µM), NMDA (20, 50, 70, 90µM), dantrolene (2, 4, 6, 8, 10µM) were also added to the medium and incubated for 24 hours. The cell viability was measured via the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) method. The data were analyzed using one-way ANOVA followed by Bonferroni test.Results: Caffeine at all the used concentrations (0.6, 0.8, 0.9, 1, and 3mM) significantly protected neuronal cells against Aβ neurotoxicity. Adenosine at the concentrations of 20, 40, 80 and 100μM diminished the neuroprotective effects of caffeine (0.6 and 1mM) against Aβ neurotoxicity. NMDA at the concentrations of 20, 50, 70 and 90μM blocked caffeine (0.6 and 1mM) neuroprotective effects. Dantrolene at the concentration of 2, 4, 6, 8 and 10μM diminished the neuroprotective effects of caffeine (0.6mM) and at the concentrations of 2 and 10μM impede caffeine (1mM) neuroprotection against Aβ neurotoxicity.Conclusion: Caffeine produced neuroprotective effect against Aβ neurotoxicity. Blockade of adenosine and NMDA receptors, as well as the activation of ryanodine receptors, may contribute to the neuroprotective effects of caffeine.

Highlights

IntroductionExtracellular aggregation of β-amyloid peptides (Aβ) and hyperphosphorylated tau protein (neurofibrillary tangles) may be the most important causes of neural degeneration in Alzheimer’s disease (AD).[1] accumulating data have implied that deregulated calcium signaling may have an important contribution to the neural cell death in AD.[2] Interestingly, altered intracellular calcium homeostasis emerges earlier than neuropathological abnormalities observed in AD.[3] Calcium is an important signal transduction molecule[4] which is involved in a wide range of neural functions like cell growth, differentiation, metabolism, exocytosis, and apoptosis.[4] Several neuronal systems, including N-methyl-D-Aspartate (NMDA), adenosine and ryanodine receptors maintain the intracellular concentration of calcium within a narrow normal range.[5,6,7] On the other hand, ryanodine, NMDA and adenosine receptors have possible roles in the pathophysiology and treatment of AD.[8,9,10] these receptors may be the targets of neuroprotective agents in AD
Extracellular aggregation of β-amyloid peptides (Aβ) and hyperphosphorylated tau protein may be the most important causes of neural degeneration in Alzheimer’s disease (AD).[1]
Adenosine at the concentrations of 20, 40, 60, 80 and 100μM diminished the neuroprotective effects of caffeine (0.6mM) against Aβ neurotoxicity (F(9)= 21.35, p=0.000) (Figure 1)

Summary

Introduction

Extracellular aggregation of β-amyloid peptides (Aβ) and hyperphosphorylated tau protein (neurofibrillary tangles) may be the most important causes of neural degeneration in Alzheimer’s disease (AD).[1] accumulating data have implied that deregulated calcium signaling may have an important contribution to the neural cell death in AD.[2] Interestingly, altered intracellular calcium homeostasis emerges earlier than neuropathological abnormalities observed in AD.[3] Calcium is an important signal transduction molecule[4] which is involved in a wide range of neural functions like cell growth, differentiation, metabolism, exocytosis, and apoptosis.[4] Several neuronal systems, including N-methyl-D-Aspartate (NMDA), adenosine and ryanodine receptors maintain the intracellular concentration of calcium within a narrow normal range.[5,6,7] On the other hand, ryanodine, NMDA and adenosine receptors have possible roles in the pathophysiology and treatment of AD.[8,9,10] these receptors may be the targets of neuroprotective agents in AD

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