Melatonin-Induced Postconditioning Suppresses NMDA Receptor through Opening of the Mitochondrial Permeability...

Area of Science:

• Neuroscience
• Mitochondrial Biology
• Pharmacology

Background:

• Mitochondrial membrane potential and the mitochondrial permeability transition pore (mPTP) are implicated in ischemic postconditioning (PostC).
• Melatonin, a hormone regulating circadian rhythms, exhibits neuroprotective effects mediated by mitochondrial melatonin receptors (MTs).
• The precise neuroprotective mechanisms of melatonin in PostC remain unclear.

Purpose of the Study:

• To investigate the involvement of MTs and the mPTP in melatonin-induced neuroprotection mimicking ischemic PostC.
• To elucidate the molecular mechanisms underlying melatonin's protective effects against ischemia-reperfusion injury in hippocampal neurons.

Main Methods:

• Utilized whole-cell patch-clamp technique on hippocampal CA1 pyramidal cells from C57BL mice.
• Measured spontaneous excitatory postsynaptic currents (sEPSCs), intracellular calcium, mitochondrial membrane potential, and N-methyl-D-aspartate receptor (NMDAR) currents.
• Employed melatonin, MT agonist (ramelteon), MT antagonist (luzindole), and mPTP inhibitor (cyclosporine A).

Main Results:

• Melatonin significantly reduced increases in sEPSCs and intracellular calcium concentrations.
• Melatonin and ramelteon suppressed NMDAR currents; this effect was blocked by cyclosporine A and luzindole.
• Melatonin and ramelteon enhanced mitochondrial membrane potential depolarization, while luzindole inhibited it.

Conclusions:

• Melatonin-induced PostC, acting via MTs, suppresses NMDAR activation.
• This suppression is linked to mPTP opening and partial mitochondrial membrane potential depolarization.
• Melatonin reduces excessive glutamate release, offering neuroprotection against ischemia-reperfusion injury.