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Melatonin as an Antioxidant

Melatonin has been shown to act as an antioxidant by scavenging the hydroxyl radicals, peroxynitrite anions, peroxyl radicals, and the superoxide anion radical (Poeggler et al. 1993; Marshall et al. 1996) through a non-receptor mediated action.  Additionally, the activation of nuclear melatonin binding site (discussed later) increases mRNA levels of superoxide dismutase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase, all of which are antioxidative enzymes (Reiter 1998).  These antioxidant actions of melatonin are hypothesized to decrease the signs of aging by protecting DNA and mitochondria from oxidative damage (Tan et al. 1993), which may decrease the signs and symptoms of aging. 

     Melatonin and GABAergic transmission

     Melatonin has been shown to bind directly to the GABAA receptor (Coloma and Niles 1988; Niles and Peace 1990)  increasing allosterically its affinity to the agonist (Wu et al. 1999).  The allosteric interaction, which occurred at micromolar concentrations, was shown not to be due to binding of melatonin at the steroid or benzodiazepine binding sites (Wu et al. 1999).  In amacrine-like cells, melatonin led to a decrease in the amplitude and desensitization kinetics of GABAA mediated currents (Li et al. 2001).  However in rod-dominant bipolar cell melatonin led to a desensitization of the GABAA mediated current, only (Li et al. 2001).  These differential sensitivities were postulated to be due to expression of different GABAA receptors subunits in each preparation (Li et al. 2001).

     While the studies described above are considered non-receptor mediated actions of melatonin, other studies have shown melatonin receptor-mediated actions on GABAA receptors.  In the SCN, MT1 receptor activation causes an enhancement of GABAA currents and in the hippocampus activation of MT2 receptors leads to an attenuation of GABAA receptor mediated currents (Wan et al. 1999).  Furthermore when MT1 and MT2 receptors were expressed in HEK 293 cells (Human embryonic kidney 293) there was either an increase (MT1), or a decrease (MT2) in GABA mediated currents.  This study in particular implicates the possibility of different pathways activated by MT1 and MT2 melatonin receptors.  Because activation of either melatonin receptor has been shown to lead to a decrease in cAMP, this decrease cannot account for the reduction in GABA currents when MT2 receptors were expressed vs. the increase in GABA currents when MT1 receptors were expressed (Wan et al. 1999). 

     Melatonin and Glutamatergic transmission

     Glutamate is the major excitatory neurotransmitter in the brain.  Glutamate leads to depolarization of neurons by activating ionotropic (AMPA, kainate, NMDA) or metabotropic (mGluR1, mGluR2, or mGluR3) glutamate receptors (Ireland and Abraham 2002; Semyanov and Kullmann 2001).  In the case of ischemia/hypoxia and severe seizures, prolonged activation of glutamate receptors can lead to cell death (Rothman and Olney 1986; Olney et al. 1986).  Melatonin has been shown to protect against damage caused by enhanced glutamate transmission (Cazevieille et al. 1997; Cazevieille and Osborne 1997; Cabrera et al. 2000; Skaper et al. 1998) by interacting with toxic oxygen species generated by glutamate-induced hyperexcitability (Avshalumov and Rice 2002).

     Melatonin has also been shown to influence glutamate-mediated transmission.  In rat striatal neurons, melatonin significantly attenuated glutamate mediated responses to sensorimotor cortical stimulation (Leon et al. 1998a).  Our own studies demonstrated that 1mM melatonin attenuated hippocampal evoked-potentials, generated by stimulation of the glutamatergic synapses (Hogan et al. 2001).  The response of hippocampal, evoked-potentials to melatonin were later shown to be mediated by melatonin receptor activation (El-Sherif et al. 2002).  While these studies demonstrate a receptor-mediated action of melatonin on glutamate-mediated neurotransmission, they did not determine the specific site of action.  Glutamate release, uptake and receptors can all be possible sites for melatonin action.  Indeed studies on the golden hamster retina have shown that melatonin can increase [3H]-glutamate uptake and release (Faillace et al. 1996).

     Melatonin and Ion Channels

     Activation of ion channels is the major way of cell to cell signaling in the brain.  The changes in permeability of voltage-gated Na+, K+ and Ca2+ channels are responsible for generation of the action potential (AP) and neurotransmitter release.  A few neurotransmitters have been shown to modify voltage-gated channels leading to a variety of changes including an increase/decrease in current (Brown et al. 2002; Sun et al. 2001; Imendra et al. 2000; Cantrell et al. 1999), shift in activation/inactivation curves (Xu et al. 2001; El-Sherif et al. 2001; Neusch et al. 2000) as well as a change in the time constants of channel activation/inactivation (White et al. 1994; Camacho and Sanchez 2002).

     In mouse ocular tissue, melatonin enhances the activation and inactivation kinetics of TTX-insensitive voltage-gated Na+ channels (Rich et al. 1999), at concentrations similar to the Kd of the cloned melatonin receptor.  At higher concentrations of melatonin (1mM), considered pharmacological, there was an enhancement of the delayed rectifier K+ channel (Rich et al. 1999).  In a study by Huan (Huan et al. 2001), melatonin (1-100mM) was able to reversibly enhance the K+ current in rat cerebellar granule cells.  The effect of melatonin appeared to be receptor mediated, as it was mimicked by lower concentrations of iodo-melatonin, blocked by pre-incubation of cells with pertussis toxin, and inclusion of GTP-g-S led to a non-reversible enhancement of the delayed rectifier K+ channel in the presence of melatonin.   Melatonin also blocks specific K+ channels (composed of the Kv1.3 subunit), by directly interacting with the channel (Varga et al. 2001). 

     Melatonin and Intracellular Molecules 

     Melatonin has been shown to directly bind to calmodulin in vitro, via a non-receptor mediated process (Benitez-King et al. 1991, 1993; Benitez-King and Anton-Tay 1993).  Melatonin’s binding antagonizes calmodulin’s normal physiological effects (Romero et al. 1998), which include activation of Ca2+/calmodulin kinase II (Benitez-King et al. 1996), modulation of nitric oxide synthetase (Leon et al. 2000), and tubulin polymerization (Benitez-King and Anton-Tay 1993).  Melatonin also binds to an orphan receptor family RZR/ROR nuclear receptor (Wiesenberg et al. 1995) leading to apoptosis of cancer cells (Winczyk et al. 2001; Ciesla 2001).


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