Glutamate Excitotoxicity and Oxidative Stress in Epilepsy: Modulatory Role of Melatonin

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Excitotoxicity and glutamate receptors in epilepsy

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Glutamate hypothesis.
1. Excessive release of glutamate
2. Increase in the influx of calcium
3. Apóptosis, ROS production and electro chain disfunction

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NMDA are primary glutamate receptors permeable to Ca²⁺
AMPA and KA are impermeable to Ca²⁺, except those AMPA receptors lacking GluR2 subunit (located in motor neurons).
Influx of Ca²⁺ is regulated by ER and mitochondria.
Mitochondrial buffering of Ca²⁺ fails when influx is uncontrollated
Agonist of AMPA receptors interrupt propagation of seizures in amygdala
Many kainate receptor agonists are epileptogenic. GluK2 has an important role on epileptogenesis mediated by kainate receptors as revealed by GluK2 KO mice.

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Antagonists of group I metabotropic receptors (mGluR1 and mGluR5) are anti-epileptogenic, while activation of group II and group III supresses seizures.
Group I MRs mechanism:
- Affect protein kinase activation in inositosol triphosphate/Ca²⁺ signal transduction pathway
- This leads to stimulation of Ca²⁺ release.

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Free radicals: superoxide radical, peroxynitrite, hydroxil radical
Calcium ion influx leads to overstimulation of NO molecules
NO interacts with superoxide to form peroxynitrite anions
Oxidative stress is defined as an imbalance between ROS/RNS and antioxidant defense
Oxidative stress damages nucleic acids, proteins and lipids
Neuronal cells specialy vulnerable to oxidative stress because:
- Brain is rich in iron (this catalyzes hydroxil radical formation).
- Brain has a large amount of polyinsaturated fatty acids prone to lipid peroxidation
- Brain has low concentrations of antioxidant enzymes:
  - Enzymatic
    - GR (glutathione reductase), SOD (superoxide dismutase), GPx (glutathione peroxidase).
  - Non-enzymatic
    - Vitamin C/E, GSH (reduced form of gluthatione)
Mitochondria are the major source of ROS

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Melatonin is synthetised from tryptophan (same precursor as serotonin).
Melatonin action is mediated by nuclear receptors RZR/ROR and melatonin receptors MT1/MT2
It is implicated in the inhibition of apopototic pathways
It is a anti-oxidant and scavenger of radical oxygen and nitrogenous species
Melatonin obstruct calcium influx, binding to ca-calmoludin complex
Melatonin increase the number of binding sites of GABA
It also inhibits indirectly glutamate release by reducing striatal dopaminergic activity