2025
2025-11 November
Introduction
- currently available therapeutics target ion channels or neurotransmitter systems
Sources of Reactive Species and Oxidative Stress
- free radical: any chemical species with one or more unpaired electrons in their external orbit
- ROS/RNS:
- oxygen, superoxide (O2\(^-\)), H2O2, Nitric oxide (NO), hydroxyl radical (HO) and peroxynitrite (ONOO\(^-\))
- recurrent seizures cause:
- production of reactive oxygen species
- altered gluthatione [GSH] redox status
- alterations in endogenous antioxidants:
- catalase, gluthatione, peroxidase (GPx)
- rodent genetically deficient on super oxide dismutase (SOD2) or thioredoxin 2 (TXN2) exhibit spontaneous seizures
- NAD: Coenzyme central to metabolism, found in all living cells, formed by two nucleotides, joined by their phosphate groups
- NAD exist in two forms: Oxidized (NAD+) and reduced form (NADH).
- It is an indicator of oxidative and glycolytic metabolism
- Melatonin modulates the electrical activity of neurons
Excitotoxicity and glutamate receptors in epilepsy
- Glutamate hypothesis.
- Excessive release of glutamate
- Increase in the influx of calcium
- Apóptosis, ROS production and electro chain disfunction
Ionotropic glutamate receptors
- 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.
Metabotropic glutamate receptors
- 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.
Glutamate and oxidative/Nitosative stress
- 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
Melatonin
- 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