Ferulic Acid: A Novel Inhibitor of Presynaptic Glutamate Release

E xcitotoxicity is the pathological process by which neurons are damaged and degenerated by overactivation of receptors such as the N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors for the neurotransmitter glutamate, an excitotoxin in the brain. ¹ Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system (CNS). During normal conditions, glutamate concentrations can be increased up to 1 mM in the synaptic cleft, which rapidly decreases in the lapse of milliseconds. ² However, excitotoxicity by excessive glutamate release from presynaptic terminals contributes to neurodegeneration in many CNS diseases, including ischemia, trauma, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease. Overactivation of NMDA and AMPA receptors causes degeneration of neurons, because it strongly stimulates extracellular Ca²⁺ influx through various types of Ca²⁺-permeable membrane channels. ^{1,3 –6} Therefore, a decrease in presynaptic glutamate release could be considered as a potentially important mechanism for neuroprotection in unbalanced glutamate concentrations in the brain. In previous studies, Dr. Wang's research group has demonstrated the inhibitory mechanism on presynaptic glutamate release by using a synaptosome, an isolated synaptic terminal from neurons to study synaptic transmission, and found that specific compounds such as Coenzyme Q10 (2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone) and riluzole, a neuroprotective drug with anticonvulsant, sedative, and anti-ischemic properties, could inhibit the presynaptic glutamate release effectively. ^7,8 The current study published on page 112 of this issue of JMF ⁹ examined whether ferulic acid (4-hydroxy-3-methoxy cinnamic acid), a phenolic phytochemical compound, could act as an inhibitor of presynaptic glutamate release stimulated by the K⁺ channel blocker 4-aminopyridine (4-AP). Ferulic acid dramatically inhibited glutamate release from synaptosomes by suppression of voltage-dependent Ca²⁺ entry through Cav2.2 and Cav2.1 channels, suggesting that ferulic acid is an effective inhibitor of presynaptic glutamate release. Ferulic acid-induced effects in synaptosomes are not confirmed in the brain in vivo. However, these results demonstrate a novel therapeutic potential of ferulic acid with a promise for the prevention of neurodegeneration by excessive release of glutamate in the brain.