Neuroprotective Action of the Pineal Hormone Melatonin against Excitotoxicity

Glutamate receptor-mediated excitotoxicity has been studied for a number of years as an important mechanism in the progressive nature of acute brain injuries, e.g., due to stroke,’ and in chronic neurodegenerative diseases. Several strategies are currently being considered for attenuating the consequences of pathological glutamate receptor activation. Although a direct blockade of glutamate receptors has an obvious appeal, it is associated with side effects that still are the subject of preclinical and clinical evaluations.2 We proposed an alternative approach in antiexcitotoxic therapy, which we termed “receptor abuse-dependent antagonism” (RADA).’ RADA implies that pathological glutamate receptor stimulation triggers a downstream mechanism that is crucial for the expression of neurotoxicity. If this intracellular mechanism is blocked, neuroprotection can be achieved even in the absence of glutamate receptor antagonism. Several downstream mechanisms have recently been identified as putative targets for RADA. They include protein phosph~rylation,~ mechanisms of programmed cell death: and oxidative stress5 Two recent lines of research point to the pineal hormone melatonin in the RADA approach to neuroprotection against excitotoxicity. Namely, melatonin was shown to be an antioxidative molecule, and to be capable of preventing the toxic effects of glutamate and a glutamate receptor agonist, kainate.