Neuroprotection by Radical Avoidance: Search for Suitable Agents

Abstract

Neurodegeneration is frequently associated with damage by free radicals. However, increases in reactive oxygen and nitrogen species, which may ultimately lead to neuronal cell death, do not necessarily reflect its primary cause, but can be a consequence of otherwise induced cellular dysfunction. Detrimental processes which promote free radical formation are initiated, e.g., by disturbances in calcium homeostasis, mitochondrial malfunction, and an age-related decline in the circadian oscillator system. Free radicals generated at high rates under pathophysiological conditions are insufficiently detoxified by scavengers. Interventions at the primary causes of dysfunction, which avoid secondary rises in radical formation, may be more efficient. The aim of such approaches should be to prevent calcium overload, to reduce mitochondrial electron dissipation, to support electron transport capacity, and to avoid circadian perturbations. L-Theanine and several amphiphilic nitrones are capable of counteracting excitotoxicity and/or mitochondrial radical formation. Resveratrol seems to promote mitochondrial biogenesis. Mitochondrial effects of leptin include attenuation of electron leakage. Melatonin combines all the requirements mentioned, additionally regulates anti- and pro-oxidant enzymes and is, with few exceptions, very well tolerated. In this review, the perspectives, problems and limits of drugs are compared which may be suitable for reducing the formation of free radicals.

Melatonin Metabolism in the Central Nervous System

“…This is supported by findings on elevated levels of melatonin's oxidation product N 1 -acetyl-N 2 -formyl-5-methoxykynuramine (AFMK) in the cerebrospinal fluid of patients with meningitis [125]. This metabolite and also its secondary product, N 1 -acetyl-5-methoxykynuramine (AMK), have been shown to possess cell-protective properties including beneficial effects in mitochondria [1,40,41,50,71,136,143]. Moreover, numerous publications have demonstrated the neuroprotective potential of melatonin under various experimental conditions [11,85,104,105,108,118,131,154].…”

“…In vivo, 6-hydroxymelatonin formed this way may not be easily distinguished from the enzymatically produced, more abundant fraction. 2-Hydroxymelatonin, which has been repeatedly detected under experimental conditions, is in equilibrium with its tautomer, 3-acetamidoethyl-5-methoxyindolin-2-one (= "2-oxomelatonin") [2,39,41] (Fig. 3).…”

“…This is especially the case when melatonin is administered at high concentrations under experimental conditions designed to counteract an artificially induced oxidative or nitrosative stress. Since various of the non-enzymatic products are also biologically active and undergo redox reactions [41,44,47,141], these metabolites should not be neglected in experiments on protection by melatonin.…”

“…AMK is of high interest because of several properties. It is a potent antioxidant [110], effective scavenger of reactive nitrogen species [36,42,43], protecting agent against mitochondrial damage [1,38,40,41], downregulator of cyclooxygenase-2 [24,86], cyclooxygenase inhibitor by far more potent than aspirin [62], and antagonist of neuronal [71] and inducible NO synthases [24,143].…”

Melatonin: A pleiotropic molecule regulating inflammation

“…Furthermore, melatonin plays an important role in activating anti-oxidant defenses such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GSH-Rd) and glucose-6-phosphate dehydrogenase (G6PD) [79,80].…”