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.

Figure 1

Several nitrones and a structurally related indolic compound, which have been tested for cell protection and attenuation of mitochondrial free radical formation. For details see current text.

Figure 2

PPARγ activating thiazolidinediones with potentially neuroprotective and anti-neuroinflammatory properties.

Figure 3

Glutamatergic modulators with antiexcitotoxic properties, and the kynurenic acid (12) precursors.

Figure 4

The phytoalexin and SIRT1 ligand, resveratrol (17) and several synthetic SIRT activators.

Figure 5

The neuroprotective indoleamine melatonin (21), its metabolites formed in the kynuramine pathway, and two synthetic agonists acting via melatonin receptors MT₁ and MT₂.