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.
Highlights
Damage by free radicals as a cause of neurodegeneration has been discussed in countless publications
The attenuation of free radical formation should be regarded as an important contribution to the protection from damage by reactive oxygen and nitrogen species
Global regulation mechanisms of radical avoidance related to the internal coordination of circadian rhythms are mainly associated with the chronobiotic actions of melatonin (21)
Summary
Damage by free radicals as a cause of neurodegeneration has been discussed in countless publications. The strongly elevated levels of nitric oxide, as occurrring in the course of an inflammatory response, can considerably contribute to cell stress In this case, the oxidative and nitrosative stress may be locally dramatic, it should not be considered to be of major importance for processes of normal aging, as far as this is related to the slow, lingering changes underlying a more or less continually progressing deterioration. The original assumption of mitochondrial mutations as a source of enhanced radical generation is not supported This conclusion does not mean that vicious cycles in the function of mitochondria do not exist. The challenge is the search for suitable agents that may reliably and efficiently attenuate radical formation without reducing life processes within the cell
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