Antioxidants, oxidative stress, and degenerative neurological disorders

Authors
Citation
Ra. Floyd, Antioxidants, oxidative stress, and degenerative neurological disorders, P SOC EXP M, 222(3), 1999, pp. 236-245
Citations number
44
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Medical Research General Topics
Journal title
PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE
ISSN journal
0037-9727 → ACNP
Volume
222
Issue
3
Year of publication
1999
Pages
236 - 245
Database
ISI
SICI code
0037-9727(199912)222:3<236:AOSADN>2.0.ZU;2-Q
Abstract
Recently, clinical trials of several neurodegenerative diseases have increa singly targeted the evaluation of the effectiveness of various antioxidants . The results so far are encouraging but variable and thus confusing, Ratio nale for the possible clinical effectiveness of antioxidants in several deg enerative conditions has arisen out of the many years of basic science gene rally showing that reactive oxygen species (ROS) and oxidative damage are i mportant factors in the processes involved. Aging is one of the most signif icant risk factors for degenerative neurological disorders, Basic science e fforts in our laboratory have centered on exploring the role of ROS and oxi dative stress in neurodegenerative processes. The present review brings tog ether some of the basic concepts we have learned by following this approach for the last 20 years and specifically the results we have obtained by fol lowing up on our serendipitous findings that a nitrone-based free radical t rap, alpha-phenyl-tert-butylnitrone (PBN), has neuroprotective activity in several experimental neurodegenerative models. The mechanistic basis of the neuroprotective activity of PEN does not appear to rely on its general fre e radical trapping or antioxidant activity per se, but its activity in medi ating the suppression of genes induced by pro-inflammatory cytokines and ot her mediators associated with enhanced neuroinflammatory processes, Neuroin flammatory processes, induced in part by pro-inflammatory cytokines, yield enhanced ROS and reactive nitric oxide species (RNS) as well as other unkno wn components that have neurotoxic properties, Neurotoxic amounts of RNS ar e formed by the activity of inducible nitric oxide synthase (iNOS), The dem onstration of enhanced 3-nitro-tyrosine formation in affected regions of th e Alzheimer's brain, in comparison to age-matched controls, reinforces the importance of neuroinflammatory processes. iNOS induction involves activati on by phosphorylation of the MAP kinase p38 and can be induced in cultured astrocytes by IL-1 beta or H2O2, The action of PEN and N-acetyl cysteine to suppress the activation of p38 was demonstrated in cultured astrocytes, Th e demonstration of activated p38 in neurons surrounding amyloid plaques in affected regions of the Alzheimer's brain attest to enhanced signal transdu ction processes in this neurodegenerative condition, The major themes of RO S and RNS formation associated with neuroinflammation processes and the sup pression of these processes by antioxidants and PEN continue to yield promi sing leads for new therapies, Outcomes of clinical trials on antioxidants w ill become less confusing as more knowledge is amassed on the basic process es involved.