Elsevier

Neuropharmacology

Volume 40, Issue 8, June 2001, Pages 959-975
Neuropharmacology

Review
Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier

https://doi.org/10.1016/S0028-3908(01)00019-3Get rights and content

Abstract

Oxidative stress (OS) has been implicated in the pathophysiology of many neurological, particularly neurodegenerative diseases. OS can cause cellular damage and subsequent cell death because the reactive oxygen species (ROS) oxidize vital cellular components such as lipids, proteins, and DNA. Moreover, the brain is exposed throughout life to excitatory amino acids (such as glutamate), whose metabolism produces ROS, thereby promoting excitotoxicity. Antioxidant defense mechanisms include removal of O2, scavenging of reactive oxygen/nitrogen species or their precursors, inhibition of ROS formation, binding of metal ions needed for the catalysis of ROS generation and up-regulation of endogenous antioxidant defenses. However, since our endogenous antioxidant defenses are not always completely effective, and since exposure to damaging environmental factors is increasing, it seems reasonable to propose that exogenous antioxidants could be very effective in diminishing the cumulative effects of oxidative damage. Antioxidants of widely varying chemical structures have been investigated as potential therapeutic agents. However, the therapeutic use of most of these compounds is limited since they do not cross the blood brain barrier (BBB). Although a few of them have shown limited efficiency in animal models or in small clinical studies, none of the currently available antioxidants have proven efficacious in a large-scale controlled study. Therefore, any novel antioxidant molecules designed as potential neuroprotective treatment in acute or chronic neurological disorders should have the mandatory prerequisite that they can cross the BBB after systemic administration.

Section snippets

Biosynthesis and effects of free radicals

A free radical is any chemical species that contains one or more unpaired electrons. Unpaired electrons alter the chemical reactivity of an atom or molecule, usually making it more reactive than the corresponding non-radical, because they act as electron acceptors and essentially “steal” electrons from other molecules. This loss of electrons is called oxidation, and free radicals are referred to as oxidizing agents because they tend to cause other molecules to donate their electrons (Halliwell

Antioxidants

Antioxidant defense mechanisms include: removal of O2, scavenging reactive oxygen/nitrogen species or their precursors, inhibition of ROS formation, binding of metal ions needed for the catalysis of ROS generation and up-regulation of endogenous antioxidant defenses. The protective efficacy of antioxidants depends on the type of ROS that is generated, the place of generation (body barriers such as the blood brain barrier reduce the permeability of most antioxidants) and the severity of the

Oxidative stress and excitatory amino acids

Although multiple factors can precipitate OS in cells, the neurotransmitter glutamate is the major effector of this process in the brain, primarily through activation of its ionotropic receptors. Glutamate and related excitatory amino acids account for most of the excitatory synaptic activity in the mammalian CNS and are released by an estimated 40% of all synapses. The ionotropic receptors can be distinguished by their pharmacological and electrophysiological properties: the

The blood brain barrier (BBB)

The brain needs a barrier that separates it from the blood, to permit the rigorous control of the brain microenvironment that is necessary for complex neural signaling. The blood brain barrier (BBB) is an endothelial barrier present in the capillaries that course through the brain (Reese and Karnovsky, 1967). According to ultrastructural studies, endothelial cells in brain differ fundamentally from those in most peripheral tissues, in two ways. First, they have very few endocytotic vesicles,

Antioxidants in the prevention and treatment of neurodegenerative disorders

The distribution of protective antioxidants in the brain has some interesting features. For instance, there is a relatively high concentration of the water-soluble antioxidant vitamin C in the brain. However, vitamin E concentrations are not remarkably different from those in other organs. The concentration of antioxidants varies within the different regions of the brain. For instance, the lowest concentration of vitamin E is found in the cerebellum (Vatassery, 1992). It has also been shown

Conclusions

Due to increased exposure to environmental damage, our endogenous antioxidant defense system is not completely effective. It seems reasonable to propose that antioxidants are very important in diminishing the cumulative effects of oxidative damage. Since OS has been implicated in the pathogenesis of many neurological, particularly neurodegenerative, diseases, antioxidants of widely varying chemical structures have been investigated for use as therapeutic agents. Most of the papers hereby

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