Free Radicals and Neuroprotection

Free Radicals
and Neuroprotection

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:

B. J. Wilder, M. D.,
Professor Emeritus of Neurology University of Florida College of Medicine
and Consultant in Neurology Department of Veterans Affairs Medical Center

A free radical is a molecule, atom or molecular fragment which contains an unpaid electron in its outer orbital shell (R ). Each atomic nucleus is surrounded by one or more orbitals containing a maximum of 2 electrons All compounds contain 2 electrons in each of its orbitals which spin in opposite directions. The covalent bonds of organic compounds share two electrons spinning in opposite directions one supplied by each atom or molecule pan in the bond. Any molecule can become a free radical by gaining or losing an electron in the outer shell. O2 + e Organic compounds also form free radicals

RH2 -e- - RH. O2

Organic molecules are held together by covalent bonds. Normally, when covalent bonds split one fragment becomes a positively charged ion by losing an electron and the other becomes a negatively charged ion by holding both of the shared pair of electrons (heterolytic splitting). Free radicals are formed from organic compounds when a covalent bond is split symmetrically and each retains an unpaired electron in its outer shell (homolytic splitting). Homolytic splitting produces free radicals which result in lipid peroxidation.

Free radicals are also formed as a product of normal cellular chemical reactions. Oxidative metabolism is a major contributor of free radicals. As O2 is reduced to water, over SO% is univalently reduced with the production of the superoxide radical O2.

O2 is combined spontaneously or dismutated with H+ to produce H2O2 which readily breaks down in the presence of the metals Fe++ &Cu+ or O2 to form OH. radicals which are highly injurious to adjacent structures: lipid membranes, proteins, DNA and precellular matrix 2 O2. + 2 H+

H202 + Fez+

O2 + H2O2

-SOD-> H2O2 + O2

- OH + OH + Fe3+

-, 0H + OH- + O2

(SOD = Superoxide dismutase)

The autoxidation of transition metals can produce superoxide radicals:

O2 + Fe++ > Fe+++ + O2

O2 + Cu+ > Cu++ + O2

Free radical formation and cellular damage is greatly accelerated in situations of oxidative stress such as tissue injury, viral and bacterial infections and also accompanies phagocytosis autoimmune disorders and degenerative diseases by yet unknown mechanisms. Some neoplasms may occur as a result of oxidative or free radical damage. Free radical damage is also accelerated by various deficiency states and inborn errors or genetic defects of metabolism

Defects in antioxidant or free radical scavenge systems result in oxidative stress and cellular damage. Parkinson's Alzheimer's and Huntington's disease, multiple sclerosis, progressive myoclonic epilepsy, familial ALS, post–traumatic epilepsy, ant arteriosclerosis, arc diseases which are now thought to be at least partly due to oxidative stress and free radical damage.

All living cells have developed mechanisms for protection against oxidative stress.Mammalian cells have very specific and elaborate antioxidant mechanisms which prevent free radical damage. Superoxide dismutase (SOD), a ubiquitous superoxide scavenging enzyme. is present in both intra– and extracellular fluid (ECF) compartments. Copper and Zinc SOD's are present in ECF and cytosol and manganese SOD is present in mitochondria. These SOD's dismutate 0~ and H+ to H~O~. H.O. is a potential cellular toxin because of its reactivity with 0 and transition metals, however, in the normal situation it is readily converted to 0. and H.0 by catalase (CAT) and glutathione peroxidase (GPX). CAT is present in mitochondna and cyrosolic peroxisomes of most tissues, however, it is found in very low concentrations in brain. GPX is the major antioxidant enzyme in the brain, being present in mitochondria and in the cytosol. GPX requires selenium as a necessary cofactor and is decreased in selenium deficient states. Glutathione transferase (GST) conjugates glutathione (GSH) to reactive organic compounds which become pharmacologically inactive. GPX requires reduced GSH which is oxidized (GSSH) during the conversion of H2O2 to 0. and H,O. GSSH is reconverted to reduced GSH by glutathione reductase which requires vitamin B, (riboflavin) as a cofactor.

Vitamin E is an important membrane antioxidant which prevents membrane peroxidation by scavenging OH'. Oxidized vitamin E is reconverted to active E by vitamin C which is another important antioxidant free radical scavenger. Beta carotene is an antioxidant which works most effectively in low oxygen tensions and is an important retinal antioxidant.

From the above, one can appreciate that the balance between cellular oxidation and free radical production is most important in maintaining homeostasis and preventing cellular damage and death. Elaborate systems have developed to accomplish this. However, a number of disease processes and defects in antioxidant mechanisms can lead tO both progression and initiation of tissue injury and cell death.

We (B.J Wilder. M. D. and Russell Hurd. M.S.) over a number of years have been working on drug injury and tissue protection with a number of antioxidants. Concurrent with our work and that of others, techniques for measuring free radical scavenging enzymes assays ( FRESA) have been developed.

In 1992 we measured FRESA levels in patients with progressive myoclonic epilepsy and familial progressive cerebellar degeneration and found abnormalities in SOD. GPX, GSH and lipid peroxidation (LP). We initiated treatment with selenium. antioxidant vitamins and N–acetylcysteine, a potent free radical and H,O. scavenger and supplier of GSH. After observing favorable clinical effects we have expanded our studies to include other progressive degenerative neurological diseases. We have been joined by other interested investigators, Drs. Basim Uthman Wendell Helveston and Jean Cebula..

We are now studying the effects of N–Acetylcysteine and antioxidant vitamins and trace metals in patients with: Friedreich's ataxia, spinocerebellar ataxia, ataxia telangiectasia, olivopontocerebellar degeneration. amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, and others.

We will soon initiate studies in other degenerative diseases and in the prevention of post traumatic epilepsy and in the amelioration of post ischemic brain injury.

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