Free Radicals and Neurodegenerative Disease
One of the most prominent current theories of aging is the "free radical theory." According to this theory, free radical molecules generated through mitochondrial metabolism can act as causative factor of abnormal function and cell death. Various toxins in the environment can injure mitochondrial enzymes, leading to increased generation of free radicals and oxidative stress, that over the life-span would eventually play a major role in aging. Free radical's oxidative damage to key intracellular targets such as DNA or proteins has been shown to be a major cause of the degenerative diseases related to aging such as cancer and Alzheimer's disease.
Luckily, mammalian cells have developed highly protective systems against including oxidative challenges over time. When properly activated, each one of these cell systems has the possibility to restore cellular homeostasis and resume the ability to fight off oxidation. Activation of antioxidant pathways is particularly important for tissue with relatively weak antioxidant defenses, such as the brain. In fact, increasing evidence points to the notion that reduced cellular expression and activity of antioxidant proteins and the consequent oxidative stress are fundamental causes for brain aging processes and neurodegenerative diseases.
HO-1 and Curcumin
There are a variety of genes encoding proteins that possess anti-oxidant properties. Of particular interest in the central nervous system (CNS) is the hemeoxygenase-1 (HO-1), which has been reported to operate as a fundamental defensive mechanism for neurons exposed to an oxidant challenge.
At the same time, a number of studies have supported the beneficial effects of some commonly used natural products in preventing various pathologic conditions. Spices and herbs often contain phenolic substances with potent antioxidative and chemopreventive properties. Among them is curcumin, a natural phenolic agent, extracted from the rhizome of Curcuma Longa, and the yellow pigment in curry, strongly induced HO-1 expression and activity in rat astrocytes.
In recent years, there has been an unprecedented interest in identifying new pharmacological strategies to increase defense mechanisms by activating multiple antioxidant defense genes, a process that has been referred to as programmed cell life. Previous studies have shown that induction of HO-1 can represent an efficient antioxidant system and a potential pharmacological target in a variety of oxidant- and inflammatory-mediated diseases, including brain aging and neurodegenerative disorders.
A New Study
A new study extends previous findings examining the neuroprotective effects of curcumin and its ability to induce HO-1 on cultured hippocampal neurons. This research effort investigated the effects of curcumin on the expression profiles of other genes involved in the cellular stress response. The study also explored subcellular localization of HO-1 protein in one of the large cells of nervous tissue after treatment with curcumin.
The investigators of a study entitled "Curcumin Cytoprotective Effect in Rat Astrocytes and Neurons is Mediated by Specific Induction of HO-1," will present their findings at the American Physiological Society's (APS) (www.the-aps.org) annual scientific conference, Experimental Biology 2003, being held April 17-21, 2004, at the Washington, D.C. Convention Center. The research team represents two countries. The Italian researchers are Giovanni Scapagnini from the Institute of Neurological Sciences, CNR, Catania, Claudia Colombrita and Vittorio Calabrese at the Dipartimento di Scienze Chimiche, Universita' di Catania, and Alessia Pascale, at the Department of Experimental and Applied Pharmacology, Universita' di Pavia, Pavia. In the United States, the researchers are Michael L. Schwartzman and Nader G. Abraham from the Department of Pharmacology, New York Medical College, Valhalla, NY.
Rat type 1 astrocytes and rat hippocampal neurons were exposed to various concentrations of curcumin. After each treatment (six or 24 hours), cells were harvested for the determination of heme oxygenase activity and protein expression. The researchers also measured the expression of HO-1 and Phase II detoxification enzymes mRNAs by real time quantitative RT-PCR.
Neurons growing in 24 wells were also exposed to different concentrations of curcumin, and cell viability was determined at 24 hours. Other neurons were pretreated for 18 hours with curcumin 15μM or curcumin 15μM + zinc protoporphyrin IX (ZnPP IX) 10μM and then exposed for two hours to 50 mu/ml glucose-oxidase (GOX), before cell viability was determined.
Treatment of astrocytes with curcumin increased expression of HO-1 protein at both cytoplasmatic and nuclear level, as shown by immunofluorescence analysis under laser-scanning confocal microscope. The researchers also found a significant expression of quinone reductase and glutathione S-transferase, two members of Phase II detoxification enzymes, in astrocytes exposed to 5-15 μM curcumin. With exploration of the effects of curcumin on HO-1 activity in cultured hippocampal neurons the researchers found elevated expression of HO-1 mRNA and protein. Higher concentrations of curcumin (50-100 μM) caused a substantial cytotoxic effect with no change in HO-1 protein expression. Interestingly, pre-incubation (18 h) with curcumin 15 μM resulted in an enhanced cellular resistance to GOX mediated oxidative damage; this cytoprotective effect was considerably attenuated by ZnPP IX, a specific inhibitor of heme oxygenase activity.
This study identifies a novel compound that could be used for therapeutic purposes as potent inducers of HO-1 for protecting brain cells against oxidative conditions. The researchers believe that additional in vitro and in vivo studies are necessary to determine whether curcumin can be used as preventive agent against acute neurodegenerative conditions that affect an increasingly aged population.
The American Physiological Society (APS) is America's oldest biomedical sciences research society. The not-for-profit society, with some 11,000 members, is the publisher of 14 scientific journals, including the American Journal of Physiology, which has been published since 1898.
Editor's Note: For further information or to schedule an interview with a member of the research team, please contact Donna Krupa at 703-967-2751 (cell), 703-527-7357 (office) or at firstname.lastname@example.org. Or contact the APS newsroom at 202-249-4009 between 9:00 AM and 6:00 PM EDT April 17-21, 2004.