Comparative Biochemistry and Physiology Part C 133 (2002) 515–525 1532-0456/02/$ - see front matter  2002 Elsevier Science Inc. All rights reserved. PII: S1532-0456 Ž 02 . 00116-3 Review Brain antioxidant regulation in mammals and anoxia-tolerant reptiles: balanced for neuroprotection and neuromodulation  M.E. Rice *, R.E. Forman , B.T. Chen , M.V. Avshalumov , S.J. Cragg , K.L. Drew a, a a a b c a Departments of Physiology and Neuroscience and Neurosurgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA b Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, UK c Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK 99775, USA Received 28 December 2001; received in revised form 5 April 2002; accepted 10 April 2002 Abstract Reactive oxygen species (ROS) generated by mitochondrial respiration and other processes are often viewed as hazardous substances. Indeed, oxidative stress, defined as an imbalance between oxidant production and antioxidant protection, has been linked to several neurological disorders, including cerebral ischemia-reperfusion and Parkinson’s disease. Consequently, cells and organisms have evolved specialized antioxidant defenses to balance ROS production and prevent oxidative damage. Research in our laboratory has shown that neuronal levels of ascorbate, a low molecular weight antioxidant, are ten-fold higher than those in much less metabolically active glial cells. Ascorbate levels are also selectively elevated in the CNS of anoxia-tolerant reptiles compared to mammals; moreover, plasma and CSF ascorbate concentrations increase markedly in cold-adapted turtles and in hibernating squirrels. Levels of the related antioxidant, glutathione, vary much less between neurons and glia or among species. An added dimension to the role of the antioxidant network comes from recent evidence that ROS can act as neuromodulators. One example is modulation of dopamine release by endogenous hydrogen peroxide, which we describe here for several mammalian species. Together, these data indicate adaptations that prevent oxidative stress and suggest a particularly important role for ascorbate. Moreover, they show that the antioxidant network must be balanced precisely to provide functional levels of ROS, as well as neuroprotection.  2002 Elsevier Science Inc. All rights reserved. Keywords: Ascorbate; Dopamine; Glutathione; Hibernation; Ischemia; Hydrogen peroxide; Oxidative stress; Reactive oxygen species; Turtle 1. Introduction Reactive oxygen species (ROS) are often con- sidered to be a potentially harmful side effect of  This paper was presented at the Workshop on Comparative Aspects of Oxidative Stress in Biological Systems, held in La Paz, Baja California Sur, Mexico, October 17–19, 2001. *Corresponding author. Tel.: q1-212-263-5438; fax: q1- 212-689-0334. E-mail address: margaret.rice@nyu.edu (M.E. Rice). cellular respiration. Indeed, increased ROS produc- tion and oxidative stress have been implicated in cell death following acute brain injury, including cerebral ischemia-reperfusion (Cao et al., 1988; Delbarre et al., 1992; Hyslop et al., 1995; Chan, 1996; Lei et al., 1997), as well as in slowly progressing neurodegenerative disorders like Par- kinson’s disease (Ebadi et al., 1996; Cohen et al., 1997; Olanow and Tatton, 1999). Under normal physiological conditions, oxidative damage is pre-