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First published online August 6, 2004
Journal of Experimental Biology 207, 3155-3162 (2004)
Published by The Company of Biologists 2004
doi: 10.1242/jeb.01114
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Hypoxia tolerance in mammalian heterotherms

K. L. Drew1,*, M. B. Harris1, J. C. LaManna2, M. A. Smith3, X. W. Zhu3 and Y. L. Ma1

1 Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK 99775, USA
2 Department of Neurology, Case Western Reserve University, Cleveland, OH 44106, USA
3 Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA



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  		Fig. 1. Anoxia or severe hypoxia typically lead to energy deficit (1), subsequent disruption of ion homeostasis and neuronal depolarization (2, 3). Release of neurotransmitters, including the excitotoxin glutamate, and activation of NMDA and AMPA receptors contribute to the flood of Ca2+ from extra- and intracellular stores, which leads to calcium overload (4). Activated microglia release inflammatory cytokines and nitric oxide and contribute to oxidative stress and neuronal cell death (5). Increased reactive oxygen species (ROS) production leads to oxidative modification of cellular components, which contributes to cell death (6). During hibernation, multiple adaptations, in addition to hypothermia, are hypothesized to act in concert to produce pronounced neuroprotection. Decreased demand for oxygen, as well as downregulation of Ca2+ channels, maintains energy balance, ion homeostasis and minimizes Ca2+ overload. Evidence suggests that immune modulation attenuates inflammatory response, and upregulation of antioxidant defense systems maintains redox balance, thus minimizing the neurodegenerative cascade (Sidky et al., 1972Go; Spurrier and Dawe, 1973Go; Drew et al., 1999Go; Zhou et al., 2001bGo; Toien et al., 2001Go). IL-1ß, interleukin-1ß; NO, nitric oxide; ROS, reactive oxygen species; ER, endoplasmic reticulum; NMDA, N-methyl-D-aspartate; Glu, glutamate; OGD, oxygen glucose deprivation.

 


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  		Fig. 2. Hypoxia activates SAPK pathways, leading to neuronal cell death. During arousal thermogenesis, attenuation of SAPK activation due to hypothermia, immune modulation and enhanced antioxidant defenses, such as increased brain ascorbate concentrations, may tip downstream consequences towards a pro-regenerative and/or synaptogenic outcome. JNK, c-Jun N-terminal kinase; ATF-2, activating transcription factor 2; ROS, reactive oxygen species.

 

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© The Company of Biologists Ltd 2004