Hibernation, a Model of Neuroprotection

The Scientific World Journal, May 2019

Fang Zhou, Mark A. Smith, Rudy J. Castellani, Raphaela Stimmelmayr, George Perry, Kelly L. Drew, Xiongwei Zhu

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Hibernation, a Model of Neuroprotection

SR 1532-2246 Fang Zhou 1 Xiongwei Zhu 0 1 Mark A. Smith 0 1 Rudy J. Castellani 0 1 Raphaela Stimmelmayr 1 George Perry 0 1 Kelly L. Drew 1 0 Institute of Pathology, CaseWestern Reserve University , 2085 Adelbert Rd. Cleveland, OH 44106 , USA 1 Institute of Arctic Biology and Department of Chemistry and Biochemistry, University of Alaska Fairbanks , Box 757000, Fairbanks, AK 99775 , USA INTRODUCTION. Hibernation, a natural model of tolerance to "cerebral ischemia", represents a state of pronounced fluctuation in cerebral blood flow where no brain damage occurs (1). Numerous neuroprotective aspects may contribute in concert to such tolerance. The purpose of this study was to determine if hibernating brain tissue is tolerant to penetrating brain injury modeled by insertion of microdialysis probes. METHODS. Guide cannulae were surgically implanted in striatum of arctic ground squirrels before any of the animals began to hibernate. Microdialysis probes were then inserted in some animals after they entered hibernation and in others while they remained euthermic. After 3 days implantation of microdialysis probes, the brain tissue from hibernating and euthermic animals was examined by hematoxylin and eosin (H & E) stain and immunocytochemical identification of activated microglia, astrocytes and HO-1 immunoreactivity. Total white blood cell counts were performed on both hibernating and euthermic animals to assess leukocytopenia. RESULTS. White blood cell counts decrease from 6357 ? 2739/mm3 in euthermic animals to 456 ? 98/mm3 in hibernating animals (mean ? SD, n=8-10, p<0.0001 main effect of state). Examination of H&E stained tissue sections indicated obvious histological changes, including reactive astrocytosis, microglial activation, macrophage infiltrate, and axonal swellings around the probe track in euthermic animals while there was no significant cellular tissue response around the probe track in hibernating tissue. - Activated microglia (Fig. 1) and astrocytes, identified by RCA-1 binding and GFAP immunoreactivity, respectively, was more intense around the probe tracts (arrow) in euthermic animals compared to hibernating animals. Hemeoxygenase-1 (HO-1) immunoreactivity, a marker of oxidative stress response induction, was dramatically attenuated around probe tracks in hibernating animals compared to euthermic controls. DISCUSSION. The present results revealed by histopathological analysis suggest that hibernation is neuroprotective. In euthermic brain tissue the typical inflammatory response was evidenced by the presence of activated microglia and astrocytes and the oxidative stress response. However, these responses were profoundly suppressed in hibernating animals. The significant degree of protection during hibernation likely results from a combination of neuroprotective aspects, including hypothermia, leukocytopenia and an increase in extracellular concentrations of ascorbate during hibernation. ACKNOWLEDGEMENT. This work was supported by the American Heart Association (AHA grant 98-AK-301), a UAF PSPF grant to K.L.D. The National Institutes of Health (grant NS38648 to M.A.S) and NS41069-01 SNRP funded in part by NINDS, NIMH and NCRR. MEDIATORS INFLAMMATION The Scientiifc World Journal Hindawi Publishing Corporation ht p:/ www.hindawi.com Hindawi Publishing Corporation ht p:/ www.hindawi.com Journal of Diabetes Research Disease Markers Journal of Hindawi Publishing Corporation ht p:/ www.hindawi.com Immunology Research PPAR Research Hindawi Publishing Corporation ht p:/ www.hindawi.com Submit your manuscr ipts http://www.hindawi.com Obesity Journal of Ophthalmology Hindawi Publishing Corporation ht p:/ www.hindawi.com Stem Cells International Hindawi Publishing Corporation ht p:/ www.hindawi.com Evidence-Based Complementary Alternative Medicine and Journal of Oncology Disease nal and Mathematical Methods Hindawi Publishing Corporation ht p:/ www.hindawi.com AIDS and 1. Lyman , C.P. ( 1948 ) J. Exp . Zool. 109 , 55 - 78 2. Snapp , B.D. and Heller , C. ( 1981 ) Physiol . Zool. 54 , 297 - 307 3. Frerichs , K.U. , Smith , C.B. , Brenner , M. , et al. ( 1998 ) Proc . Natl. Acad. Sci. U S A 95 ( 24 ), 14511 - 14516 4. Drew , K.L. , Osborne , P.G. , Frerichs , K.U. , et al. ( 1999 ) Brain Res . 851 ( 1-2 ), 1 -8 ology

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Fang Zhou, Mark A. Smith, Rudy J. Castellani, Raphaela Stimmelmayr, George Perry, Kelly L. Drew, Xiongwei Zhu. Hibernation, a Model of Neuroprotection, The Scientific World Journal, DOI: 10.1100/tsw.2001.132