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Glial cell survival is enhanced during melatonin-induced neuroprotection against cerebral ischemia

CESARIO V. BORLONGAN^*1, MITSUHARU YAMAMOTO, NORIE TAKEI, MICHIKO KUMAZAKI, CHUTCHARIN UNGSUPARKORN, HIDEKI HIDA, PAUL R. SANBERG and HITOO NISHINO¹

^* Cellular Neurobiology Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA;
Department of Neurological Surgery and Program in Neuroscience, University of South Florida College of Medicine, Tampa, Florida 33612, USA; and
Department of Physiology, Nagoya City University Medical School, Nagoya 467, Japan

¹Correspondence: Cellular Neurobiology Branch, National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Dr., Baltimore, Maryland 21224, USA. E-mail: cborlong{at}intra.nida.nih.gov; or H.N, E-mail: hitoo-n{at}med.nagoya-cu.ac.jp

The role of glial cells in neuronal death has become a major research interest. Glial cell activation has been demonstrated to accompany cerebral ischemia. However, there is disagreement whether such gliosis is a cell death or a neuroprotective response. In the present study, we examined alterations in glial cell responses to the reported neuroprotective action of the free radical scavenger, melatonin, against cerebral ischemia. Adult male Wistar rats were given oral injections of either melatonin (26 µmol/rat) or saline just prior to 1 h occlusion of the middle cerebral artery (MCA), then once daily for 11 or 19 consecutive days. At 11 and 19 days after reperfusion of the MCA, randomly selected animals were killed and their brains removed for immunohistochemical assays. Melatonin significantly enhanced survival of glial cells (as revealed by glial cell specific markers, glial fibrillary acidic protein and aquaporin-4 immunostaining) at both time periods postischemia, and the preservation of these glial cells in the ischemic penumbra corresponded with a markedly reduced area of infarction (detected by immunoglobulin G and hematoxylin-eosin staining), as well as increased neuronal survival. The ischemia-induced locomotor deficits were partially ameliorated in melatonin-treated animals. In vitro replications of ischemia by serum deprivation or by exposure to free radical-producing toxins (sodium nitroprusside and 3-nitropropionic acid) revealed that melatonin (10 µg/ml or 100 µM) treatment of pure astrocytic cultures significantly reduced astrocytic cell death. These results suggest a potential strategy directed at enhancing glial cell survival as an alternative protective approach against ischemic damage.—Borlongan, C. V., Yamamoto, M., Takei, N., Kumazaki, M., Ungsuparkorn, C., Hida, H., Sanberg, P. R., Nishino, H. Glial cell survival is enhanced during melatonin-induced neuroprotection against cerebral ischemia.

Key Words: stroke • gliosis • astrocytes • cell death • free radicals

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