Abstract
Recent evidence suggests that admission hyperglycemia has deleterious effects on the survival and functional outcome of patients with intracerebral hemorrhage (ICH). In this study, we first induced acute hyperglycemia in male adult Sprague-Dawley rats by intraperitoneal injection of 50% glucose (6 mL/kg), and created the ICH model thereafter by delivering autologous whole blood or homologous normalglucose blood into the right basal ganglia. Twentyfour hours later, we assessed the neurological injury, evaluated the hematoma and brain water content, and investigated autophagy. We found elevations of neurological deficit scores, brain water content, and microtubule-associated protein light chain-3 (LC3) and beclin-1 protein levels, and decreased SQSTM1/ p62 levels after ICH with normal-glucose blood (without hyperglycemia). Acute hyperglycemia with ICH of high-glucose blood hematoma was associated with significantly increased forelimb-use asymmetry test scores, brain water content and SQSTM1/p62 protein levels, and evident decreases in the ratio of LC3-II/LC3-I and beclin-1 protein levels. On the other hand, acute hyperglycemia and ICH with normalglucose blood hematoma only slightly increased the neurological deficit scores and brain water content (P >0.05). In conclusion, the autophagy pathway was activated after ICH, and acute hyperglycemia with hematoma of high-glucose blood exacerbates the neurological injury, and reduces autophagy around the hematoma.
Keywords: intracerebral hemorrhage, hyperglycemia, autophagy
References
- [1].Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet. 2009;373:1632–1644. doi: 10.1016/S0140-6736(09)60371-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2].Brouwers HB, Goldstein JN. Therapeutic strategies in acute intracerebral hemorrhage. Neurotherapeutics. 2012;9:87–98. doi: 10.1007/s13311-011-0091-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [3].Bejot Y, Aboa-Eboule C, Hervieu M, Jacquin A, Osseby GV, Rouaud O, et al. The deleterious effect of admission hyperglycemia on survival and functional outcome in patients with intracerebral hemorrhage. Stroke. 2012;43:243–245. doi: 10.1161/STROKEAHA.111.632950. [DOI] [PubMed] [Google Scholar]
- [4].Mehrpour M, Esclatine A, Beau I, Codogno P. Autophagy in health and disease. 1. Regulation and significance of autophagy: an overview. Am J Physiol Cell Physiol. 2010;298:C776–785. doi: 10.1152/ajpcell.00507.2009. [DOI] [PubMed] [Google Scholar]
- [5].He Y, Wan S, Hua Y, Keep RF, Xi G. Autophagy after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab. 2008;28:897–905. doi: 10.1038/sj.jcbfm.9600578. [DOI] [PubMed] [Google Scholar]
- [6].Kobayashi S, Xu X, Chen K, Liang Q. Suppression of autophagy is protective in high glucose-induced cardiomyocyte injury. Autophagy. 2012;8:577–592. doi: 10.4161/auto.18980. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].Hua Y, Schallert T, Keep RF, Wu J, Hoff JT, Xi G. Behavioral tests after intracerebral hemorrhage in the rat. Stroke. 2002;33:2478–2484. doi: 10.1161/01.STR.0000032302.91894.0F. [DOI] [PubMed] [Google Scholar]
- [8].Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 2000;19:5720–5728. doi: 10.1093/emboj/19.21.5720. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [9].Kang R, Zeh HJ, Lotze MT, Tang D. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ. 2011;18:571–580. doi: 10.1038/cdd.2010.191. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [10].Bjorkoy G, Lamark T, Johansen T. p62/SQSTM1: a missing link between protein aggregates and the autophagy machinery. Autophagy. 2006;2:138–139. doi: 10.4161/auto.2.2.2405. [DOI] [PubMed] [Google Scholar]
- [11].Appelboom G, Piazza MA, Hwang BY, Carpenter A, Bruce SS, Mayer S, et al. Severity of intraventricular extension correlates with level of admission glucose after intracerebral hemorrhage. Stroke. 2011;42:1883–1888. doi: 10.1161/STROKEAHA.110.608166. [DOI] [PubMed] [Google Scholar]
- [12].Qureshi AI, Palesch YY, Martin R, Novitzke J, Cruz-Flores S, Ehtisham A, et al. Association of serum glucose concentrations during acute hospitalization with hematoma expansion, perihematomal edema, and three month outcome among patients with intracerebral hemorrhage. Neurocrit Care. 2011;15:428–435. doi: 10.1007/s12028-011-9541-8. [DOI] [PubMed] [Google Scholar]
- [13].Stead LG, Jain A, Bellolio MF, Odufuye A, Gilmore RM, Rabinstein A, et al. Emergency Department hyperglycemia as a predictor of early mortality and worse functional outcome after intracerebral hemorrhage. Neurocrit Care. 2010;13:67–74. doi: 10.1007/s12028-010-9355-0. [DOI] [PubMed] [Google Scholar]
- [14].Liu J, Gao BB, Clermont AC, Blair P, Chilcote TJ, Sinha S, et al. Hyperglycemia-induced cerebral hematoma expansion is mediated by plasma kallikrein. Nat Med. 2011;17:206–210. doi: 10.1038/nm.2295. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [15].Song EC, Chu K, Jeong SW, Jung KH, Kim SH, Kim M, et al. Hyperglycemia exacerbates brain edema and perihematomal cell death after intracerebral hemorrhage. Stroke. 2003;34:2215–2220. doi: 10.1161/01.STR.0000088060.83709.2C. [DOI] [PubMed] [Google Scholar]
- [16].Ergul A, Li W, Elgebaly MM, Bruno A, Fagan SC. Hyperglycemia, diabetes and stroke: focus on the cerebrovasculature. Vascul Pharmacol. 2009;51:44–49. doi: 10.1016/j.vph.2009.02.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [17].Gisselsson L, Smith ML, Siesjo BK. Hyperglycemia and focal brain ischemia. J Cereb Blood Flow Metab. 1999;19:288–297. doi: 10.1097/00004647-199903000-00007. [DOI] [PubMed] [Google Scholar]
- [18].Li PA, Vogel J, He QP, Smith ML, Kuschinsky W, Siesjo BK. Preischemic hyperglycemia leads to rapidly developing brain damage with no change in capillary patency. Brain Res. 1998;782:175–183. doi: 10.1016/S0006-8993(97)01150-5. [DOI] [PubMed] [Google Scholar]
- [19].Dietrich WD, Alonso O, Busto R. Moderate hyperglycemia worsens acute blood-brain barrier injury after forebrain ischemia in rats. Stroke. 1993;24:111–116. doi: 10.1161/01.STR.24.1.111. [DOI] [PubMed] [Google Scholar]
- [20].Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404:787–790. doi: 10.1038/35008121. [DOI] [PubMed] [Google Scholar]
- [21].Stepien A, Izdebska M, Grzanka A. The types of cell death. Postepy Hig Med Dosw (Online) 2007;61:420–428. [PubMed] [Google Scholar]
- [22].Cold Spring Harb Perspect Biol. 2012. [DOI] [PMC free article] [PubMed]
- [23].Xu F, Gu JH, Qin ZH. Neuronal autophagy in cerebral ischemia. Neurosci Bull. 2012;28:658–666. doi: 10.1007/s12264-012-1268-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [24].Matsui Y, Kyoi S, Takagi H, Hsu CP, Hariharan N, Ago T, et al. Molecular mechanisms and physiological significance of autophagy during myocardial ischemia and reperfusion. Autophagy. 2008;4:409–415. doi: 10.4161/auto.5638. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [25].Hu S, Xi G, Jin H, He Y, Keep RF, Hua Y. Thrombin-induced autophagy: a potential role in intracerebral hemorrhage. Brain Res. 2011;1424:60–66. doi: 10.1016/j.brainres.2011.09.062. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [26].Prod’homme M, Rieu I, Balage M, Dardevet D, Grizard J. Insulin and amino acids both strongly participate to the regulation of protein metabolism. Curr Opin Clin Nutr Metab Care. 2004;7:71–77. doi: 10.1097/00075197-200401000-00012. [DOI] [PubMed] [Google Scholar]