Minocycline inhibits glial proliferation in the H-Tx rat model of congenital hydrocephalus
Tóm tắt
Reactive astrocytosis and microgliosis are important features of the pathophysiology of hydrocephalus, and persistent glial "scars" that form could exacerbate neuroinflammation, impair cerebral perfusion, impede neuronal regeneration, and alter biomechanical properties. The purpose of this study was to determine the efficacy of minocycline, an antibiotic known for its anti-inflammatory properties, to reduce gliosis in the H-Tx rat model of congenital hydrocephalus. Minocycline (45 mg/kg/day i.p. in 5% sucrose at a concentration of 5-10 mg/ml) was administered to hydrocephalic H-Tx rats from postnatal day 15 to day 21, when ventriculomegaly had reached moderate to severe stages. Treated animals were compared to age-matched non-hydrocephalic and untreated hydrocephalic littermates. The cerebral cortex (both gray matter laminae and white matter) was processed for immunohistochemistry (glial fibrillary acidic protein, GFAP, for astrocytes and ionized calcium binding adaptor molecule, Iba-1, for microglia) and analyzed by qualitative and quantitative light microscopy. The mean number of GFAP-immunoreactive astrocytes was significantly higher in untreated hydrocephalic animals compared to both types of controls (p < 0.001). Minocycline treatment of hydrocephalic animals reduced the number of GFAP immunoreactive cells significantly (p < 0.001). Likewise, the mean number of Iba-1 immunoreactive microglia was significantly higher in untreated hydrocephalic animals compared to both types of controls (p < 0.001). Furthermore, no differences in the numbers of GFAP-positive astrocytes or Iba-1-positive microglia were noted between control animals receiving no minocycline and control animals receiving minocycline, suggesting that minocycline does not produce an effect under non-injury conditions. Additionally, in six out of nine regions sampled, hydrocephalic animals that received minocycline injections had significantly thicker cortices when compared to their untreated hydrocephalic littermates. Overall, these data suggest that minocycline treatment is effective in reducing the gliosis that accompanies hydrocephalus, and thus may provide an added benefit when used as a supplement to ventricular shunting.
Tài liệu tham khảo
Lo P, Drake JM: Shunt malfunctions. Neurosurg Clin N Am. 2001, 12: 695-701.
Marmarou A, Shulman K, LaMorgese J: Compartmental analysis of compliance and outflow resistance of the cerebrospinal fluid system. J Neurosurg. 1975, 43: 523-534. 10.3171/jns.1975.43.5.0523.
Khan OH, Enno TL, Del Bigio MR: Brain damage in neonatal rats following kaolin induction of hydrocephalus. Exp Neurol. 2006, 200: 311-320. 10.1016/j.expneurol.2006.02.113.
Del Bigio MR: Cellular damage and prevention in childhood hydrocephalus. Brain Pathol. 2004, 14: 317-324.
Del Bigio MR: Pathophysiologic consequences of hydrocephalus. Neurosurg Clin N Am. 2001, 12: 639-649.
Del Bigio MR, McAllister JP: Pathophysiology of Hydrocephalus. Pediatric Neurosurgery. Edited by: Choux M, DiRocco R, Hockley AD, Walker ML. 1999, Philadelphia: Churchill Livingstone, 217-236. 4
Del Bigio MR: Neuropathological changes caused by hydrocephalus. Acta Neuropathol. 1993, 85: 573-585. 10.1007/BF00334666.
McAllister JP, Chovan P: Neonatal hydrocephalus. Mechanisms and consequences. Neurosurg Clin N Amer. 1998, 9: 73-93.
Miller JM, McAllister JP: Reduction of astrogliosis and microgliosis by cerebrospinal fluid shunting in experimental hydrocephalus. Cerebrospinal Fluid Res. 2007, 4: 5-10.1186/1743-8454-4-5.
Mangano FT, McAllister JP, Jones HC, Johnson MJ, Kriebel RM: The microglial response to progressive hydrocephalus in a model of inherited aqueductal stenosis. Neurol Res. 1998, 20: 697-704.
Arvin KL, Han BH, Du Y, Lin SZ, Paul SM, Holtzman DM: Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury. Ann Neurol. 2002, 52: 54-61. 10.1002/ana.10242.
Fan LW, Pang Y, Lin S, Rhodes PG, Cai Z: Minocycline attenuates lipopolysaccharide-induced white matter injury in the neonatal rat brain. Neuroscience. 2005, 133: 159-168. 10.1016/j.neuroscience.2005.02.016.
Ryu JK, Franciosi S, Sattayaprasert P, Kim SUMJ: Minocycline inhibits neuronal death and glial activation induced by beta-amyloid peptide in rat hippocampus. Glia. 2004, 48: 85-90. 10.1002/glia.20051.
Fox C, Dingman A, Derugin N, Wendland MF, Manabat C, Ji S, Ferriero DM: Minocycline confers early but transient protection in the immature brain following focal cerebral ischemia-reperfusion. J Cereb Blood Flow Metab. 2005, 25: 1138-1149. 10.1038/sj.jcbfm.9600121.
Cai Z, Lin S, Fan LW, Pang Y, Rhodes PG: Minocycline alleviates hypoxic-ischemic injury to developing oligodendrocytes in the neonatal rat brain. Neuroscience. 2006, 137: 425-435. 10.1016/j.neuroscience.2005.09.023.
Lechpammer M, Manning SM, Samonte F, Nelligan J, Sabo E, Talos DM: Minocycline treatment following hypoxic/ischaemic injury attenuates white matter injury in a rodent model of periventricular leucomalacia. Neuropathol Appl Neurobiol. 2008, 34: 379-393. 10.1111/j.1365-2990.2007.00925.x.
Carty ML, Wixey JA, Colditz PB, Buller KM: Post-insult minocycline treatment attenuates hypoxia-ischemia-induced neuroinflammation and white matter injury in the neonatal rat: a comparison of two different dose regimens. Int J Dev Neurosci. 2008, 26: 477-485. 10.1016/j.ijdevneu.2008.02.005.
Buller KM, Carty ML, Reinebrant HE, Wixey JA: Minocycline: A neuroprotective agent for hypoxic-ischemic brain injury in the neonate?. J Neurosci Res. 2009, 15: 599-607. 10.1002/jnr.21890.
Hailer NP: Immunosuppression after traumatic or ischemic CNS damage: it is neuroprotective and illuminates the role of microglial cells. Prog Neurobiol. 2008, 84: 211-233. 10.1016/j.pneurobio.2007.12.001.
Kohn DF, Chinookoswong N, Chou SM: A new model of congenital hydrocephalus in the rat. Acta Neuropathol. 1981, 54: 211-218. 10.1007/BF00687744.
Jones HC, Bucknall RM: Inherited prenatal hydrocephalus in the H-Tx rat: a morphological study. Neuropathol Appl Neurobiol. 1988, 14: 263-274. 10.1111/j.1365-2990.1988.tb00887.x.
Mashayekhi F, Draper CE, Bannister CM, Pourghasem M, Owen L, Miyan JA: Deficient cortical development in the hydrocephalic Texas (H-Tx) rat: a role for CSF. Brain. 2002, 125: 1859-1874. 10.1093/brain/awf182.
Jones HC: Aqueduct stenosis in animal models of hydrocephalus. Child's Nerv Syst. 1998, 13: 503-504. 10.1007/s003810050124.
Nojima Y, Enzan H, Hayashi Y, Nakayama H, Kiyoku H, Hiroi M, Mori K: Neuroepithelial and ependymal changes in HTX rats with congenital hydrocephalus: an ultrastructural and immunohistochemical study. Pathol Int. 1998, 48: 115-125. 10.1111/j.1440-1827.1998.tb03880.x.
Jones HC, Yehia B, Chen GF, Carter BJ: Genetic analysis of inherited hydrocephalus in a rat model. Exp Neurol. 2004, 190: 79-90. 10.1016/j.expneurol.2004.06.019.
Yager JY, Ashwal S: Animal Models of Perinatal Hypoxic-Ischemic Brain Damage. Pediatr Neurol. 2009, 40: 156-167. 10.1016/j.pediatrneurol.2008.10.025.
Harris NG, Jones HC, Williams SC: MR imaging for measurements of ventricles and cerebral cortex in postnatal rats (H-Tx strain) with progressive inherited hydrocephalus. Exp Neurol. 1992, 118: 1-6. 10.1016/0014-4886(92)90016-J.
Fagan SC, Edwards DJ, Borlongan CV, Xu L, Arora A, Feuerstein G, Hess DC: Optimal delivery of minocycline to the brain: implication for human studies of acute neuroprotection. Exp Neurol. 2004, 186: 248-251. 10.1016/j.expneurol.2003.12.006.
Romero-Sandoval A, Chai N, Nutile-McMenemy N, DeLeo JA: A comparison of spinal Iba1 and GFAP expression in rodent models of acute and chronic pain. Brain Res. 2008, 1219: 116-126. 10.1016/j.brainres.2008.05.004.
Tinsley CJ, Bennett GW, Mayhew TM, Parker TL: Stereological analysis of regional brain volumes and neuron numbers in rats displaying a spontaneous hydrocephalic condition. Exp Neurol. 2001, 168: 88-95. 10.1006/exnr.2000.7578.
West MJ, Slomianka L, Gundersen HJG: Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optial fractionator. Anat Rec. 1991, 231: 482-497. 10.1002/ar.1092310411.
Del Bigio MR, Bruni JE: Periventricular pathology in hydrocephalic rabbits before and after shunting. Acta Neuropathol. 1988, 77: 186-195.
Del Bigio MR, Bruni JE, Fewer HD: Human neonatal hydrocephalus. An electron microscopic study of the periventricular tissue. J Neurosurg. 1985, 63: 56-63. 10.3171/jns.1985.63.1.0056.
Del Bigio MR, Cardoso ER, Halliday WC: Neuropathological changes in chronic adult hydrocephalus: cortical biopsies and autopsy findings. Can J Neurol Sci. 1997, 24: 121-126.
Del Bigio MR, Zhang YW: Cell death, axonal damage, and cell birth in the immature rat brain following induction of hydrocephalus. Exp Neurol. 1998, 154: 157-169. 10.1006/exnr.1998.6922.
Glees P, Hasan M: Ultrastructure of human cerebral macroglia and microglia: maturing and hydrocephalic frontal cortex. Neurosurg Rev. 1990, 13: 231-242. 10.1007/BF00313025.
Del Bigio MR, da Silva MC, Drake JM, Tuor UI: Acute and chronic cerebral white matter damage in neonatal hydrocephalus. Can J Neurol Sci. 1994, 21: 299-305.
Yoshida Y, Koya G, Tamayama K, Kumanishi T, Abe S: Development of GFAP-positive cells and reactive changes associated with cystic lesions in HTX rat brain. Neurol Med Chir. 1990, 30: 445-450. 10.2176/nmc.30.445.
Yoshida Y, Koya G, Tamayama K, Kumanishi T, Abe S: Histopathology of cystic cavities in the cerebral white matter of HTX rats with inherited hydrocephalus. Neurol Med Chir. 1990, 30: 229-233. 10.2176/nmc.30.229.
Albrechtsen M, Sorensen PS, Gjerris F, Bock E: High cerebrospinal fluid concentration of glial fibrillary acidic protein (GFAP) in patients with normal pressure hydrocephalus. J Neurol Sci. 1985, 70: 269-274. 10.1016/0022-510X(85)90168-6.
Petzold A, Keir G, Kerr M, Kay A, Kitchen N, Smith M, Thompson EJ: Early identification of secondary brain damage in subarachnoid hemorrhage: a role for glial fibrillary acidic protein. J Neurotrauma. 2006, 23: 1179-1184. 10.1089/neu.2006.23.1179.
Tullberg M, Rosengren L, Blomsterwall E, Karlsson JE, Wikkelso C: CSF neurofilament and glial fibrillary acidic protein in normal pressure hydrocephalus. Neurology. 1998, 50: 1122-1127.
Tullberg M, Blennow K, Mansson JE, Fredman P, Tisell M, Wikkelso C: Ventricular cerebrospinal fluid neurofilament protein levels decrease in parallel with white matter pathology after shunt surgery in normal pressure hydrocephalus. Eur J Neurol. 2007, 14: 248-254.
Beems T, Simons KS, Van Geel WJ, De Reus HP, Vos PE, Verbeek MM: Serum- and CSF-concentrations of brain specific proteins in hydrocephalus. Acta Neurochir (Wien). 2003, 145: 37-43. 10.1007/s00701-002-1019-1.
Petzold A, Keir G, Green AJE, Giovannoni G, Thompson EJ: An ELISA for glial fibrillary acidic protein. J Immunol Meth. 2004, 287: 169-177. 10.1016/j.jim.2004.01.015.
Gehrmann J, Banati RB, Wiessner C, Hossmann KA, Kreutzberg GW: Reactive microglia in cerebral ischaemia: an early mediator of tissue damage?. Neuropathol Appl Neurobiol. 1995, 21: 277-289. 10.1111/j.1365-2990.1995.tb01062.x.
Gehrmann J, Bonnekoh P, Miyazawa T, Hossmann KA, Kreutzberg GW: Immunocytochemical study of an early microglial activation in ischemia. J Cereb Blood Flow Metab. 1992, 12: 257-269.
Kreutzberg GW: Microglia: a sensor for pathological events in the CNS. TINS. 1996, 19: 312-318.
Streit WJ, Graeber MB, Kreutzberg GW: Functional plasticity of microglia: a review. Glia. 1988, 1: 301-307. 10.1002/glia.440010502.
SoLtys Z, Ziaja M, Pawlinski R, Setkowicz Z, Janeczko K: Morphology of reactive microglia in the injured cerebral cortex. Fractal analysis and complementary quantitative methods. J Neurosci Res. 2001, 63: 90-97. 10.1002/1097-4547(20010101)63:1<90::AID-JNR11>3.0.CO;2-9.
Miller JM, Kumar R, McAllister JP, Krause GS: Gene expression analysis of the development of congenital hydrocephalus in the H-Tx rat. Brain Res. 2006, 1075: 36-47. 10.1016/j.brainres.2005.12.094.
Weller RO, Mitchell J, Griffin RL, Gardner MJ: The effects of hydrocephalus upon the developing brain. Histological and quantitative studies of the ependyma and subependyma in hydrocephalic rats. J Neurol Sci. 1978, 36: 383-402. 10.1016/0022-510X(78)90046-1.
Lu J, Kaur C, Ling EA: An immunohistochemical study of the intraventricular macrophages in induced hydrocephalus in prenatal rats following a maternal injection of 6-aminonicotinamide. J Anat. 1996, 188: 491-495.
Carbonell WS, Murase SI, Horwitz AF, Mandell JW: Infiltrative microgliosis: activation and long-distance migration of subependymal microglia following periventricular insults. J Neuroinflammation. 2005, 2: 5-10.1186/1742-2094-2-5.
Orlowski D, SoLtys Z, Janeczko K: Morphological development of microglia in the postnatal rat brain. A quantitative study. Int J Dev Neurosci. 2003, 21: 445-450. 10.1016/j.ijdevneu.2003.09.001.
Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH, Friedlander RM: Minocycline inhibits caspase 1 and caspase 3 expression and delays mortality in a transgenic mouse model of Huntington's disease. Nat Med. 2000, 6: 797-801. 10.1038/80538.
Fernandez-Gomez FJ, Galindo MF, Gomez-Lazaro M, Gonzalez-Garcia C, Cena V, Aguirre N, Jordan J: Involvement of mitochondrial potential and calcium buffering capacity in minocycline cytoprotective actions. Neuroscience. 2005, 133: 959-967. 10.1016/j.neuroscience.2005.03.019.
Sanchez Mejia RO, Ona VO, Li M, Friedlander RM: Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. Neurosurgery. 2001, 48: 1393-1401. 10.1097/00006123-200106000-00051.
Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J: Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. The Journal of Neuroscience. 2001, 21: 2580-2588.
Tikka TM, Koistinaho JE: Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol. 2001, 166: 7527-7533.
Ravina BM, Fagan SC, Hart RG, Hovinga CA, Murphy DD, Dawson TM, Marler JR: Neuroprotective agents for clinical trials in Parkinson's disease: a systematic assessment. Neurology. 2003, 60: 1234-
Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J: A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. PNAS. 1999, 96: 13496-13500. 10.1073/pnas.96.23.13496.
Del Bigio MR, Massicotte EM: Protective effect of nimodipine on behavior and white matter of rats with hydrocephalus. J Neurosurg. 2001, 94: 788-794. 10.3171/jns.2001.94.5.0788.
Khan OH, McPhee LC, Moddemann LN, Del Bigio MR: Calcium antagonism in neonatal rats with kaolin-induced hydrocephalus. J Child Neurol. 2007, 22: 1161-1166. 10.1177/0883073807306259.
Del Bigio MR, Wang X, Wilson MJ: Sodium channel-blocking agents are not of benefit to rats with kaolin-induced hydrocephalus. Neurosurgery. 2002, 51: 460-466. 10.1097/00006123-200208000-00029.
Khan OH, Enno T, Del Bigio MR: Magnesium sulfate therapy is of mild benefit to young rats with kaolin-induced hydrocephalus. Pediatr Res. 2003, 53: 970-976. 10.1203/01.PDR.0000061561.42921.5B.