Minocycline ameliorates cognitive impairment induced by whole-brain irradiation: an animal study

Radiation Oncology

Ye Tian¹  Hongying Yang⁵  Peigeng Huang²  JianFeng Ji³  Yuan Zhang³  Rui Sun³  Kun Li⁴  Liyuan Zhang¹ 

[1] Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, Jiangsu Province, PR China;Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, 100 Blossom Street, Boston 02114, MA, USA;Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou 215004, Jiangsu Province, PR China;Department of Medical Oncology, Affiliated Hospital of Taishan Medical University, Taian 271000, Shandong Province, PR China;School of Radiation Medicine and Protection, Medical College of Soochow University/School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, 199 Renai Road, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, PR China

关键词: Neurogenesis;    Apoptosis;    Newborn neuron;    Minocycline;    Cognitive deficit;    Whole-brain irradiation;   

Others  :  1150586
DOI  :  10.1186/s13014-014-0281-8

 received in 2014-09-19, accepted in 2014-11-28,  发布年份 2014

【 摘 要 】

Background

It has been long recognized that cranial irradiation used for the treatment of primary and metastatic brain tumor often causes neurological side-effects such as intellectual impairment, memory loss and dementia, especially in children patients. Our previous study has demonstrated that whole-brain irradiation (WBI) can cause cognitive decline in rats. Minocycline is an antibiotic that has shown neuroprotective properties in a variety of experimental models of neurological diseases. However, whether minocycline can ameliorate cognitive impairment induced by ionizing radiation (IR) has not been tested. Thus this study aimed to demonstrate the potential implication of minocycline in the treatment of WBI-induced cognitive deficits by using a rat model.

Methods

Sprague Dawley rats were cranial irradiated with electron beams delivered by a linear accelerator with a single dose of 20 Gy. Minocycline was administered via oral gavages directly into the stomach before and after irradiation. The open field test was used to assess the anxiety level of rats. The Morris water maze (MWM) was used to assess the spatial learning and memory of rats. The level of apoptosis in hippocampal neurons was measured using immunohistochemistry for caspase-3 and relative markers for mature neurons (NeuN) or for newborn neurons (Doublecortin (DCX)). Neurogenesis was determined by BrdU incorporation method.

Results

Neither WBI nor minocycline affected the locomotor activity and anxiety level of rats. However, compared with the sham-irradiated controls, WBI caused a significant loss of learning and memory manifest as longer latency to reach the hidden platform in the MWM task. Minocycline intervention significantly improved the memory retention of irradiated rats. Although minocycline did not rescue neurogenesis deficit caused by WBI 2 months post-IR, it did significantly decreased WBI-induced apoptosis in the DCX positive neurons, thereby resulting in less newborn neuron depletion 12 h after irradiation.

Conclusions

Minocycline significantly inhibits WBI-induced neuron apoptosis, leading to less newborn neurons loss shortly after irradiation. In the long run, minocycline improves the cognitive performance of rats post WBI. The results indicate a potential clinical implication of minocycline as an effective adjunct in radiotherapy for brain tumor patients.

【 授权许可】

   
2014 Zhang et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]DeAngelis LM, Delattre JY, Posner JB: Radiation-induced dementia in patients cured of brain metastases. Neurology 1989, 39:789-796.
• [2]Jinguji S, Yoshimura J, Nishiyama K, Aoki H, Nagasaki K, Natsumeda M, Yoneoka Y, Fukuda M, Fujii Y: Factors affecting functional outcomes in long-term survivors of intracranial germinomas: a 20-year experience in a single institution. J Neurosurg Pediatr 2013, 11:454-463.
• [3]Kiehna EN, Mulhern RK, Li C, Xiong X, Merchant TE: Changes in attentional performance of children and young adults with localized primary brain tumors after conformal radiation therapy. J Clin Oncol 2006, 24:5283-5290.
• [4]Surma-aho O, Niemelä M, Vilkki J, Kouri M, Brander A, Salonen O, Paetau A, Kallio M, Pyykkönen J, Jääskeläinen J: Adverse long-term effects of brain radiotherapy in adult low-grade glioma patients. Neurology 2001, 56:1285-1290.
• [5]Deweer B, Pillon B, Pochon JB, Dubois B: Is the HM story only a “remote memory”? Some facts about hippocampus and memory in humans. Behav Brain Res 2001, 127:209-224.
• [6]Abayomi OK: Pathogenesis of cognitive decline following therapeutic irradiation for head and neck tumors. Acta Oncol 2002, 41:346-350.
• [7]Monje ML, Mizumatsu S, Fike JR, Palmer TD: Irradiation induces neural precursor-cell dysfunction. Nat Med 2002, 8:955-962.
• [8]Yazlovitskaya EM, Edwards E, Thotala D, Fu A, Osusky KL, Whetsell WO Jr, Boone B, Shinohara ET, Hallahan DE: Lithium treatment prevents neurocognitive deficit resulting from cranial irradiation. Cancer Res 2006, 66:11179-11186.
• [9]Tada E, Parent JM, Lowenstein DH, Fike JR: X-irradiation causes a prolonged reduction in cell proliferation in the dentate gyrus of adult rats. Neuroscience 2000, 99:33-41.
• [10]Nagai R, Tsunoda S, Asada H, Urabe N: Proliferating cell nuclear antigen positive cells in the hippocampal subgranular zone decline after irradiation in a rodent model. Neurol Res 2002, 24:517-520.
• [11]Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD, Fike JR: Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res 2003, 63:4021-4027.
• [12]Greene-Schloesser D, Moore E, Robbins ME: Molecular pathways: radiation- induced cognitive impairment. Clin Cancer Res 2013, 19:2294-2300.
• [13]Rola R, Zou Y, Huang TT, Fishman K, Baure J, Rosi S, Milliken H, Limoli CL, Fike JR: Lack of extracellular superoxide dismutase (EC-SOD) in the microenvironment impacts radiation-induced changes in neurogenesis. Free Radic Biol Med 2007, 42:1133-1145.
• [14]Rodgers SP, Trevino M, Zawaski JA: Neurogenesis, exercise, and cognitive late effects of pediatric radiotherapy. Neural Plast 2013, 2013:698528.
• [15]Ji JF, Ji SJ, Sun R, Li K, Zhang Y, Zhang LY, Tian Y: Forced running exercise attenuates hippocampal neurogenesis impairment and the neurocognitive deficits induced by whole-brain irradiation via the BDNF-mediated pathway. Biochem Biophys Res Commun 2014, 443(2):646-651.
• [16]Acharya MM, Christie LA, Hazel TG, Johe KK, Limoli CL: Transplantation of human fetal-derived neural stem cells improves cognitive function following cranial irradiation. Cell Transplant 2014, 23(10):1255-1266.
• [17]Manji HK, Moore GJ, Chen G: Lithium at 50: have the neuroprotective effects of this unique cation been overlooked? Biol Psychiatry 1999, 46(7):929-940.
• [18]Yang ES, Wang H, Jiang G, Nowsheen S, Fu A, Hallahan DE, Xia F: Lithium-mediated protection of hippocampal cells involves enhancement of DNA-PK-dependent repair in mice. J Clin Invest 2009, 119:1124-1135.
• [19]Kraus RL, Pasieczny R, Lariosa-Willingham K, Turner MS, Jiang A, Trauger JW: Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-scavenging activity. J Neurochem 2005, 94:819-827.
• [20]Plane JM, Shen Y, Pleasure DE, Deng W: Prospects for minocycline neuroprotection. Arch Neurol 2010, 67:1442-1448.
• [21]Zhang LY, Chen LS, Sun R, Ji SJ, Ding YY, Wu J, Tian Y: Effects of expression level of DNA repair-related genes involved in the NHEJ pathway on radiation-induced cognitive impairment. J Radiat Res 2013, 54:235-242.
• [22]Tian Y, Shi Z, Yang S, Chen Y, Bao S: Changes in myelin basic protein and demyelination in the rat brain within 3 months of single 2-, 10-, or 30-Gy whole-brain radiation treatments. J Neurosurg 2008, 109:881-888.
• [23]Garthe A, Kempermann G: An old test for new neurons: refining the Morris water maze to study the functional relevance of adult hippocampal neurogenesis. Front Neurosci 2013, 7:63.
• [24]Czurkó A, Czéh B, Seress L, Nadel L, Bures J: Severe spatial navigation deficit in the Morris water maze after single high dose of neonatal x-ray irradiation in the rat. Proc Natl Acad Sci U S A 1997, 94:2766-2771.
• [25]Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E: Neurogenesis in the adult is involved in the formation of trace memories. Nature 2001, 410(6826):372-376.
• [26]Winocur G, Wojtowicz JM, Sekeres M, Snyder JS, Wang S: Inhibition of neurogenesis interferes with hippocampus-dependent memory function. Hippocampus 2006, 16(3):296-304.
• [27]Jessberger S, Clark RE, Broadbent NJ, Clemenson GD Jr, Consiglio A, Lie DC, Squire LR, Gage FH: Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. Learn Mem 2009, 16(2):147-154.
• [28]Saxe MD, Battaglia F, Wang JW, Malleret G, David DJ, Monckton JE, Garcia AD, Sofroniew MV, Kandel ER, Santarelli L, Hen R, Drew MR: Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc Natl Acad Sci U S A 2006, 103(46):17501-17506.
• [29]Madsen TM, Kristjansen PE, Bolwig TG, Wörtwein G: Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat. Neuroscience 2003, 119(3):635-642.
• [30]Kohman RA, Bhattacharya TK, Kilby C, Bucko P, Rhodes JS: Effects of minocycline on spatial learning, hippocampal neurogenesis and microglia in aged and adult mice. Behav Brain Res 2013, 242:17-24.
• [31]Ng SY, Semple BD, Morganti-Kossmann MC, Bye N: Attenuation of microglial activation with minocycline is not associated with changes in neurogenesis after focal traumatic brain injury in adult mice. J Neurotrauma 2012, 29(7):1410-1425.
• [32]Mattei D, Djodari-Irani A, Hadar R, Pelz A, de Cossío LF, Goetz T, Matyash M, Kettenmann H, Winter C, Wolf SA: Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia. Brain Behav Immun 2014, 38:175-184.
• [33]Kong F, Chen S, Cheng Y, Ma L, Lu H, Zhang H, Hu W: Minocycline attenuates cognitive impairment induced by isoflurane anesthesia in aged rats. PLoS One 2013, 8(4):e61385.
• [34]Ivanov VN, Hei TK: A role for TRAIL/TRAIL-R2 in radiation-induced apoptosis and radiation-induced bystander response of human neural stem cells. Apoptosis 2014, 19:399-413.
• [35]Jin WJ, Feng SW, Feng Z, Lu SM, Qi T, Qian YN: Minocycline improves postoperative cognitive impairment in aged mice by inhibiting astrocytic activation. Neuroreport 2014, 25(1):1-6.
• [36]Cai ZY, Yan Y, Chen R: Minocycline reduces astrocytic reactivation and neuroinflammation in the hippocampus of a vascular cognitive impairment rat model. Neurosci Bull 2010, 26(1):28-36.