title: Minocycline ameliorates cognitive impairment induced by whole-brain irradiation: an animal study.
abstract: 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.
authors.affiliation: Department of Radiotherapy and Oncology, Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, PR China. zhangliyuan126@126.com.|Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, PR China. zhangliyuan126@126.com.|Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu Province, 215123, PR China. zhangliyuan126@126.com.
authors.forename: Liyuan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Radiotherapy and Oncology, Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, PR China. lixiahui456@163.com.|Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, PR China. lixiahui456@163.com.|Department of Medical Oncology, Affiliated Hospital of Taishan Medical University, Taian, Shandong Province, 271000, PR China. lixiahui456@163.com.
authors.forename: Kun
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Radiotherapy and Oncology, Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, PR China. rui198608@163.com.|Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, PR China. rui198608@163.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.affiliation: Department of Radiotherapy and Oncology, Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, PR China. zhangyuan19880210@126.com.|Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, PR China. zhangyuan19880210@126.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Radiotherapy and Oncology, Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, PR China. pointbreakjjf@163.com.|Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, PR China. pointbreakjjf@163.com.
authors.forename: JianFeng
authors.initials: J
authors.lastname: Ji
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, 100 Blossom Street, Boston, MA, 02114, USA. PHuang4@partners.org.
authors.forename: Peigeng
authors.initials: P
authors.lastname: Huang
authors.affiliation: Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu Province, 215123, PR China. yanghongying@suda.edu.cn.|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, Jiangsu Province, 215123, PR China. yanghongying@suda.edu.cn.
authors.forename: Hongying
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Radiotherapy and Oncology, Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, PR China. dryetian@hotmail.com.|Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, PR China. dryetian@hotmail.com.|Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu Province, 215123, PR China. dryetian@hotmail.com.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000528:radiation effects; D003071:Cognition / Q000187:drug effects* / Q000528:radiation effects; D016371:Cranial Irradiation / Q000009:adverse effects*; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D007150:Immunohistochemistry; D008297:Male; D008911:Minocycline / Q000494:pharmacology*; D055495:Neurogenesis / Q000187:drug effects / Q000528:radiation effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D011837:Radiation-Protective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D018696:Neuroprotective Agents; D011837:Radiation-Protective Agents; D008911:Minocycline