title: Anti-depressant effects of phosphodiesterase 3 inhibitor cilostazol in chronic mild stress-treated mice after ischemic stroke.
abstract: BACKGROUND
  Phosphodiesterase 3 (PDE3) inhibitor cilostazol ameliorates negative effects of cerebral hypoperfusion against cerebral ischemic injury through the phosphodiesterase 3-cyclic adenosine monophosphate (cAMP) signaling cascade.
  
  
  OBJECTIVE
  We investigated the question of whether cilostazol would have an anti-depressant effect on chronic mild stress (CMS)-treated mice after ischemic stroke.
  
  
  METHODS
  An animal model of post-stroke depression was developed by additional CMS procedures in middle cerebral artery occlusion (MCAO). We performed behavioral, histological, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), immunohistochemical, Western blot and enzyme linked immunosorbent assays (ELISA).
  
  
  RESULTS
  In the open field, sucrose preference, forced swim and Morris water maze test, treatment with cilostazol resulted in reduction of all depressive behaviors examined, particularly in the Morris water maze test. Treatment with cilostazol reduced prominent atrophic changes in the ipsilateral striatum and hippocampus of CMS-treated ischemic mice through inhibition of neuronal cell death and microglial activation. In addition, treatment of the CMS-treated ischemic mice with cilostazol resulted in significantly increased phosphorylation of cAMP response element-binding protein (CREB) and expression of mature brain-derived neurotrophic factor (BDNF) with its receptor tropomyosin receptor kinase B (TrkB) in the ipsilateral striatum and hippocampus. Phosphorylation of CREB was also demonstrated in the dopaminergic neurons of the midbrain. Treatment with cilostazol also resulted in an increased number of newly formed cells and enhanced differentiation into neurons in the ipsilateral striatum and hippocampus.
  
  
  CONCLUSIONS
  Our results suggest that phosphodiesterase 3 inhibitor cilostazol may have anti-depressant effects on post-stroke depression through inhibition of neurodegeneration in the primary lesion and secondary extrafocal sites and promotion of neurogenesis. These beneficial effects on post-stroke depression may be involved in activation of CREB/BDNF signaling.
authors.affiliation: Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Gyeongnam, Yangsan, 626-870, Republic of Korea.
authors.forename: Yu Ri
authors.initials: YR
authors.lastname: Kim
authors.affiliation: Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Gyeongnam, Yangsan, 626-870, Republic of Korea.|Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, 626-870, Republic of Korea.
authors.forename: Ha Neui
authors.initials: HN
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, 626-870, Republic of Korea.
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Hong
authors.affiliation: Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Gyeongnam, Yangsan, 626-870, Republic of Korea.|Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, 626-870, Republic of Korea.|Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Gyeongnam, Yangsan, 626-870, Republic of Korea.
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
authors.affiliation: Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Gyeongnam, Yangsan, 626-870, Republic of Korea. choibt@pusan.ac.kr.|Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, 626-870, Republic of Korea. choibt@pusan.ac.kr.|Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Gyeongnam, Yangsan, 626-870, Republic of Korea. choibt@pusan.ac.kr.
authors.forename: Byung Tae
authors.initials: BT
authors.lastname: Choi
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D000077407:Cilostazol; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000209:etiology / Q000523:psychology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000378:metabolism / Q000523:psychology; D008297:Male; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D013315:Stress, Psychological / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000523:psychology; D020521:Stroke / Q000150:complications* / Q000378:metabolism / Q000523:psychology; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D000077407:Cilostazol
keywords: BDNF; Chronic mild stress; Cilostazol; Depression; Stroke