Yu Ri Kim1, Ha Neui Kim1,2, Ki Whan Hong3, Hwa Kyoung Shin1,2,4, Byung Tae Choi5,6,7. 1. Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Gyeongnam, Yangsan, 626-870, Republic of Korea. 2. Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, 626-870, Republic of Korea. 3. Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, 626-870, Republic of Korea. 4. Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Gyeongnam, Yangsan, 626-870, Republic of Korea. 5. Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Gyeongnam, Yangsan, 626-870, Republic of Korea. choibt@pusan.ac.kr. 6. Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, 626-870, Republic of Korea. choibt@pusan.ac.kr. 7. Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Gyeongnam, Yangsan, 626-870, Republic of Korea. choibt@pusan.ac.kr.
Abstract
RATIONALE: 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. OBJECTIVES: 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.
RATIONALE: 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. OBJECTIVES: 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 ischemicmice through inhibition of neuronal cell death and microglial activation. In addition, treatment of the CMS-treated ischemicmice 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: Nobukazu Miyamoto; Loc-Duyen D Pham; Kazuhide Hayakawa; Toshinori Matsuzaki; Ji Hae Seo; Caroline Magnain; Cenk Ayata; Kyu-Won Kim; David Boas; Eng H Lo; Ken Arai Journal: Stroke Date: 2013-07-23 Impact factor: 7.914
Authors: Mahmoud S Abdallah; Ahmed N Ramadan; Hend Omara-Reda; Noha O Mansour; Mohamed A Elsokary; Hozaifa K Elsawah; Shimaa Abdelsattar Zaki; Hend E Abo Mansour; Esraa M Mosalam Journal: CNS Neurosci Ther Date: 2021-09-21 Impact factor: 5.243