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Behav Brain Res. 2019 Jun 3;365:133-140. doi: 10.1016/j.bbr.2019.03.013. Epub 2019 Mar 6.

Augmented improvement of cognition and memory by aripiprazole add-on for cilostazol treatment in the chronic cerebral hypoperfusion mouse model.

Author information

1
Department of Pharmacology, School of Medicine, Pusan National University, Gyeongsangnam-do, Republic of Korea; Gene & Cell Therapy Research Center for Vessel-Associated Diseases, Pusan National University, Gyeongsangnam-do, Republic of Korea.
2
Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Gyeongsangnam-do, Republic of Korea.
3
Department of Pharmacology, School of Medicine, Pusan National University, Gyeongsangnam-do, Republic of Korea.
4
Gene & Cell Therapy Research Center for Vessel-Associated Diseases, Pusan National University, Gyeongsangnam-do, Republic of Korea.
5
Department of Pharmacology, School of Medicine, Pusan National University, Gyeongsangnam-do, Republic of Korea; Gene & Cell Therapy Research Center for Vessel-Associated Diseases, Pusan National University, Gyeongsangnam-do, Republic of Korea. Electronic address: chidkim@pusan.ac.kr.

Abstract

Cerebrovascular dysfunction is associated with cognitive impairment in vascular dementia patients. This study aimed to explore augmented improvement of cognition and memory by aripiprazole add-on for cilostazol treatment in vascular dementia model. Male C57BL/6 mice were subjected to BCAS, and spatial probe and memory retention were examined using the Morris water maze (MWM) test. In the present study, the escape latency on the first day after 3rd week was 21.4 ± 4.0 s in sham-operated mice, and 76.3 ± 4.2 s in the vehicle-treated BCAS mice. In the spatial probe tests in the 3rd week, aripiprazole (1 mg/kg/day) showed time-dependently amelioration in spatial learning and memory impairments in contrast to 0.5 mg/kg/day. After treatment with 20 mg/kg/day of cilostazol for 3 weeks, the escape latency significantly decreased to 26.6 ± 5.8 s on the first day and further shortened to 21.6 ± 6.8 s on the fourth day. When the BCAS mice were concurrently treated with 0.5 mg/kg/day aripiprazole plus 20 mg/kg/day of cilostazol for 3 weeks, the escape latency was more shortened from 20.4 ± 1.2 s (1st day) to 14.9 ± 1.7 s on the 4th day of the 3-week trials. Furthermore, decreased spatial memory retention in BCAS mice was significantly alleviated by aripiprazole plus cilostazol cotreatment, indicating the benefit of aripiprazole add-on therapy. In line with these, significantly increased mBDNF and P-CREB levels and reduced apoptosis were identified in the BCAS mouse brain dentate gyrus by cotreatment as contrasted to each monotherapy. These results may provide the synergistic therapeutic avenues for augmented improvement of cognition and memory by cotreatment with aripiprazole plus cilostazol in cases of vascular dementia.

KEYWORDS:

Apoptosis; Aripiprazole; BDNF; Chronic cerebral hypoperfusion; Cilostazol; Vascular dementia; p-CREB

PMID:
30851315
DOI:
10.1016/j.bbr.2019.03.013

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