title: Immunotoxicological Effects of Aripiprazole: In vivo and In vitro Studies.
abstract: Aripiprazole (ARI) is a commonly prescribed medication used to treat schizophrenia and bipolar disorder. To date, there have been no studies regarding the molecular pathological and immunotoxicological profiling of aripiprazole. Thus, in the present study, we prepared two different formulas of aripiprazole [Free base crystal of aripiprazole (ARPGCB) and cocrystal of aripiprazole (GCB3004)], and explored their effects on the patterns of survival and apoptosis-regulatory proteins under acute toxicity and cytotoxicity test conditions. Furthermore, we also evaluated the modulatory activity of the different formulations on the immunological responses in macrophages primed by various stimulators such as lipopolysaccharide (LPS), pam3CSK, and poly(I:C) via toll-like receptor 4 (TLR4), TLR2, and TLR3 pathways, respectively. In liver, both ARPGCB and GCB3004 produced similar toxicity profiles. In particular, these two formulas exhibited similar phospho-protein profiling of p65/nuclear factor (NF)-κB, c-Jun/activator protein (AP)-1, ERK, JNK, p38, caspase 3, and bcl-2 in brain. In contrast, the patterns of these phospho-proteins were variable in other tissues. Moreover, these two formulas did not exhibit any cytotoxicity in C6 glioma cells. Finally, the two formulations at available in vivo concentrations did not block nitric oxide (NO) production from activated macrophage-like RAW264.7 cells stimulated with LPS, pam3CSK, or poly(I:C), nor did they alter the morphological changes of the activated macrophages. Taken together, our present work, as a comparative study of two different formulas of aripiprazole, suggests that these two formulas can be used to achieve similar functional activation of brain proteins related to cell survival and apoptosis and immunotoxicological activities of macrophages.
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Baek
authors.affiliation: Central Institute, GCB, Yongin 446-908, Korea.
authors.forename: Shinbyoung
authors.initials: S
authors.lastname: Ahn
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea.
authors.forename: Jaehwi
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Han Gyung
authors.initials: HG
authors.lastname: Kim
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Jun Ho
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Nak Yoon
authors.initials: NY
authors.lastname: Sung
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Sungjae
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Mi Seon
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Sungyoul
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Biosafety Research Institute, Chonbuk National University, Jeonju 561-756, Korea.
authors.forename: Jong-Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Jae Youl
authors.initials: JY
authors.lastname: Cho
keywords: Acute toxicity; Aripiprazole; Cocrystal; Immunotoxicology; Survival proteins