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Immunotoxicological Effects of Aripiprazole: In vivo and In vitro Studies.

Baek KS, Ahn S, Lee J, Kim JH, Kim HG, Kim E, Kim JH, Sung NY, Yang S, Kim MS, Hong S, Kim JH, Cho JY - Korean J. Physiol. Pharmacol. (2015)

Bottom Line: In contrast, the patterns of these phospho-proteins were variable in other tissues.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Korea.

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.

No MeSH data available.


Related in: MedlinePlus

Effect of ARPGCB or GCB3004 on the level of cell death-related molecules in organs. (A, B, and C) The levels of cell death-related proteins such as (p65/NF-κB, c-Jun/AP-1, ERK/MAPK, JNK/MAPK, p38/MAPK, caspase 3, bcl-2, and β-actin) were identified by immunoblotting from tissue lysates prepared from mice orally administered with ARPGCB or GCB3004 (each of 500 mg/kg). The results shown are representative of three independent experiments.
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Figure 2: Effect of ARPGCB or GCB3004 on the level of cell death-related molecules in organs. (A, B, and C) The levels of cell death-related proteins such as (p65/NF-κB, c-Jun/AP-1, ERK/MAPK, JNK/MAPK, p38/MAPK, caspase 3, bcl-2, and β-actin) were identified by immunoblotting from tissue lysates prepared from mice orally administered with ARPGCB or GCB3004 (each of 500 mg/kg). The results shown are representative of three independent experiments.

Mentions: To evaluate the toxicological properties of aripiprazole in each organ, we next investigated whether aripiprazole was able to modulate the levels of activated survival/death-regulatory proteins such as p65/NF-κB, c-Jun/AP-1, and MAPKs as well as apoptosis-regulatory proteins such as bcl-2 and caspase-3 which are involved in controlling cell growth, proliferation, and apoptosis [2021]. This analysis was performed by preparing whole tissue lysates from mice treated with a single dose of one of the two aripiprazole formulations and evaluating the phosphorylated levels of p65, c-Jun, ERK, JNK, caspase 3, and bcl-2 in immunoblotting analysis. As shown in Fig. 2, the phospho- and total protein patterns of these proteins were variable between organs in each group. First of all, phospho-protein levels of ERK, JNK, and p38 and total protein levels of caspase 3 and bcl-2 were increased by the two formulations in the brain, which is the known target organ of aripiprazole [5], while p-p65 but not p-c-Jun was decreased by aripiprazole treatment (Fig. 2). With respect to other organs (thymus, heart, lung, liver, spleen, stomach, kidney, intestine, and bladder), the two formulations exhibited opposite effects on protein expression in tissues for p-p65, p-JNK, caspase-3, and bcl-2 levels, but similar patterns for p-c-Jun level in mice (Fig. 2).


Immunotoxicological Effects of Aripiprazole: In vivo and In vitro Studies.

Baek KS, Ahn S, Lee J, Kim JH, Kim HG, Kim E, Kim JH, Sung NY, Yang S, Kim MS, Hong S, Kim JH, Cho JY - Korean J. Physiol. Pharmacol. (2015)

Effect of ARPGCB or GCB3004 on the level of cell death-related molecules in organs. (A, B, and C) The levels of cell death-related proteins such as (p65/NF-κB, c-Jun/AP-1, ERK/MAPK, JNK/MAPK, p38/MAPK, caspase 3, bcl-2, and β-actin) were identified by immunoblotting from tissue lysates prepared from mice orally administered with ARPGCB or GCB3004 (each of 500 mg/kg). The results shown are representative of three independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4499649&req=5

Figure 2: Effect of ARPGCB or GCB3004 on the level of cell death-related molecules in organs. (A, B, and C) The levels of cell death-related proteins such as (p65/NF-κB, c-Jun/AP-1, ERK/MAPK, JNK/MAPK, p38/MAPK, caspase 3, bcl-2, and β-actin) were identified by immunoblotting from tissue lysates prepared from mice orally administered with ARPGCB or GCB3004 (each of 500 mg/kg). The results shown are representative of three independent experiments.
Mentions: To evaluate the toxicological properties of aripiprazole in each organ, we next investigated whether aripiprazole was able to modulate the levels of activated survival/death-regulatory proteins such as p65/NF-κB, c-Jun/AP-1, and MAPKs as well as apoptosis-regulatory proteins such as bcl-2 and caspase-3 which are involved in controlling cell growth, proliferation, and apoptosis [2021]. This analysis was performed by preparing whole tissue lysates from mice treated with a single dose of one of the two aripiprazole formulations and evaluating the phosphorylated levels of p65, c-Jun, ERK, JNK, caspase 3, and bcl-2 in immunoblotting analysis. As shown in Fig. 2, the phospho- and total protein patterns of these proteins were variable between organs in each group. First of all, phospho-protein levels of ERK, JNK, and p38 and total protein levels of caspase 3 and bcl-2 were increased by the two formulations in the brain, which is the known target organ of aripiprazole [5], while p-p65 but not p-c-Jun was decreased by aripiprazole treatment (Fig. 2). With respect to other organs (thymus, heart, lung, liver, spleen, stomach, kidney, intestine, and bladder), the two formulations exhibited opposite effects on protein expression in tissues for p-p65, p-JNK, caspase-3, and bcl-2 levels, but similar patterns for p-c-Jun level in mice (Fig. 2).

Bottom Line: In contrast, the patterns of these phospho-proteins were variable in other tissues.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Korea.

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.

No MeSH data available.


Related in: MedlinePlus