Beneficial in vivo effect of aripiprazole on neuronal regeneration following neuronal loss in the dentate gyrus: evaluation using a mouse model of trimethyltin-induced neuronal loss/self-repair in the dentate gyrus.

Aripiprazole is used clinically as an atypical antipsychotic. We evaluated the effect of in vivo treatment with aripiprazole on the proliferation and differentiation of neural stem/progenitor cells in a mouse model, trimethyltin-induced neuronal loss/self-repair in the hippocampal dentate gyrus (referred as "impaired animals") [Ogita et al., J Neurosci Res. 82, 609 - 621 (2005)]. In the impaired animals, an increased number of 5-bromo-2'-deoxyuridine (BrdU)-positive cells was seen in the dentate gyrus at the initial time window of the self-repair stage. At the same time window, a single treatment with aripiprazole significantly increased the number of cells positive for both BrdU and nestin in the dentate gyrus of the impaired animals. Chronic treatment with aripiprazole promoted the proliferation/survival and neuronal differentiation of the cells newly-generated following the neuronal loss in the dentate gyrus of the impaired animals. The chronic treatment with aripiprazole improved depression-like behavior seen in the impaired animals. Taken together, our data suggest that aripiprazole had a beneficial effect on neuronal regeneration following neuronal loss in the dentate gyrus through indirectly promoted proliferation/survival and neuronal differentiation of neural stem/progenitor cells in the subgranular zone of the dentate gyrus.

HPLC-method for deliberation of drug mammary transfer-evaluation of over-the-counter drugs (Loxonin(®)-S, Bufferin(®) A) in mother mice.

Loxoprofen (Loxonin(®)), an antipyretic painkiller, was approved as an over-the-counter (OTC) drug (Loxonin(®)-S) in January 2011. With regard to self-medication using OTC drugs, the information that pharmacists provide to consumers is very important. Although loxoprofen is a very versatile drug and can be used during breastfeeding, information regarding its mammary gland transfer is inadequate. In this study, we established a simple method to evaluate mammary transfer of drugs, and compared loxoprofen's mammary gland transfer with that of aspirin. Loxoprofen 12 mg/kg and aspirin 132 mg/kg was orally administered to mother mice (ddY), and blood and milk samples were collected. Twenty microliters of ethanol was added to the blood and milk samples (10 µL), and the mixture was centrifuged for 15 min (12000 g); the supernatant was analyzed by high-performance liquid chromatography. Since aspirin was immediately metabolized, we analyzed salicylic acid concentrations. Maximum concentration of loxoprofen was observed at around 15 min after its oral administration, with the concentrations in the blood and milk being 2.9 and 0.5 µg/mL, respectively. The drug was metabolized promptly thereafter. In contrast, maximum concentration of salicylic acid was observed at 30 min after aspirin administration, with the concentrations in the blood and milk being 187.2 and 64.4 µg/mL, respectively. These concentrations remained constant from 60 to 120 min. Salicylic acid could be detected 240 min after aspirin administration. Thus, mammary gland transfer of loxoprofen is lower than that of aspirin, suggesting that loxoprofen does not accumulate in milk.

In vivo and in vitro treatment with edaravone promotes proliferation of neural progenitor cells generated following neuronal loss in the mouse dentate gyrus.

Edaravone is clinically used in Japan for treatment of patients with acute cerebral infarction. To clarify the effect of edaravone on neurogenesis in the hippocampus following neuronal injury in the hippocampal dentate gyrus, we investigated the effect of in vitro and in vivo treatment with edaravone on the proliferation of neural stem/progenitor cells prepared from the mouse dentate gyrus damaged by trimethyltin (TMT). Histological assessment revealed the presence of large number of nestin(+) cells in the dentate gyrus on days 3 - 5 post-TMT treatment. We prepared cells from the dentate gyrus of naïve, TMT-treated mice or TMT/edaravone-treated mice. The cells obtained from the dentate gyrus of TMT-treated animals were capable of BrdU incorporation and neurosphere formation when cultured in the presence of growth factors. The TMT-treated group had a larger number of nestin(+) cells and nestin(+)GFAP(+) cells than the naïve one. Under the culture condition used, sustained exposure of the cells from the damaged dentate gyrus to edaravone at 10(-11) and 10(-8) M promoted the proliferation of nestin(+) cells. The systemic in vivo treatment with edaravone for 2 days produced a significant increase in the number of nestin(+) cells among the cells prepared from the dentate gyrus on day 4 post-TMT treatment, and as well as one in the number of neurospheres formed from these cells in the culture. Taken together, our data indicated that edaravone had the ability to promote the proliferation of neural stem/progenitor cells generated following neuronal damage in the dentate gyrus.