Sonic hedgehog enhances calcium oscillations in hippocampal astrocytes.

Sonic hedgehog (SHH) is important for organogenesis during development. Recent studies have indicated that SHH is also involved in the proliferation and transformation of astrocytes to the reactive phenotype. However, the mechanisms underlying these are unknown. Involvement of SHH signaling in calcium (Ca) signaling has not been extensively studied. Here, we report that SHH and Smoothened agonist (SAG), an activator of the signaling receptor Smoothened (SMO) in the SHH pathway, activate Ca oscillations in cultured murine hippocampal astrocytes. The response was rapid, on a minute time scale, indicating a noncanonical pathway activity. Pertussis toxin blocked the SAG effect, indicating an involvement of a Gi coupled to SMO. Depletion of extracellular ATP by apyrase, an ATP-degrading enzyme, inhibited the SAG-mediated activation of Ca oscillations. These results indicate that SAG increases extracellular ATP levels by activating ATP release from astrocytes, resulting in Ca oscillation activation. We hypothesize that SHH activates SMO-coupled Gi in astrocytes, causing ATP release and activation of Gq/11-coupled P2 receptors on the same cell or surrounding astrocytes. Transcription factor activities are often modulated by Ca patterns; therefore, SHH signaling may trigger changes in astrocytes by activating Ca oscillations. This enhancement of Ca oscillations by SHH signaling may occur in astrocytes in the brain in vivo because we also observed it in hippocampal brain slices. In summary, SHH and SAG enhance Ca oscillations in hippocampal astrocytes, Gi mediates SAG-induced Ca oscillations downstream of SMO, and ATP-permeable channels may promote the ATP release that activates Ca oscillations in astrocytes.

Effect of initial ziprasidone dose on treatment outcome of korean patients with acute manic or mixed episodes.

OBJECTIVE: We investigated the efficacy and tolerability of ziprasidone combined with divalproex to determine the relationship between the initial dose of ziprasidone and the treatment effect among Korean patients with acute bipolar manic or mixed disorders. METHODS: This study was a 6-week, open-label, prospective investigation of Korean patients with an acute manic or mixed episode of bipolar disorder. Sixty-five patients were recruited. The patients were categorized based on the initial dose of ziprasidone as follows: low (20-79 mg/day) and standard (80 mg/day). Ziprasidone was given in combination with divalproex in flexible doses, according to the clinical response and tolerability. RESULTS: The response and remission rates were significantly higher in the standard-dose group than the low-dose group. The combination of ziprasidone and divalproex was well-tolerated and adverse events were mostly mild with no statistically significant increase in body weight. CONCLUSION: The results of this study showed that a standard starting dose of ziprasidone in combination with divalproex for bipolar disorder is more effective than a low starting dose.