For stand-alone therapy for enhancing cognition, 5-HT(1A) partial agonists, 5-HT(2A) antagonists, 5-HT(4) partial agonists and 5-HT(6) antagonists are all likely to induce at least modest improvement in cognition in schizophrenia. If "add-on therapy" is contemplated, antipsychotic drugs with weak affinities for serotonin receptors should be used to avoid confounds. It is likely that serotonergic drugs will soon be available as cognition enhancing medications for disorders other than schizophrenia (e.g. dementia).

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Blum AE, Joseph SM, Przybylski RJ, Dubyak GR. Rho-family GTPases modulate Ca 2ϩ -dependent ATP release from astrocytes. Am J Physiol Cell Physiol 295: C231-C241, 2008. First published May 21, 2008 doi:10.1152/ajpcell.00175.2008.-Previously, we reported that activation of G protein-coupled receptors (GPCR) in 1321N1 human astrocytoma cells elicits a rapid release of ATP that is partially dependent on a G q/phophospholipase C (PLC)/Ca 2ϩ mobilization signaling cascade. In this study we assessed the role of Rho-family GTPase signaling as an additional pathway for the regulation of ATP release in response to activation of protease-activated receptor-1 (PAR1), lysophosphatidic acid receptor (LPAR), and M3-muscarinic (M3R) GPCRs. Thrombin (or other PAR1 peptide agonists), LPA, and carbachol triggered quantitatively similar Ca 2ϩ mobilization responses, but only thrombin and LPA caused rapid accumulation of active GTP-bound Rho. The ability to elicit Rho activation correlated with the markedly higher efficacy of thrombin and LPA, relative to carbachol, as ATP secretagogues. Clostridium difficile toxin B and Clostridium botulinum C3 exoenzyme, which inhibit Rho-GTPases, attenuated the thrombin-and LPA-stimulated ATP release but did not decrease carbachol-stimulated release. Thus the ability of certain G q-coupled receptors to additionally stimulate Rho-GTPases acts to strongly potentiate a Ca 2ϩ -activated ATP release pathway. However, pharmacological inhibition of Rho kinase I/II or myosin light chain kinase did not attenuate ATP release. PAR1-induced ATP release was also reduced twofold by brefeldin treatment suggesting the possible mobilization of Golgi-derived, ATP-containing secretory vesicles. ATP release was also markedly repressed by the gap junction channel inhibitor carbenoxolone in the absence of any obvious thrombin-induced change in membrane permeability indicative of hemichannel gating. Rho GTPase; astrocyte; hemichannel EXTRACELLULAR NUCLEOTIDES act as autocrine/paracrine signaling molecules by targeting multiple P2 purinergic receptor subtypes that are differentially expressed in most tissues (7). Cells are able to tightly regulate the concentration of ATP and other nucleotides in the extracelluar space through a balance of release and extracellular metabolism of these nucleotides. The four sources of extracellular nucleotides are cell lysis, exocytosis, transport-mediated ATP release, and extracellular nucleotide kinases. In nonexcitable cells, such as astrocytes, unequivocal determination of ATP release mechanisms has remained elusive.In the brain, ATP can be released by astrocytes, or by other glial cell types, in response to diverse metabolic, mechanical, or inflammatory stimuli (8, 9). Extracellular ATP can target glia and neurons, as well as the smooth muscle cells and endothelial cells that populate cerebrovascular interfaces (1,21,32). Although purinergic signaling is an important element of the communication network between astrocytes and surrounding cells, the signaling events upstream of ATP ...

Mast cell tumor (MCT) is the most common cutaneous neoplasm in dogs and wide surgical resection is the current first-line treatment. However, recurrence is common and often requires more specialist and expensive therapies. Tigilanol tiglate is a novel small molecule drug delivered by intratumoral injection that is currently under development to provide a new option for treating MCT. The aim of this study was to characterize a safe and effective dose of tigilanol tiglate for canine MCT and to gather preliminary data on the drug's pharmacokinetics. A multicenter, open-label, uncontrolled, non-randomized, dose de-escalation design was used. Eligibility was MCT stage I/IIa and a tumor size of 0.1–6.0 cm 3 . Dosing was based on tumor size (50% v/v tumor) and 3 drug concentrations (1.0, 0.5, 0.2 mg/mL) were evaluated. Twenty-seven dogs were treated in 3 dose de-escalation cohorts (10, 10, and 7 dogs, respectively). Efficacy at 21 days was defined using international accepted solid tumor response criteria (RECIST). Greatest efficacy (90% complete response) was observed at the highest drug concentration (1.0 mg/mL) and adverse events were generally low grade, mild and transient, and directly associated with the mode of action of the drug. Hematological and serum biochemistry were generally unremarkable with plasma concentration curves typical of a non-intravenous parenteral medication. Intratumoral treatment of MCT with tigilanol tiglate at a concentration of 1.0 mg/mL was highly efficacious and well-tolerated. These results support the drug's further development for the treatment of MCT and other solid tumors.

Author Contributions: K.G. conceived and supervised the study. V.V. performed the pathway modelling and statistical analyses. A.C., M.I.C., J.S.W., and N.J.S. contributed tissue samples. A.K.C coordinated the clinical annotation of all samples in the study. J.W. performed pathology review of tissue specimens. A.K. and J.W performed immunohistochemistry analysis. Y.G. and Y.S performed quality assessment, transcript assembly and abundance estimation using RNA sequence data. S.D.M. provided colon cancer cell lines. A.