Caffeic acid recovers ischemia-induced synaptic dysfunction without direct effects on excitatory synaptic transmission and plasticity in mouse hippocampal slices.

Caffeic acid is a polyphenolic compound present in a vast array of dietary components. We previously showed that caffeic acid reduces the burden of brain ischemia joining evidence by others that it can attenuate different brain diseases. However, it is unknown if caffeic acid affects information processing in neuronal networks. Thus, we now used electrophysiological recordings in mouse hippocampal slices to test if caffeic acid directly affected synaptic transmission, plasticity and dysfunction caused by oxygen-glucose deprivation (OGD), an in vitro ischemia model. Caffeic acid (1-10 µM) was devoid of effect on synaptic transmission and paired-pulse facilitation in Schaffer collaterals-CA1 pyramidal synapses. Also, the magnitude of either hippocampal long-term potentiation (LTP) or the subsequent depotentiation were not significantly modified by 10 µM caffeic acid. However, caffeic acid (10 µM) increased the recovery of synaptic transmission upon re-oxygenation following 7 min of OGD. Furthermore, caffeic acid (10 µM) also recovered plasticity after OGD, as heralded by the increased magnitude of LTP after exposure. These findings show that caffeic acid does not directly affect synaptic transmission and plasticity but can indirectly affect other cellular targets to correct synaptic dysfunction. Unraveling the molecular mechanisms of action of caffeic acid may allow the design of hitherto unrecognized novel neuroprotective strategies.

Exercise decreases aberrant corticostriatal plasticity in an animal model of l-DOPA-induced dyskinesia.

Physical exercise attenuates the development of l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID) in 6-hydroxydopamine-induced hemiparkinsonian mice through unknown mechanisms. We now tested if exercise normalizes the aberrant corticostriatal neuroplasticity associated with experimental murine models of LID. C57BL/6 mice received two unilateral intrastriatal injections of 6-hydroxydopamine (12 µg) and were treated after 3 wk with l-DOPA/benserazide (25/12.5 mg/kg) for 4 wk, with individualized moderate-intensity running (60%-70% V̇o2peak) or not (untrained). l-DOPA converted the pattern of plasticity in corticostriatal synapses from a long-term depression (LTD) into a long-term potentiation (LTP). Exercise reduced LID severity and decreased aberrant LTP. These results suggest that exercise attenuates abnormal corticostriatal plasticity to decrease LID.

Expression of potassium channels is relevant for cell survival and migration in a murine bone marrow stromal cell line.

S17 is a clonogenic bone marrow stromal (BMS) cell line derived from mouse that has been extensively used to assess both human and murine hematopoiesis support capacity. However, very little is known about the expression of potassium ion channels and their function in cell survival and migration in these cells. Thus, the present study was designed to characterize potassium ion channels using electrophysiological and molecular biological approaches in S17 BMS cells. The whole-cell configuration of the patch clamp technique has been applied to identify potassium ion currents and reverse transcription polymerase chain reaction (RT-PCR) used to determine their molecular identities. Based on gating kinetics and pharmacological modulation of the macroscopic currents we found the presence of four functional potassium ion channels in S17 BMS cells. These include a current rapidly activated and inactivated, tetraethylammonium-sensitive, (IKV ) in most (50%) cells; a fast activated and rapidly inactivating A-type K + current (IK A -like); a delayed rectifier K + current (IK DR ) and an inward rectifier potassium current (IK IR ), found in, respectively 4.5%, 26% and 24% of these cells. RT-PCR confirmed the presence of mRNA transcripts for the alpha subunit of the corresponding functional ion channels. Additionally, functional assays were performed to investigate the importance of potassium currents in cell survival and migration. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analyses revealed a reduction in cell viability, while wound healing assays revealed reduced migration potential in cells incubated with different potassium channel blockers. In conclusion, our data suggested that potassium currents might play a role in the maintenance of overall S17 cell ionic homeostasis directly affecting cell survival and migration.

The structurally related auxin and melatonin tryptophan-derivatives and their roles in Arabidopsis thaliana and in the human malaria parasite Plasmodium falciparum.

Indole compounds are involved in a range of functions in many organisms. In the human malaria parasite Plasmodium falciparum, melatonin and other tryptophan derivatives are able to modulate its intraerythrocytic cycle, increasing the schizont population as well as parasitemia, likely through ubiquitin-proteasome system (UPS) gene regulation. In plants, melatonin regulates root development, in a similar way to that described for indoleacetic acid, suggesting that melatonin and indoleacetic acid could co-participate in some physiological processes due to structural similarities. In the present work, we evaluate whether the chemical structure similarity found in indoleacetic acid and melatonin can lead to similar effects in Arabidopsis thaliana lateral root formation and P. falciparum cell cycle modulation, as well as in the UPS of gene regulation, by qRT-PCR. Our data show that P. falciparum is not able to respond to indoleacetic acid either in the modulation of the intraerythrocytic cycle or in the gene regulation mediated by the UPS as observed for melatonin. The similarities of these indole compounds are not sufficient to confer synergistic functions in P. falciparum cell cycle modulation, but could interplay in A. thaliana lateral root formation.

Dissecting Major Signaling Pathways throughout the Development of Prostate Cancer.

Prostate cancer (PCa) is one of the most common malignancies found in males. The development of PCa involves several mutations in prostate epithelial cells, usually linked to developmental changes, such as enhanced resistance to apoptotic death, constitutive proliferation, and, in some cases, to differentiation into an androgen deprivation-resistant phenotype, leading to the appearance of castration-resistant PCa (CRPCa), which leads to a poor prognosis in patients. In this review, we summarize recent findings concerning the main deregulations into signaling pathways that will lead to the development of PCa and/or CRPCa. Key mutations in some pathway molecules are often linked to a higher prevalence of PCa, by directly affecting the respective cascade and, in some cases, by deregulating a cross-talk node or junction along the pathways. We also discuss the possible environmental and nonenvironmental inducers for these mutations, as well as the potential therapeutic strategies targeting these signaling pathways. A better understanding of how some risk factors induce deregulation of these signaling pathways, as well as how these deregulated pathways affect the development of PCa and CRPCa, will further help in the development of new treatments and prevention strategies for this disease.

Voltage-dependent calcium and chloride currents in S17 bone marrow stromal cell line.

The bone marrow stromal cell line S17 has been used to study hematopoiesis in vitro. In this study, we demonstrate the presence of calcium and chloride currents in cultured S17 cells. Calcium currents were of low amplitude or barely detectable (50-100 pA). Hence to amplify the currents, we have used barium as a charge carrier. Barium currents were identified based on their distinct voltage-dependence, and sensitivity to dihydropyridines. S17 cells also exhibited a slowly activating outward current without inactivation, most commonly seen when the sodium of the extracellular solution was replaced either by TEA (TEA/Cs saline) or NMDG (NMDG saline), or by addition of amiloride to the extracellular solution. This current was abolished either by 500 microM SITS (4,4'-diisothiocyanatostilbene-2-2'-disulfonic acid) or 500 microM DPC (diphenylamine-2-carboxylic acid) a cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel blocker, identifying it as a Cl(-) current. RT-PCR identified the presence of ENaC and CFTR transcripts. CFTR blockade reduced cell proliferation, suggesting that this channel plays a physiological role in regulation of S17 cell proliferation.