Moderate concentrations of 4-O-methylhonokiol potentiate GABAA receptor currents stronger than honokiol

BACKGROUND Magnolia bark preparations from Magnolia officinalis of Asian medicinal systems are known for their muscle relaxant effect and anticonvulsant activity. These CNS related effects are ascribed to the presence of the biphenyl-type neolignans honokiol and magnolol that exert a potentiating effect on GABAA receptors. 4-O-methylhonokiol isolated from seeds of the North-American M. grandiflora was compared to honokiol for its activity to potentiate GABAA receptors and its GABAA receptor subtype-specificity was established. METHODS Different recombinant GABAA receptors were functionally expressed in Xenopus oocytes and electrophysiological techniques were used determine to their modulation by 4-O-methylhonokiol. RESULTS 3μM 4-O-methylhonokiol is shown here to potentiate responses of the α₁β₂γ₂ GABAA receptor about 20-fold stronger than the same concentration of honokiol. In the present study potentiation by 4-O-methylhonokiol is also detailed for 12 GABAA receptor subtypes to assess GABAA receptor subunits that are responsible for the potentiating effect. CONCLUSION The much higher potentiation of GABAA receptors at identical concentrations of 4-O-methylhonokiol as compared to honokiol parallels previous observations made in other systems of potentiated pharmacological activity of 4-O-methylhonokiol over honokiol. GENERAL SIGNIFICANCE The results point to the use of 4-O-methylhonokiol as a lead for GABAA receptor potentiation and corroborate the use of M. grandiflora seeds against convulsions in Mexican folk medicine.

North Atlantic Eddy-Driven Jet in interglacial and glacial winter climates

The atmospheric westerly flow in the North Atlantic (NA) sector is dominated by atmospheric waves or eddies generating via momentum flux convergence, the so-called eddy-driven jet. The position of this jet is variable and shows for the present-day winter climate three preferred latitudinal states: a northern, central, and southernposition in the NA. Here, the authors analyze the behavior of the eddy-driven jet under different glacial and interglacial boundary conditions using atmosphere–land-only simulations with the CCSM4 climate model. As state-of-the-art climate models tend to underestimate the trimodality of the jet latitude, the authors apply a bias correction and successfully extract the trimodal behavior of the jet within CCSM4. The analysis shows that during interglacial times (i.e., the early Holocene and the Eemian) the preferred jet positions are rather stable and the observed multimodality is the typical interglacial character of the jet. During glacial times, the jet is strongly enhanced, its position is shifted southward, and the trimodal behavior vanishes. This is mainly due to the presence of the Laurentide ice sheet (LIS). The LIS enhances stationary waves downstream, thereby accelerating and displacing the NA eddy-driven jet by anomalous stationary momentum flux convergence. Additionally, changes in the transient eddy activity caused by topography changes as well as other glacial boundary conditions lead to an acceleration of the westerly winds over the southern NA at the expenseof more northernareas. Consequently, bothstationaryand transient eddiesfoster the southward shift of the NA eddy-driven jet during glacial winter times.

Optical recording of calcium currents during impulse conduction in cardiac tissue

We explore the feasibility of obtaining a spatially resolved picture of Ca2+Ca2+ inward currents (ICaICa) in multicellular cardiac tissue by differentiating optically recorded Ca2+Ca2+ transients that accompany propagating action potentials. Patterned growth strands of neonatal rat ventricular cardiomyocytes were stained with the Ca2+Ca2+ indicators Fluo-4 or Fluo-4FF. Preparations were stimulated at 1 Hz, and Ca2+Ca2+ transients were recorded with high spatiotemporal resolution (50  μm50  μm, 2 kHz analog bandwidth) with a photodiode array. Signals were differentiated after appropriate digital filtering. Differentiation of Ca2+Ca2+ transients resulted in optically recorded calcium currents (ORCCs) that carried the temporal and pharmacological signatures of L-type Ca2+Ca2+ inward currents: the time to peak amounted to ∼2.1  ms∼2.1  ms (Fluo-4FF) and ∼2.4  ms∼2.4  ms (Fluo-4), full-width at half-maximum was ∼8  ms∼8  ms, and ORCCs were completely suppressed by 50  μmol/L50  μmol/LCdCl2CdCl2. Also, and as reported before from patch-clamp studies, caffeine reversibly depressed the amplitude of ORCCs. The results demonstrate that the differentiation of Ca2+Ca2+ transients can be used to obtain a spatially resolved picture of the initial phase of ICaICa in cardiac tissue and to assess relative changes of activation/fast inactivation of ICaICa following pharmacological interventions.

A new chromanone derivative isolated from Hypericum lissophloeus (Hypericaceae) potentiates GABAA receptor currents in a subunit specific fashion.

A phytochemical investigation of the lipophilic extract of Hypericum lissophloeus (smoothbark St. John's wort, Hypericaceae) was conducted, resulting in the isolation and identification of a new chromanone derivative: 5,7-dihydroxy-2,3-dimethyl-6-(3-methyl-but-2-enyl)-chroman-4-one (1). This compound was demonstrated to act as a potent stimulator of currents elicited by GABA in recombinant α1β2γ2 GABAA receptors, with a half-maximal potentiation observed at a concentration of about 4μM and a maximal potentiation of >4000%. Significant potentiation was already evident at a concentration as low as 0.1μM. Extent of potentiation strongly depends on the type of α subunit, the type of β subunit and the presence of the γ subunit.

Barium in seawater and sediments from the Artic Ocean

As part of ongoing circulation studies in the Arctic, seawater samples for dissolved Ba concentrations were obtained during Sep.-Oct., 1992 at several locations in the Bering Strait, Eastern Chukchi and Southern Beaufort Seas. The results reveal a dynamic rang (10 to 150 nmol/kg) for this element in the Arctic equal to or greater than that in combined Atlantic, Indian and Pacific oceans. Lowest levels are observed in surface waters, with values tending to decrease northwards in the direction of currents generally flowing frorn the Bering Strait along the Alaskan coast. Low surfacc concentrations tend to be accompanied by relatively enriched near bottom levels. On the basis of these spatial distributions, hydrographic observations and a knowledge of its behavior in other marine settings, it appears that Ba can be significantly depleted from surface waters as a result of the highly seasonal biological aclivities over Arctic marginal shelves. Removal at the surface is counteracted to some extent by regeneration at depth or in the sediments and by riverine inputs. The biologically related drawdown is likely to enhance the contrast between 'background' surface Ba levels in the Arctic and waters imprinted by regeneration and/or rivers, These preliminary findings suggest that Ba holds particular promise for tracing river waters and the ventilation of halodine waters hy laterally sinking brines produced during ice formation over the shelves.