The Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnIIITE-2-PyP5+ (AEOL-10113) has proven effective in treating oxidative stress-induced conditions including cancer, radiation damage, diabetes, and central nervous system trauma. The ortho cationic pyridyl nitrogens of MnTE-2-PyP5+ are essential for its high antioxidant potency. The exceptional ability of MnIIITE-2-PyP5+ to dismute O2.- parallels its ability to reduce ONOO- and CO3-. Decreasing levels of these species are considered its predominant mode of action, which may also involve redox regulation of signaling pathways. Recently, Ferrer-Sueta at al. (Free Radic. Biol. Med. 41:503-512; 2006) showed, with submitochondrial particles, that>or=3 microM MnIIITE-2-PyP5+ was able to protect components of the mitochondrial electron transport chain from peroxynitrite-mediated damage. Our study complements their data in showing, for the first time that micromolar mitochondrial concentrations of MnIIITE-2-PyP5+ are obtainable in vivo. For this study we have developed a new and sensitive method for MnIIITE-2-PyP5+ determination in tissues. The method is based on the exchange of porphyrin Mn2+ with Zn2+, followed by the HPLC/fluorescence detection of ZnIITE-2-PyP4+. At 4 and 7 h after a single 10 mg/kg intraperitoneal administration of MnIIITE-2-PyP5+, the mice (8 in total) were anesthetized and perfused with saline. Mitochondria were then isolated by the method of Mela and Seitz (Methods Enzymol.55:39-46; 1979). We found MnIIITE-2-PyP5+ localized in heart mitochondria to 2.95 ng/mg protein. Given the average value of mitochondrial volume of 0.6 microL/mg protein, the calculated MnIIITE-2-PyP5+ concentration is 5.1 microM, which is sufficient to protect mitochondria from oxidative damage. This study establishes, for the first time, that MnIIITE-2-PyP5+, a highly charged metalloporphyrin, is capable of entering mitochondria in vivo at levels sufficient to exert there its antioxidant action; such a result encourages its development as a prospective therapeutic agent.

[1] Many high-latitude modeling studies utilize the horizontal ionospheric Hall current in calculating ground-based magnetic perturbations, but low-latitude and midlatitude studies should include current systems such as the magnetospheric, field-aligned, and Pedersen currents. Recently, by including all these current systems, a more precise groundbased perturbation calculator has been implemented in the Space Weather Modeling Framework. Using this new method, ground-based perturbations generated by different current systems are analyzed at low, middle, and high latitudes. As a result of the current systems, MLT-UT maps of ground-based perturbations are studied. Furthermore, nine storms events are simulated at more than 20 low-latitude and midlatitude magnetometer locations and compared with observational ground-based perturbations. These studies show that for specifying the northward component of the ground magnetic perturbations, the inclusion of magnetospheric, field-aligned, and Pedersen current is important and improves the prediction significantly over the prediction only considering the Hall current in the calculation. The improvement is the most during the storm main phase. However, for the vertical and eastward components of the perturbations, which were typically smaller than the northward component, the inclusion of these current systems actually made the specifications worse because the ring current in the model rotates more toward the dayside than in reality.

Heavy ions of ionospheric origin (O+) play an important role in altering global magnetospheric dynamics. While the heavy ions mainly originate from the dayside cusp and the nightside auroral region, the impact of these heavy ions on magnetospheric dynamics has not been differentiated. Controversy also remains on the role of heavy ions on tail stability and their energization mechanism in the magnetosphere. Two global MHD simulations are carried out to investigate the influence of heavy ion outflow from different source regions on reconnection rates, tail stability, and ring current energization. The local reconnection rate at the subsolar point and the total dayside reconnection rate are reduced after the outflow begins, but the decrease is more significant when the outflow comes out of the cusp region. Furthermore, the magnetotail is more disturbed when heavy ions flow out of the dayside cusp region as opposed to the nightside auroral zone. This implies that the role of O+ on tail stability is not definitively positive or negative; instead, the location of the source of heavy ions may be important in determining tail dynamics. Finally, the simulation reveals that the heavy ions originating from the dayside cusp region experience first adiabatic heating while traveling from the tail reconnection site toward the Earth and then further energization caused by flow braking near the outer boundary of the ring current.

[1] Geomagnetically induced currents (GICs) can disrupt power grid operations, causing significant interference for many people; therefore, predictions of ground-based magnetic perturbations and their time derivatives are quite important. This study quantifies how well the University of Michigan's Global MHD code predicts approximately 150 ground-based magnetometer traces for a number of storm-time intervals. It is found that in order to accurately represent the magnetic perturbation, Biot-Savart integrals over the entire hemisphere are needed, especially when calculating the vertical component. The 4 May 1998 storm is examined in detail. The code compares well with some stations, quantified by a normalized root mean squared error and cross correlation, while missing even the general trends for other stations. When multiple magnetometer station perturbations are averaged together, the model does an adequate job in the north and vertical components but reverses the trends in the eastward component. The code does significantly better when comparing an AL-like index but does not have as strong a variation as the actual data. Comparison of dB/dt in a wide window rather than simultaneously shows better model performance in capturing events but worse in yielding false alarms. It is further found that the MHD code models the magnetic perturbations better in the summer hemisphere than in the winter hemisphere.Citation: Yu, Y., and A. J. Ridley (2008), Validation of the space weather modeling framework using ground-based magnetometers, Space Weather, 6, S05002,