Associated degeneration of ventral tegmental area dopaminergic neurons in the rat nigrostriatal lactacystin model of parkinsonism and their neuroprotection by valproate

AbstractParkinson’s disease (PD) manifests clinically as bradykinesia, rigidity, and development of a resting tremor, primarily due to degeneration of dopaminergic nigrostriatal pathways in the brain. Intranigral administration of the irreversible ubiquitin proteasome system inhibitor, lactacystin, has been used extensively to model nigrostriatal degeneration in rats, and study the effects of candidate neuroprotective agents on the integrity of the dopaminergic nigrostriatal system. Recently however, adjacent extra-nigral brain regions such as the ventral tegmental area (VTA) have been noted to also become affected in this model, yet their integrity in studies of candidate neuroprotective agents in the model have largely been overlooked. Here we quantify the extent and distribution of dopaminergic degeneration in the VTA of rats intranigrally lesioned with lactacystin, and quantify the extent of VTA dopaminergic neuroprotection after systemic treatment with an epigenetic therapeutic agent, valproate, shown previously to protect dopaminergic SNpc neurons in this model. We found that unilateral intranigral administration of lactacystin resulted in a 53.81% and 31.72% interhemispheric loss of dopaminergic SNpc and VTA neurons, respectively. Daily systemic treatment of lactacystin lesioned rats with valproate however resulted in dose-dependant neuroprotection of VTA neurons. Our findings demonstrate that not only is the VTA also affected in the intranigral lactacystin rat model of PD, but that this extra-nigral brain region is substrate for neuroprotection by valproate, an agent shown previously to induce neuroprotection and neurorestoration of SNpc dopaminergic neurons in this model. Our results therefore suggest that valproate is a candidate for extra-nigral as well as intra-nigral neuroprotection

Studies on the Mechanisms of Chemical Leukaemogenesis

Following a single injection of MNU into “intact” mice, a high incidence of leukaemia (90%) is obtained, with a 50% induction time of 200 days. Immunological studies indicate that the θ antigen is expressed on the leukaemic cells. Thymectomized MNU treated mice had a 50% induction time of 500 days, and the incidence was somewhat lower. Leukaemias failed to develop in MNU treated T lymphocyte deficient animals and in lethally irradiated, or thymectomized lethally irradiated mice reconstituted with MNU treated bone marrow. It is suggested that the T lymphocytes rather than the haemopoietic stem cells or pre-T cells are the “target cells” in MNU leukaemogenesis

The Post-Pericenter Evolution of the Galactic Center Source G2

In early 2014 the fast-moving near-infrared source G2 reached its closest approach to the supermassive black hole Sgr A* in the Galactic Center. We report on the evolution of the ionized gaseous component and the dusty component of G2 immediately after this event, revealed by new observations obtained in 2015 and 2016 with the SINFONI integral field spectrograph and the NACO imager at the ESO VLT. The spatially resolved dynamics of the Br$\gamma$ line emission can be accounted for by the ballistic motion and tidal shearing of a test-particle cloud that has followed a highly eccentric Keplerian orbit around the black hole for the last 12 years. The non-detection of a drag force or any strong hydrodynamic interaction with the hot gas in the inner accretion zone limits the ambient density to less than a few 10$^3$ cm$^{-3}$ at the distance of closest approach (1500 $R_s$), assuming G2 is a spherical cloud moving through a stationary and homogeneous atmosphere. The dust continuum emission is unresolved in L'-band, but stays consistent with the location of the Br$\gamma$ emission. The total luminosity of the Br$\gamma$ and L' emission has remained constant to within the measurement uncertainty. The nature and origin of G2 are likely related to that of the precursor source G1, since their orbital evolution is similar, though not identical. Both object are also likely related to a trailing tail structure, which is continuously connected to G2 over a large range in position and radial velocity.Comment: 17 pages, 12 figures; accepted for publication in Ap