Time-dependent metabolomic profiling of Ketamine drug action reveals hippocampal pathway alterations and biomarker candidates

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has fast-acting antidepressant activities and is used for major depressive disorder (MDD) patients who show treatment resistance towards drugs of the selective serotonin reuptake inhibitor (SSRI) type. In order to better understand Ketamine's mode of action, a prerequisite for improved drug development efforts, a detailed understanding of the molecular events elicited by the drug is mandatory. In the present study we have carried out a time-dependent hippocampal metabolite profiling analysis of mice treated with Ketamine. After a single injection of Ketamine, our metabolomics data indicate time-dependent metabolite level alterations starting already after 2 h reflecting the fast antidepressant effect of the drug. In silico pathway analyses revealed that several hippocampal pathways including glycolysis/gluconeogenesis, pentose phosphate pathway and citrate cycle are affected, apparent by changes not only in metabolite levels but also connected metabolite level ratios. The results show that a single injection of Ketamine has an impact on the major energy metabolism pathways. Furthermore, seven of the identified metabolites qualify as biomarkers for the Ketamine drug response

The Expression and Activity of Cathepsins D, H and K in Asthmatic Airways

Tumstatin is an anti-angiogenic collagen IV α3 fragment, levels of which are reduced in the airways of asthmatics. Its reduction may be due to the degradation by extracellular matrix (ECM) proteases. Cathepsins play a role in ECM remodelling, with cathepsin D, H and K (CTSD, CTSH and CTSK) being associated with lung diseases. CTSD modulates the NC1 domains of collagen molecules including tumstatin, while CTSH and CTSK are involved in ECM degradation. The role of these cathepsins in the regulation of tumstatin in the lung has not previously been examined. We demonstrated that CTSB, D, F, H, K, L and S mRNA was expressed in the airways. Quantification of immunohistochemistry showed that there is no difference in the global expression of CTSD, CTSH and CTSK between asthmatics and non-asthmatics. CTSD and CTSK, but not CTSH had the capacity to degrade tumstatin. No difference was observed in the activity of CTSD and H in bronchoalveolar lavage fluid of asthmatic and non-asthmatics, while CTSK was undetectable. This indicates that while CTSD possesses the potential to directly regulate tumstatin, and thus angiogenesis through this mechanism however, it is not likely to be involved in the dysregulation of tumstatin found in asthmatic airways. © 2013 Faiz et al

Electrical resistivity image of the South Atlantic continental margin derived from onshore and offshore magnetotelluric data

We present a deep electrical resistivity image from the passive continental margin in Namibia. The approximately 700 km long magnetotelluric profile follows the Walvis Ridge offshore, continues onshore across the Kaoko Mobile Belt and reaches onto the Congo Craton. Two-dimensional inversion reveals moderately resistive material offshore, atypically low for oceanic lithosphere, reaching depths of 15–20 km. Such moderate resistivities are consistent with seismic P wave velocity models, which suggest up to 35 km thick crust. The Neoproterozoic rocks of the Kaoko Mobile Belt are resistive, but NNW-striking major shear-zones are imaged as subvertical, conductive structures in the upper and middle crust. Since the geophysical imprint of the shear zones is intact, opening of the South Atlantic in the Cretaceous did not alter the middle crust. The transition into the cratonic region coincides with a deepening of the high-resistive material to depths of more than 60 km

3-D Magnetotelluric Image of Offshore Magmatism at the Walvis Ridge and Rift Basin

Highlights • We report on marine 3D Magnetotelluric study on Walvis Ridge • Derived 3D electrical resistivity model shows a large scale resistive zone, which we link to crustal extension due to local uplift. It might indicate the location where the hot-spot impinged on the crust prior to rifting • Smaller scale resistive region is attributed to magma ascent during rifting • Rift basin is identified by low resistivity region The Namibian continental margin marks the starting point of the Tristan da Cunha hotspot trail, the Walvis Ridge. This section of the volcanic southwestern African margin is therefore ideal to study the interaction of hotspot volcanism and rifting, which occurred in the late Jurassic/early Cretaceous. Offshore magnetotelluric data image electromagnetically the landfall of Walvis Ridge. Two large-scale high resistivity anomalies in the 3-D resistivity model indicate old magmatic intrusions related to hot-spot volcanism and rifting. The large-scale resistivity anomalies correlate with seismically identified lower crustal high velocity anomalies attributed to magmatic underplating along 2-D offshore seismic profiles. One of the high resistivity anomalies (above 500 Ωm) has three arms of approximately 100 km width and 300 km to 400 km length at 120 degree angles in the lower crust. One of the arms stretches underneath Walvis Ridge. The shape is suggestive of crustal extension due to local uplift. It might indicate the location where the hot-spot impinged on the crust prior to rifting. A second, smaller anomaly of 50 km width underneath the continent ocean boundary may be attributed to magma ascent during rifting. We attribute a low resistivity anomaly east of the continent ocean boundary and south of Walvis Ridge to the presence of a rift basin that formed prior to the rifting

Ketamine's antidepressant effect is mediated by energy metabolism and antioxidant defense system.

Fewer than 50% of all patients with major depressive disorder (MDD) treated with currently available antidepressants (ADs) show full remission. Moreover, about one third of the patients suffering from MDD does not respond to conventional ADs and develop treatment-resistant depression (TRD). Ketamine, a non-competitive, voltage-dependent N-Methyl-D-aspartate receptor (NMDAR) antagonist, has been shown to have a rapid antidepressant effect, especially in patients suffering from TRD. Hippocampi of ketamine-treated mice were analysed by metabolome and proteome profiling to delineate ketamine treatment-affected molecular pathways and biosignatures. Our data implicate mitochondrial energy metabolism and the antioxidant defense system as downstream effectors of the ketamine response. Specifically, ketamine tended to downregulate the adenosine triphosphate (ATP)/adenosine diphosphate (ADP) metabolite ratio which strongly correlated with forced swim test (FST) floating time. Furthermore, we found increased levels of enzymes that are part of the 'oxidative phosphorylation' (OXPHOS) pathway. Our study also suggests that ketamine causes less protein damage by rapidly decreasing reactive oxygen species (ROS) production and lend further support to the hypothesis that mitochondria have a critical role for mediating antidepressant action including the rapid ketamine response