HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damage.

Ischemic stroke is amongst the leading causes of death and disabilities. The available treatments are suitable for only a fraction of patients and thus novel therapies are urgently needed. Blockage of one of the cerebral arteries leads to massive and persisting inflammatory reaction contributing to the nearby neuronal damage. Targeting the detrimental pathways of neuroinflammation has been suggested to be beneficial in conditions of ischemic stroke. Nuclear receptor 4A-family (NR4A) member Nurr1 has been shown to be a potent modulator of harmful inflammatory reactions, yet the role of Nurr1 in cerebral stroke remains unknown. Here we show for the first time that an agonist for the dimeric transcription factor Nurr1/retinoid X receptor (RXR), HX600, reduces microglia expressed proinflammatory mediators and prevents inflammation induced neuronal death in in vitro co-culture model of neurons and microglia. Importantly, HX600 was protective in a mouse model of permanent middle cerebral artery occlusion and alleviated the stroke induced motor deficits. Along with the anti-inflammatory capacity of HX600 in vitro, treatment of ischemic mice with HX600 reduced ischemia induced Iba-1, p38 and TREM2 immunoreactivities, protected endogenous microglia from ischemia induced death and prevented leukocyte infiltration. These anti-inflammatory functions were associated with reduced levels of brain lysophosphatidylcholines (lysoPCs) and acylcarnitines, metabolites related to proinflammatory events. These data demonstrate that HX600 driven Nurr1 activation is beneficial in ischemic stroke and propose that targeting Nurr1 is a novel candidate for conditions involving neuroinflammatory component.

Economy in track runners and orienteers during path and terrain running.

The aims of the present study were to assess running economy in track runners and orienteers and to identify the factors responsible for any differences. The participants were 11 orienteers and 10 track runners of similar age, body mass, maximal oxygen uptake and training background. However, the orienteers included heavy terrain running in their daily training, whereas the track runners ran almost entirely on the roads and tracks. Maximal oxygen uptake and running economy were calculated during horizontal path running and during cross-country running in rough terrain with steep hills, using a telemetric system (K2, Cosmed, Italy). Running economy during path running was 217+/-12 and 212+/-14 ml x kg(-1) x km(-1) (mean +/- s) in the orienteers and the track runners, respectively. Running economy was impaired by 41-52% in heavy terrain (P < 0.05), and was less pronounced in the orienteers than in the track runners (88+/-18 vs 109+/-26 ml x kg(-1) x km(-1); P < 0.05). In conclusion, the better running economy of orienteers when changing from horizontal path to heavy terrain running could be an innate ability, or it could be speculated that specific training may improve running economy, indicating the importance of specific training for orienteers.

Orienteering performance and ingestion of glucose and glucose polymers.

The benefit of glucose polymer ingestion in addition to 2.5 per cent glucose before and during a prolonged orienteering competition was studied. The final time in the competition in the group ingesting 2.5 per cent glucose (group G, n = 10) was 113 min 37 s +/- 8 min 11 s, and in the group which had additionally ingested glucose polymer (group G + GP, n = 8) 107 min 18s +/- 4 min 41 s (NS). One fifth (21 per cent) of the time difference between the two groups was due to difference in orienteering errors. Group G + GP orienteered the last third of the competition faster than group G (p less than 0.05). The time ratio between the last third of the competition and the first third of the competition was lower in group G + GP than in group G (p less than 0.05). After the competition, there was statistically insignificant tendency to higher serum glucose and lower serum free fatty acid concentrations in group G + GP, and serum insulin concentration was higher in group G + GP than in group G (p less than 0.05). Three subjects reported that they exhausted during the competition. These same three subjects had the lowest serum glucose concentrations after the competition (2.9 mmol.1(-1), 2.9 mmol.1(-1), 3.5 mmol.1(-1] and all of them were from group G. It is concluded that glucose polymer syrup ingestion is beneficial for prolonged psychophysical performance.