Neuroprotection with or without erythropoiesis; sometimes less is more.

Erythropoietin (EPO) is a pleiotropic cytokine with a therapeutic potential that goes well beyond the treatment of anaemia. The study by Wang et al (2007b) examined the protective effects of EPO in a rat model of embolic stroke. The efficacy and haematological side effects of EPO were compared to those of a carbamylated EPO variant (CEPO). Treatment with EPO dose-dependently reduced infarct volume and improved long-term functional outcome. However, an increase in hematocrit was seen even for doses of EPO that did not offer neuroprotection. These data do not suggest the existence of a therapeutic window between effect and side effect for treatment with EPO. Treatment with CEPO was without haematological side effects.

Evaluation of CA1 damage using single-voxel 1H-MRS and un-biased stereology: Can non-invasive measures of N-acetyl-asparate following global ischemia be used as a reliable measure of neuronal damage?

Global brain ischemia provoked by transient occlusion of the carotid arteries (2VO) in gerbils results in a severe loss of neurons in the hippocampal CA1 region. We measured the concentration of the neuron specific N-acetyl-aspartate, [NAA], in the gerbil dorsal hippocampus by proton MR spectroscopy (1H-MRS) in situ, and HPLC, 4 days after global ischemia. The [NAA] was correlated with graded hippocampus damage scoring and stereologically determined neuronal density. A basal hippocampal [NAA] of 8.37+/-0.10 and 9.81+/-0.44 mmol/l were found from HPLC and 1H-MRS, respectively. HPLC measurements of [NAA] obtained from hippocampus 4 days after 2VO showed a 20% reduction in the [NAA] following 4 min of ischemia (P<0.001). 1H-MRS measurements on gerbils subjected to 4 or 8 min of ischemia showed a similar 24% decline in the [NAA] (P<0.05). Thus, there was correlation between the HPLC and 1H-MRS determined NAA decline. There was also a significant correlation between 1H-MRS [NAA] and the corresponding reduction in CA1 neuronal density (P<0.004). In summary our findings show that single voxel 1H-MRS can be used as a supplement to histological evaluation of neuronal injury in studies after global brain ischemia. Accordingly, volume selective spectroscopy has a potential for assessment of neuroprotective therapeutic compounds/strategies with respect to neuronal rescue for delayed ischemic brain damage.

Is the 5-HT2C receptor a therapeutic target in cerebral ischaemia?

This study examines the effect of a 5-HT2C agonist (RO 60-0175, (s)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine) and a 5-HT2C antagonist (RO 43-0440, benzofuran-2-carboxamidine) for neuroprotective activity in a rat model of global cerebral ischaemia. A mini-osmotic pump implanted subcutaneously delivered 0.25 mg/kg/hr. Seven days after ischaemia the rats were sacrificed and the damage in the CA1 pyramidal cell layer in hippocampus was estimated and the treated groups were compared with vehicle groups. Pretreatment with the 5-HT2C agonist RO 60-0175 significantly increased the damage, whereas the 5-HT2C antagonist RO 43-0440 had no effect on the cell damage. Measurement of the core temperature in a RO 60-0175-treated group of rats revealed no effect compared to a vehicle-treated group. Thus the aggravation of damage in the RO 60-0175-treated group cannot be explained by temperature effect. Our data do not indicate the 5-HT2C receptor as a therapeutic target in cerebral ischaemia.

Neuroprotective effect of 8-OH-DPAT in global cerebral ischemia assessed by stereological cell counting.

The neuroprotective effect of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was tested in a 2-vessel occlusion model in rats. The post-ischemic core temperature was carefully monitored for 24 h. After 7 days of survival, the viable CA1 neurons were counted in an 8-OH-DPAT (125 microg/kg/h) and vehicle-treated group using the optical fractionator method. The vehicle-treated ischemic rats had a median number of dorsal CA1 neurons of 49,900 whereas the 8-OH-DPAT-treated ischemic rats had a significant lower median number of dorsal CA1 neurons 105,200 (P=0. 018). 8-OH-DPAT significantly lowered the core temperature compared to the vehicle-treated group during the 24-h post-ischemic period. Hypothermia is proposed as a possible explanation of the neuroprotective effect of 8-OH-DPAT.