Physiological effects and brain protection by hypothermia and Cerebrolysin after moderate forebrain ischemia in rats

Abstract

The "therapeutic window" of neuroprotective intervention due to hypoxic-ischemic brain injuries are initial disturbances of the neuronal function in regions of only moderate decrease of local cerebral blood flow (ICBF). Because of limited effects of single therapeutic principles therapeutic combinations should be tested. Neuroprotective effects of mild hypothermia and the nootropic drug Cerebrolysin (Cerebrolysin, EBEWE, Austria) on ICBF and development of brain edema were used. Four groups of adult Wistar rats (untreated and Cerebrolysin treated animals with 35 degrees C and 37 degrees C rectal temperature) were subjected to moderate forebrain ischemia by permanent bilateral carotid artery ligation for 6 h. The ICBF was measured continuously in the frontal and the occipital cortex by a 2-channel Laser Doppler flowmeter. The ECoG was derived from 4 ECoG leads above the frontal and occipital cortex and quantified by spectral analysis. Six hours after the onset of ischemia, the function of the blood-brain barrier to proteins was determined by staining with Evans Blue, the animals were sacrificed and the brain water content was estimated by gravimetry. Permanent bilateral carotid artery ligation led to an abrupt ICBF reduction to between 40-50% of baseline levels. Within a few minutes, however, the ICBF increased again to 50-80% of the baseline. The reduced spectral band power of the ECoG was correlated with the decreased ICBF values (p < 0.05) that indirectly indicated changes in the energy state of the neurons (p < 0.05). Changes in the ECoG appeared only with a delay of approximately 4 sec after the onset of ICBF reduction. Six hours after the onset of ischemia, a cytotoxic brain edema was shown in the frontoparietal cortex and hippocampus. Reducing the temperature by 2 degrees C diminished the decrease in ICBF between 10 min and 2 h after the onset of ischemia (p < 0.05). This effect was noted in the frontal but not in the occipital cortex. Furthermore, mild hypothermia prevented the loss of ECoG spectral power in the beta, alpha and theta bands (p < 0.05) as well as the development of cytotoxic brain edema. Cerebrolysin prevented the development of brain edema, too, both under normo- and hypothermic conditions. The ICBF was restored to higher levels in the occipital cortex in comparison both to the normothermic Cerebrolysin treated and hypothermic untreated rats (p < 0.05). This effect of Cerebrolysin was associated with only slight changes in ECoG, indicating that the neuronal activity state and the energy supply was obviously not decisively influenced. In conclusion, moderate ICBF reduction in rats to about 50-80% of baseline values was detectable in the ECoG by using spectral analysis. This reduction led to the development of cytotoxic brain edema in rats within 6 h. Thus, hypothermia prevents the development of cytotoxic brain edema. Cerebrolysin enhanced the effects of hypothermia on ICBF reduction and on the development of brain edema.