Morphofunctional effects of moderate forebrain ischemia combined with short-term hypoxia in rats - Protective effects of Cerebrolysin

Morphofunctional effects of combined moderate forebrain ischemia due to permanent bilateral carotid artery ligation and short-term systemic hypoxia in rats were investigated. Moreover, a putative effect of brain protection by Cerebrolysin (Cerebrolysin(R), EBEWE, Austria), a brain tissue hydrolysate containing a mixture of 85 % free amino acids and 15 % small peptides (MW < 10000), was studied. Eighty-seven adult Wistar rats (24 Cerebrolysin treated and 63 controls) were subjected to chronic moderate forebrain ischemia by permanent bilateral carotid artery ligation for 7 days. Twenty-four hours after the onset of ischemia, 56 of them underwent an additional hypoxic hypoxia (Fi(O2), = 0.08) of 15 min. A first group (19 out of 56 animals) received Cerebrolysin (every dose 2.5 ml/kg body weight sc.) after ligation, after hypoxia and then daily. A second group (6 out of 56 animals) received an equal volume of physiological saline after ligation and Cerebrolysin the first time after hypoxia and then once a day. An untreated control group (31 out 56 animals) received physiological saline. Changes in behavior were scored and elctrophysiological activity was quantified by spectral ECoG analysis before carotid artery ligation, before and after hypoxia, and once a day during the following 7 days. On the 7th day after hypoxia, the animals were sacrificed and the grade of histological damage was quantified by morphometry. After permanent carotid artery ligation, 20 out of 63 (31.7 %) untreated control animals died within 24 h but only 4 out of 20 (16.7 %) Cerebrolysin treated animals. However, Cerebrolysin had not detectable effect on mortality after the additional acute hypoxia. Within 24 h after hypoxia, ECoG power of the higher frequency ranges remained low (p < 0.05). Surviving animals showed a significantly higher ECoG power during and 15 min after hypoxia than those animals that died within 48 h after hypoxia (p < 0.05). All animals showed reduced behavioral activity (p < 0.01) 20 min after hypoxia, however, basal reflex responses were not altered. The major patterns of neuronal damage were coagulation necrosis and general sponginess of the neuropil which is a sign of brain edema. These changes occurred predominantly within the superolateral convexities of the pa rietal cortex, in the entorhinal and in the piriform cortex as well as in the CA1 and CA4 region and in the dentate gyrus of the hippocampus. The striatum and the origin nuclei of the brain nerves were also affected. We did not observe a relationship between behavior, ECoG depression and the extent of morphological damage after hypoxia nor did we find any protective effects of Cerebrolysin on these parameters. Rather it is suggested that the degree of ECoG depression immediately after hypoxic hypoxia could be a predictor for prognosis of animal survival. Cerebrolysin reduced the amount of early mortality which was caused by moderate global forebrain ischemia. However, no protective influences of the amount of brain tissue damage could be shown.