Cannabinoidrezeptor CB1 und Endothelin-B-Rezeptor: Interaktion im Hippokampus

Abstract

Cell membrane standing receptors are known to mediate antiapoptotic signalling in the brain of juvenile rats. This thesis illuminates the interaction between two cell membrane standing receptors CB1 and ET-B in the brain of Wistar-Imamichi rats. ET-B-receptors mediate anti-apoptotic actions. Lack of functional ET-B-receptors leads to increased neuronal apoptosis in the hippocampus. The increased apoptosis must be compensated by other mechanisms; however, as ET-B-deficient rats display normal overall brain morphology. To illuminate brain plasticity in ET-B-receptor deficiency, we study the expression and function of another neuroprotective system, the cannabinoid CB1-receptors, in a Wistar-Imamichi rat ET-B-subtraction model. CB1 and ET-B-receptors are known to play a role in neuronal cell survival in juvenile rats. We show that CB1 expression in the hippocampus increases postnatally in all rats but the increase in CB1-receptor expression is significantly higher in ET-B-deficient compared to wildtype littermates. A negative correlation between CB1 expression and cell death has been observed. Neuronal apoptosis decreases during brain maturation but remains on a significantly higher level in the ET-B-deficient compared to wildtype dentate. When investigating survival of hippocampal neurons in culture, we found significant protection against hypoxia-induced cell death with CB1-analogs (noladin, (9-tetrahydrocannabinol) in ET-B-deficient neurons. No protective effect has been shown by administration of THC in a Hypoxia/Ischemia-model with juvenile Wistar-Imamichi rats with a functional ET-B-receptor in vivo. The endogenous cannabinoid system plays a role in the substitution of ET-B deficiency in neuronal cells. This effect is not apparent in wildtype cells in vitro and juvenile rats in vivo. We suggest that CB1-receptor upregulation in the ET-B-mutant hippocampus reflects an attempt to compensate for the lack of ET-B-receptors. Even though there is no beneficial effect on cell survival in vitro in wildtype animals, there might be a future clinical relevance of these findings in diseases with ET-B downregulation like bacterial meningitis.