Hippocampal cannabinoid-1 receptor upregulation upon endothelin-B receptor deficiency: a neuroprotective substitution effect?
Endothelin (ETB)-receptors mediate anti-apoptotic actions. Lack of functional ETB-receptors leads to increased neuronal apoptosis in the hippocampus. The increased apoptosis must be compensated by other mechanisms, however, as ETB-deficient rats display normal overall brain morphology. To illuminate on brain plasticity in ETB-receptor deficiency, we studied the expression and function of another neuroprotective system, the cannabinoid CB1-receptors, in ETB-deficient hippocampus. We show that CB1 expression in hippocampus increases postnatally in all rats but that the increase in CB1-receptor expression is significantly higher in ETB-deficient compared to wildtype littermates. Neuronal apoptosis decreases during brain maturation but remains on a significantly higher level in the ETB-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) only in ETB-deficient neurons. We suggest that CB1-receptor upregulation in the ETB-mutant hippocampus reflects an attempt to compensate for the lack of ETB-receptors.
Unzicker
Christian
C
Division of Clinical Neuroscience, Max-Planck-Institute for Experimental Medicine, Göttingen, Germany.
Erberich
Heike
H
Moldrich
Gabriella
G
Woldt
Helge
H
Bulla
Jan
J
Mechoulam
Raphael
R
Ehrenreich
Hannelore
H
Sirén
Anna-Leena
AL
D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000502:physiology; D002478:Cells, Cultured; D013759:Dronabinol / Q000378:metabolism; D005260:Female; D005989:Glycerides / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000172:deficiency* / Q000235:genetics; D015854:Up-Regulation
D005989:Glycerides; D018696:Neuroprotective Agents; D043884:Receptor, Cannabinoid, CB1; D044023:Receptor, Endothelin B; C424442:noladin ether; D013759:Dronabinol