Hippocampal Cannabinoid-1 Receptor Upregulation Upon Endothelin-B Receptor Deficiency: A Neuroprotective Substitution Effect?

Abstract

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.

Retinal removal up‐regulates cannabinoid CB1 receptors in the chick optic tectum

“…Our data are in agreement with a transient protection hypothesis for the endocannabinoid system; we observed a peak of CB 1 expression after 7 days of survival time in visual structures. Several studies indeed demonstrate increased levels of endocannabinoids and up-regulation of CB 1 receptors in brain injury models in rats and mice (Romero et al, 2000;Hansen et al, 2001;Panikashvili et al, 2001;van der Stelt et al, 2001;Unzicker et al, 2005). For example, Hansen and collaborators (2001), using rats with mild neurodegenerative processes induced by changes of glutamatergic neurotransmission and of endocannabinoid homeostasis, found higher levels of anandamide, but not of 2-AG, and increased binding and mRNA of CB 1 receptors.…”

“…Several studies demonstrated increased levels of endocannabinoids and up-regulation of CB 1 receptors in brain damage models in rats and mice (Romero et al, 2000;Hansen et al, 2001;Panikashvili et al, 2001;van der Stelt et al, 2001;Unzicker et al, 2005). The observed accummulation of endocannabinoids and CB 1 up-regulation could represent a protective response contributing to rescue neurons from death.…”

The CB1 Cannabinoid Receptor Mediates Excitotoxicity-induced Neural Progenitor Proliferation and Neurogenesis

“…The CB 1 receptor is ideally located to regulate neural cell fate decisions as it is present along the neural lineage from progenitor to differentiated cells (9,23), its expression increases after injury in various in vivo models (37,38), and its activation regulates neural cell survival and proliferation (11,12), migration, and axonal growth (23). In addition, the synthesis of the endogenous ligands AEA and 2AG is increased after different types of brain insults including excitotoxicity and during neuronal activity (9,10).…”

Cell Type Specific Signalling by Hematopoietic Growth Factors in Neural Cells

“…We have previously shown by using this method that at day 6 in culture rat hippocampal neurons grow extended neuronal processes, express markers for mature neurons (MAP-2, NF-200), display high vulnerability to hypoxia and show less than 10% contamination with astrocytes [23,[27][28][29]. Briefly, hippocampi were removed, digested with solution containing papain and DNAse and subjected to density gradient centrifugation.…”