Anandamide is an endogenous ligand for central cannabinoid receptors and is released after neuronal depolarization. Anandamide increased protein tyrosine phosphorylation in rat hippocampal slices and neurons in culture. The action of anandamide resulted from the inhibition of adenylyl cyclase and cyclic adenosine 3', 5'-monophosphate-dependent protein kinase. One of the proteins phosphorylated in response to anandamide was an isoform of pp125-focal adhesion kinase (FAK+) expressed preferentially in neurons. Focal adhesion kinase is a tyrosine kinase involved in the interactions between the integrins and actin-based cytoskeleton. Thus, anandamide may exert neurotrophic effects and play a role in synaptic plasticity.
In the present study, we show that cultured rat brain macrophages release a soluble factor that stimulates the migration of bone marrow-derived macrophages, as determined by an in vitro chemotaxis assay. A checkerboard analysis indicated that most of this effect resulted from a polarized migration of the cells (chemotactic phenomenon), rather than in an increase in cell motility (chemokinesis). This activity was significantly decreased by an immune serum directed against the rat monocyte chemoattractant protein-1 (chemokine MCP-1). Northern blot analysis demonstrated expression of the MCP-1 gene in cultured brain macrophages, but its absence in unstimulated bone marrow-derived macrophages. Up-regulation of MCP-1 expression was observed when lipopolysaccharide was added to cultured brain macrophages, a peak occurring after a 6 h period of stimulation. Also, inflammatory cytokines such as interleukin (IL)-1 beta, colony stimulating factor-1, tumour necrosis factor-alpha and IL-6 individually increased the basal level of MCP-1 mRNA. Subsequently, we demonstrated the in vivo production of MCP-1 in the adult rat brain following injury induced by a local injection of kainic acid. MCP-1 synthesis was localized in both astrocytes and brain macrophages. These results suggest that the activation of resting microglial cells into brain macrophages and their subsequent secretion of chemokines could contribute to the mechanism(s), leading to the infiltration of the CNS by blood-derived monocytes, as observed in several pathologies.
Numerous observations strongly support the hypothesis that dopaminergic neurons could be particularly vulnerable to an impairment of their energetic metabolism. In order to demonstrate the existence of such a selective vulnerability, the toxic effects of rotenone, an inhibitor of complex I of the respiratory chain, and of glutamate, which is very likely involved in the neurotoxicity induced by an energetic stress, were analyzed on cultured mouse mesencephalic neurons. Toxicity toward dopaminergic and GABAergic neurons was compared by measuring the residual uptakes of dopamine and GABA. Exposure to 5 nM rotenone for 6 hr or to a low concentration of glutamate (100 microM) for 1 hr did not lead to a high selective toxic effect on dopaminergic neurons. In contrast, dopaminergic neurons were three times less resistant to the sequential exposure to rotenone and glutamate than GABAergic neurons. A particular resistance of mesencephalic GABAergic neurons to the synergistic toxic effects of rotenone and glutamate was ruled out since two other neuronal types, the striatal cholinergic and GABAergic neurons, displayed the same weak vulnerability as the mesencephalic GABAergic neurons. This selective toxic effect of glutamate on rotenone- pretreated dopaminergic neurons was blocked by either AMPA or NMDA receptor antagonists and mimicked by combined treatment with AMPA and NMDA, or by NMDA alone when the medium was deprived of Mg2+ ions. Moreover, this NMDA-selective neurotoxicity was critically dependent on the presence of a physiological extracellular sodium concentration, since the use of choline chloride instead of sodium chloride had a protective effect on dopaminergic neurons.
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