Role of virus-induced neuropeptides in the brain in the pathogenesis of rabies.

Rabies virus (RABV) infection is characterized by the rapid neuronal spread of RABV into the CNS before a protective immune response is raised. Therefore, a typical feature of RABV infection is the paucity of inflammatory reactions in the brain. Here we examined whether the induction of immunosuppressive neuropeptides, in particular CGRP, may contribute to the ability of RABV to evade immune responses. RABV infection of mice caused a strong induction of calcitonin gene-related peptide (CGRP) in neurons and fibres in the neocortex as well as in the dentate gyrus and CA1 region of the hippocampus although RABV did not infect neurons in which CGRP expression was upregulated. Neuropeptide Y (NPY) or vasoactive intestinal peptide (VIP) expressing neurons also were not infected by RABV. In contrast, somatostatin neurons were infected by RABV. There was evidence for an RABV-induced increase of VIP and somatostatin but not of NPY. To test how CGRP expression is related to TNFalpha-induced enhancement of CNS innate and adaptive immunity during RABV infection, we used recombinant RABVs that contained either an active (SPBN-TNFalpha(+)) or an inactive (SPBN-TNFalpha(-)) TNFalpha gene. As compared to SPBN-TNFalpha(-), infection with SPBN-TNFalpha(+) attenuated the induction of CGRP but simultaneously enhanced induction of the invariant chain of MHC II, microglial activation and T cell infiltration. In conclusion, distinct neuropeptidergic neurons in the brain are remarkably spared from RABV infection suggesting a pivotal role of neuropeptides during CNS virus infection. Given the inhibitory effect of CGRP on antigen presentation, we propose that the strong RABV-induced upregulation of CGRP in the brain may contribute to the mechanism by which RABV escapes immune detection. Targeting the expression of neuropeptides, in particular CGRP, that are induced during RABV infection may open a new avenue for therapeutic intervention in human rabies.

Endocannabinoids and the regulation of bone metabolism.

In mammals, including humans, bone metabolism is manifested as an ongoing modelling/remodelling process whereby the bone mineralised matrix is being continuously renewed. Recently, the main components of the endocannabinoid system have been reported in the skeleton. Osteoblasts, the bone forming cells, and other cells of the osteoblastic lineage, as well as osteoclasts, the bone resorbing cells, and their precursors, synthesise the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG). CB(1) cannabinoid receptors are present in sympathetic nerve terminals in close proximity to osteoblasts. Activation of these CB(1) receptors by elevated bone 2-AG levels communicates brain-to-bone signals as exemplified by traumatic brain injury-induced stimulation of bone formation. In this process, the retrograde CB(1) signalling inhibits noradrenaline release and alleviates the tonic sympathetic restrain of bone formation. CB(2) receptors are expressed by osteoblasts and osteoclasts. Their activation stimulates bone formation and suppresses bone resorption. CB(2)-deficient mice display a markedly accelerated age-related bone loss. Ovariectomy-induced bone loss can be both prevented and rescued by a CB(2) specific agonist. Hence, synthetic CB(2) ligands, which are stable and orally available, provide a basis for developing novel anti-osteoporotic therapies, free of psychotropic effects. The CNR2 gene (encoding CB(2)) in women is associated with low bone mineral density, offering an assay for identifying females at risk of developing osteoporosis.