Age-related neuroimmune signatures in dorsal root ganglia of a Fabry disease mouse model.

Pain in Fabry disease (FD) is generally accepted to result from neuronal damage in the peripheral nervous system as a consequence of excess lipid storage caused by alpha-galactosidase A (α-Gal A) deficiency. Signatures of pain arising from nerve injuries are generally associated with changes of number, location and phenotypes of immune cells within dorsal root ganglia (DRG). However, the neuroimmune processes in the DRG linked to accumulating glycosphingolipids in Fabry disease are insufficiently understood.Therefore, using indirect immune fluorescence microscopy, transmigration assays and FACS together with transcriptomic signatures associated with immune processes, we assessed age-dependent neuroimmune alterations in DRG obtained from mice with a global depletion of α-Gal A as a valid mouse model for FD. Macrophage numbers in the DRG of FD mice were unaltered, and BV-2 cells as a model for monocytic cells did not show augmented migratory reactions to glycosphingolipids exposure suggesting that these do not act as chemoattractants in FD. However, we found pronounced alterations of lysosomal signatures in sensory neurons and of macrophage morphology and phenotypes in FD DRG. Macrophages exhibited reduced morphological complexity indicated by a smaller number of ramifications and more rounded shape, which were age dependent and indicative of premature monocytic aging together with upregulated expression of markers CD68 and CD163.In our FD mouse model, the observed phenotypic changes in myeloid cell populations of the DRG suggest enhanced phagocytic and unaltered proliferative capacity of macrophages as compared to wildtype control mice. We suggest that macrophages may participate in FD pathogenesis and targeting macrophages at an early stage of FD may offer new treatment options other than enzyme replacement therapy.

Pharmacokinetics of Orally Applied Cannabinoids and Medical Marijuana Extracts in Mouse Nervous Tissue and Plasma: Relevance for Pain Treatment.

Cannabis sativa plants contain a multitude of bioactive substances, which show broad variability between different plant strains. Of the more than a hundred naturally occurring phytocannabinoids, Δ9-Tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) have been the most extensively studied, but whether and how the lesser investigated compounds in plant extracts affect bioavailability or biological effects of Δ9-THC or CBD is not known. We therefore performed a first pilot study to assess THC concentrations in plasma, spinal cord and brain after oral administration of THC compared to medical marijuana extracts rich in THC or depleted of THC. Δ9-THC levels were higher in mice receiving the THC-rich extract. Surprisingly, only orally applied CBD but not THC alleviated mechanical hypersensitivity in the mouse spared nerve injury model, favoring CBD as an analgesic compound for which fewer unwanted psychoactive effects are to be expected.