Patrick Pierre Michel

To study the anti‐inflammatory potential of the two synthetic cannabinoids 4′‐F‐CBD and HU‐910, we used post‐natal brain cultures of mouse microglial cells and astrocytes activated by reference inflammogens. We found that 4′‐F‐CBD and HU‐910 efficiently curtailed the release of TNF‐α, IL‐6, and IL‐1β in microglia and astrocytes activated by the bacterial Toll‐Like Receptor (TLR)4 ligand LPS. Upon LPS challenge, 4′‐F‐CBD and HU‐910 also prevented the activation of phenotypic activation markers specific to microglia and astrocytes, that is, Iba‐1 and GFAP, respectively. In microglial cells, the two test compounds also efficiently restrained LPS‐stimulated release of glutamate, a non‐cytokine inflammation marker for these cells. The immunosuppressive effects of the two cannabinoid compounds were concentration‐dependent and observable between 1 and 10 μM. These effects were not dependent on cannabinoid or cannabinoid‐like receptors. Both 4′‐F‐CBD and HU‐910 were also capable of restraining the inflammogenic activity of Pam3CSK4, a lipopeptide that activates TLR2, and of BzATP, a prototypic agonist of P2X7 purinergic receptors, suggesting that these two cannabinoids could exert immunosuppressive effects against a variety of inflammatory stimuli. Using LPS‐stimulated microglia and astrocytes, we established that the immunosuppressive action of 4′‐F‐CBD and HU‐910 resulted from the inhibition of ROS produced by NADPH oxidase and subsequent repression of NF‐κB‐dependent signaling events. Our results suggest that 4′‐F‐CBD and HU‐910 may have therapeutic utility in pathological conditions where neuroinflammatory processes are prominent.

Chlordecone (CLD) is an organochlorine pesticide (OCP) that is currently banned but still contaminates ecosystems in the French Caribbean. Because OCPs are known to increase the risk of Parkinson’s disease (PD), we tested whether chronic low-level intoxication with CLD could reproduce certain key characteristics of Parkinsonism-like neurodegeneration. For that, we used culture systems of mouse midbrain dopamine (DA) neurons and glial cells, together with the nematode C. elegans as an in vivo model organism. We established that CLD kills cultured DA neurons in a concentration- and time-dependent manner while exerting no direct proinflammatory effects on glial cells. DA cell loss was not impacted by the degree of maturation of the culture. The use of fluorogenic probes revealed that CLD neurotoxicity was the consequence of oxidative stress-mediated insults and mitochondrial disturbances. In C. elegans worms, CLD exposure caused a progressive loss of DA neurons associated with locomotor deficits secondary to alterations in food perception. L-DOPA, a molecule used for PD treatment, corrected these deficits. Cholinergic and serotoninergic neuronal cells were also affected by CLD in C. elegans, although to a lesser extent than DA neurons. Noticeably, CLD also promoted the phosphorylation of the aggregation-prone protein tau (but not of α-synuclein) both in midbrain cell cultures and in a transgenic C. elegans strain expressing a human form of tau in neurons. In summary, our data suggest that CLD is more likely to promote atypical forms of Parkinsonism characterized by tau pathology than classical synucleinopathy-associated PD.