Assessing the Therapeutic Properties of Novel Phytocannabinoid Compounds in Models of Neuroinflammation

Phytocannabinoids derived from the Cannabis sativa plant, have been identified as modulators of inflammation, in particular demonstrating anti-inflammatory and neuroprotective effects in neurological disorders. In this study the properties of several phytocannabinoids compounds (blinded for research purposes) were examined in Toll-like receptor (TLR)-mediated models of acute neuroinflammation. Neuroinflammation is a key pathophysiological feature of many acute and chronic brain diseases. These complex disorders have proven difficult to treat, however targeting the neuroinflammation may provide a therapeutic benefit. It manifests as a heightened immune response initiated by glial cells which induce neuronal dysfunction and subsequent disease progression. Inflammatory challenges include bacterial and viral pathogens, and endogenous damage signals. The inflammatory response initiated by such stimuli is largely mediated by glial cells and the activation of specific membrane-bound TLRs. TLR subtypes TLR2 and TLR4 are known to play primary roles in the pathogenesis of disorders associated with neuroinflammation, therefore offering an attractive target for therapeutic intervention. Strong links between neuroinflammation and neuronal hyperexcitability have also been identified, as inflammatory mediators are capable of driving neuronal activity. In this study we have revealed the potential of several phytocannabinoids compounds to significantly attenuate proinflammatory responses in microglial BV2 cells exposed to a TLR2 agonist. Moreover, we report that these effects extended to mitigation of TLR-mediated inflammatory responses in neuronal cell lines. Two compounds in particular were found to display antioxidant effects in neuronal cells subjected to an oxidative challenge. Potential mechanisms of action were assessed through targeting of specific signalling pathways previously reported to play a role in cannabinoid action. Furthermore, whole-cell electrophysiology was used to assess the impact of one lead phytocannabinoid on neuronal excitability and firing under control and inflammatory conditions as well as potassium (K+) currents that are important determinants of neuronal excitability. This compound was found to reduce action potential firing of CA1 pyramidal neurons under control conditions and mitigate inflammatory-induced hyperexcitability. Taken together these findings reveal the potential of plant-derived compounds to modulate immune and neuronal responses to TLR-mediated inflammatory conditions. These compounds demonstrated anti-inflammatory, antioxidant and potential antiepileptogenic effects which suggests therapeutic benefit, particularly in the context of neuroinflammation. In addition, further investigation would be required to understand the molecular mechanisms underlying these effects. Finally, the understanding of their therapeutic potential would greatly benefit from widening this study to include an in vivo investigation