Ergolide Regulates Microglial Activation and Inflammatory-Mediated Dysfunction: A Role for the Cysteinyl Leukotriene Pathway

Neurodegenerative diseases are characterised by the progressive loss of neurons, leading to a decline in specific brain functions. Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent, affecting approximately 60 million people worldwide. The pathogenesis of these diseases is complex, combining inflammatory, oxidative, and excitotoxic processes that result in neuronal dysfunction and death. Despite recent advances, there is currently no cure for AD and PD. Available therapies demonstrate limited efficacy, highlighting the continuing need for novel therapeutic approaches. Ergolide, a naturally occurring sesquiterpene lactone from the Inula brittanica plant, has shown immunoregulatory properties in systemic immune cells and potential applications in certain cancers. This study examines whether the therapeutic effects of ergolide extend to the brain. We explored its mechanisms of action in vitro, and its capacity to restore behavioural integrity in zebrafish models of inflammation and neurotoxicity in vivo. We report the ability of ergolide to attenuate inflammatory cytokine and nitric oxide (NO) production from microglia in response to Toll-like Receptor activation. We further propose a role for the NFκB and cysteinyl leukotriene (CysLT) pathways in ergolide-mediated regulation of microglial activation. Ergolide did not protect against oxidative-induced neuronal death in vitro or mitigate seizure activity in zebrafish. Instead, we revealed a pro-oxidant and cytotoxic effect on neuroblastoma cells. Importantly, ergolide improved survival and alleviated the dysfunction in sensorimotor behaviour in a zebrafish model of inflammation. Our findings reveal a neuroprotective effect of ergolide, likely stemming from its immunoregulatory capacity. We also support further investigation of the CysLT pathway as a therapeutic target for neuroinflammatory-related disease.

NFκB; TLR; cytokines; microglia; nitric oxide; zebrafish larvae.