Melatonin-sulforaphane hybrid ITH12674 induces neuroprotection in oxidative stress conditions by a 'drug-prodrug' mechanism of action

Background and PurposeNeurodegenerative diseases are a major problem afflicting ageing populations; however, there are no effective treatments to stop their progression. Oxidative stress and neuroinflammation are common factors in their pathogenesis. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the master regulator of oxidative stress, and melatonin is an endogenous hormone with antioxidative properties that reduces its levels with ageing. We have designed a new compound that combines the effects of melatonin with Nrf2 induction properties, with the idea of achieving improved neuroprotective properties. Experimental ApproachCompound ITH12674 is a hybrid of melatonin and sulforaphane designed to exert a dual drug-prodrug mechanism of action. We obtained the proposed hybrid in a single step. To test its neuroprotective properties, we used different in vitro models of oxidative stress related to neurodegenerative diseases and brain ischaemia. Key ResultsITH12674 showed an improved neuroprotective profile compared to that of melatonin and sulforaphane. ITH12674 (i) mediated a concentration-dependent protective effect in cortical neurons subjected to oxidative stress; (ii) decreased reactive oxygen species production; (iii) augmented GSH concentrations in cortical neurons; (iv) enhanced the Nrf2-antioxidant response element transcriptional response in transfected HEK293T cells; and (v) protected organotypic cultures of hippocampal slices subjected to oxygen and glucose deprivation and re-oxygenation from stress by increasing the expression of haem oxygenase-1 and reducing free radical production. Conclusion and ImplicationsITH12674 combines the signalling pathways of the parent compounds to improve its neuroprotective properties. This opens a new line of research for such hybrid compounds to treat neurodegenerative diseases.