BACKGROUND AND PURPOSE: Subarachnoid haemorrhage (SAH) is an uncommon and severe subtype of stroke, but the availability of drugs for its treatment is limited. Enhanced autophagy is believed to attenuate SAH pathology
however, autophagy level is tentatively up-regulated and then down-regulated after SAH onset in mice. Clemastine, a first-generation histamine H1R antagonist, is believed to persistently enhance autophagy. However, the precise mechanism of clemastine in the treatment of SAH remains largely elusive. EXPERIMENTAL APPROACH: Haemoglobin-induced neuron injury model and autologous-blood-injected SAH-model mice were used to investigate the effects of clemastine in vitro and in vivo, respectively. The expressions of Nrf2/Keap1 and autophagy-related proteins were detected using western blotting and immunofluorescence. Neuronal injury and hyperoxide level were measured via Fluoro-Jade C and dihydroethidium staining. Neurological behaviours were evaluated using modified Garcia Scale, beam balance test, Morris water maze, Y-maze and novel object recognition test. The structures of autophagosomes and mitochondria were visualised using transmission electron microscope. The binding sites of clemastine was predicted and verified using database and drug affinity-responsive target stability. KEY RESULTS: Clemastine ameliorated SAH pathogenesis in vivo and in vitro. Moreover, the intraperitoneal injection of clemastine and its oral administration reduced neuronal death and improved cognitive deficits in SAH-model mice. Mechanistically, clemastine directly bound to muscarinic acetylcholine receptor M4, prevented Nrf2 degradation via Nrf2/Keap1/SQSTM1 pathway and promoted Nrf2 nuclear translocation, thus enhancing autophagy-related gene transcription and autophagy activation. CONCLUSIONS AND IMPLICATIONS: Clemastine can attenuate SAH pathology via the activation of Nrf2/SQSTM1 autophagy and could be a useful therapeutic in the context of SAH.