Neuroprotective effects of dantrolene in neurodegenerative disease: Role of inhibition of pathological inflammation

Abstract

Neurodegenerative diseases (NDs) refer to a group of diseases in which slow, continuous cell death is the main pathogenic event in the nervous system. Most NDs are characterized by cognitive dysfunction or progressive motor dysfunction. Treatments of NDs mainly target alleviating symptoms, and most NDs do not have disease-modifying drugs. The pathogenesis of NDs involves inflammation and apoptosis mediated by mitochondrial dysfunction. Dantrolene, approved by the US Food and Drug Administration, acts as a RyRs antagonist for the treatment of malignant hyperthermia, spasticity, neuroleptic syndrome, ecstasy intoxication and exertional heat stroke with tolerable side effects. Recently, dantrolene has also shown therapeutic effects in some NDs. Its neuroprotective mechanisms include the reduction of excitotoxicity, apoptosis and neuroinflammation. In summary, dantrolene can be considered as a potential therapeutic candidate for NDs.

Keywords: Alzheimer’s disease; Apoptosis; Calcium; Cognitive dysfunction; Progressive motor dysfunction; Pyroptosis.

Fig. 1.

Pyroptosis. Glutamate excitotoxicity result in pathological and excessive activation of NMDAR and/or AMPAR, leading to pathological Ca2+ influx into cytosol space, increasing cytosolic and mitochondria Ca2+ concentration, mitochondrial reactive oxygen species (ROS) and then cytosol ROS. Over activation of RyR results in excessive Ca2+ release from ER and subsequent ER stress. The upstream Ca2+ dysregulation eventually results in activation of NLRP3 inflammasome, activated caspase-1 and cleaved GSDMD to generate N terminal GSDMD and releasing IL-1beta and IL-18 to generate pathological inflammation.