Dantrolene : From Malignant Hyperthermia to Alzheimer's Disease

Abstract

Dantrolene, a ryanodine receptor antagonist, is primarily known as the only clinically acceptable and effective treatment for Malignant Hyperthermia (MH). Inhibition of Ryanodine Receptor (RyR) by dantrolene decreases the abnormal calcium release from the Sarcoplasmic Reticulum (SR) or Endoplasmic Reticulum (ER), where RyR is located. Recently, emerging researches on dissociated cells, brains slices, live animal models and patients have demonstrated that altered RyR expression and function can also play a vital role in the pathogenesis of Alzheimer's Disease (AD). Therefore, dantrolene is now widely studied as a novel treatment for AD, targeting the blockade of RyR channels or another alternative pathway, such as the inhibitory effects of NMDA glutamate receptors and the effects of ER-mitochondria connection. However, the therapeutic effects are not consistent. In this review, we focus on the relationship between the altered RyR expression and function and the pathogenesis of AD, and the potential application of dantrolene as a novel treatment for the disease.

Keywords: Alzheimer’s disease; amyloid; calcium; dantrolene; mild cognitive impairment; ryanodine receptor..

Fig. (1).

The role of RyR in the AD pathology. The mutations of APP and PS disrupt Ca²⁺ homeostasis via overexpression of RyR. Aβ accumulation also causes post-translational modifications of RyR. RyR remodeling in turn enhanced βAPP processing and Aβ production, leading to neuronal death, synaptic structure and plasticity dysfunctions and learning and memory decline.