Intranasal nasal dantrolene nanoparticles alone, or in combination with lithium, can provide protection against depression and dementia with minimal or no side effects.
Major depression disorder (MDD) affects 350 million patients in the world and about 16% of the population in USA. In addition, up to 50% of Alzheimer’s disease (AD) patients suffer from depression while depression could be a risk factor for development of AD.
Dantrolene and lithium are the FDA approved drugs for treatment of malignant hyperthermia and bipolar disease, respectively. Both compounds have considerable clinical information about their clinical use and safety. However, lithium has a narrow therapeutic window, rendering it vulnerable to some side effects/organ toxicity.
Previously
Dr. Wei had discovered that intranasal administration of dantrolene nanoparticles led to an increased retention in the brain and decreased blood concentrations as compared to oral delivery. Dantrolene delivered intranasally led to reduction of memory loss and AD pathologies in AD animal models (
Docket #18-8664). Now it has been demonstrating that intranasal dantrolene alone or lithium nanoparticles can abolish signs of depression in wild type and AD animal models. This novel method of administration provides an opportunity to achieve a better therapeutic effect in CNS while reducing side effects and could potentially be used for treatment of depressions and dementia.
The mechanism of dantrolene to treat major depressive disorder (MDD). Pathological activation of N-methyl-D-aspartate receptors (NMDAR) by glutamate in MDD leads to excessive Ca2+ influx into the cytosol, which can be inhibited by ketamine. Lipopolysaccharides (LPS) increase endogenous agonists of the ryanodine receptors (RyRs), cyclic ADP-ribose (cADPR), via the activation of toll-like receptor 4 (TLR4), leading to excessive Ca2+ release from the endoplasmic reticulum (ER) into the cytosol, which is exacerbated by the Ca2+ induced Ca2+ release (CICR) mechanism. The Alzheimer’s disease (AD) presenilin (ADPS) mutation renders RyR overactivation. Overall, the cytosolic ([Ca2+]c) and mitochondrial Ca2+ ([Ca2+]m) are significantly elevated in MDD, resulting in activation of Ca2+-dependent phospholipase A2 (cPLA2) and excess production of reactive oxygen species (ROS). This activates NLRP3, and consequently ,caspase-1 and the formation of N-terminal Gasdermin D (N-GSDMD). This eventually causes cell death by pyroptosis. Dantrolene inhibits RyRs, which restores neuronal Ca2+ homeostasis and prevents downstream events leading to MDD.