Intranasal delivering of dantrolene nanoparticles could potentially be used to inhibit memory loss and reduce amyloid plaques in patients with Alzheimer's disease. Problem: Alzheimer’s disease (AD) is a devastating neurodegenerative disease. The deficit in the development of new drugs targeting the amyloid pathology over the past several decades warrants exploration of alternative pathways that could be the primary cause of AD cognitive dysfunction. Solution: Disruption of intracellular calcium homeostasis by over activation of ryanodine receptor (RYRs) and/or NMDA receptors contributes to synaptic dysfunction even before the appearance of amyloid and tau pathology and symptoms of cognitive dysfunction in AD. Dr. Wei at the University of Pennsylvania has evaluated dantrolene, a ryanodine receptor antagonist, as a potential treatment for treatment of AD. Intranasal administrating of dantrolene nanoparticles showed improved brain uptake of dantrolene with significantly increased brain to blood concentration ratio, compared to commonly used oral or subcutaneous approach, and inhibited memory loss in AD animal models, with minimal side effects or organ toxicity with chronic use. Technology: Dr. Wei discovered that dantrolene, a well know inhibitor of ryanodine receptor calcium channel located on the endoplasmic reticulum membrane, was effective at restoring intracellular calcium homeostasis in AD. Intranasal use of dantrolene nanoparticles increased dantrolene brain concentration, promoted neuroprotective effects in CNS, decreased peripheral concentrations, and reduced peripheral side effects. These results suggest that intranasal dantrolene nanoparticles treatment can potentially be used to inhibit the learning and memory loss in AD patients, with minimal side effects or organ toxicity with chronic use. In addition, Dr. Wei has shown that intranasal use of dantrolene can reduce inflammation induced depression symptoms, which is highly prevalent in AD (Docket #24-10502). Advantages:
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Mechanisms of dantrolene and lithium synergetic neuroprotection in Alzheimer’s Disease (AD). Excessive elevation of glutamate in Alzheimer’s disease (AD) brain activates N-methyl-D-aspartate receptors (NMDARs) pathologically, leading to excessive Ca2+ influx into the cytosol. Alzheimer’s presenilin (ADPS) mutation pathologically increased numbers and function of ryanodine receptors (RyRs) and InsP3 receptors (InsP3Rs), resulting excessive Ca2+ release from endoplasmic reticulum (ER) into cytosol. Abnormally increased cytosol Ca2+ influx into mitochondria via voltage-dependent anion channel 1 (VDAC1), leading to Ca2+ overloading in mitochondria and subsequent impairment of electron transport chain (ETC) function and decreases of ATP production. Mitochondria Ca2+ overloading also results in excessive production of reactive oxygen species (ROS). Above mitochondria dysfunction results in neurodegeneration and impairment of neurogenesis, leading overall final cognitive dysfunction. Dantrolene and lithium combination provide synergetic inhibition of different Ca2+ channel overactivation, and therefore ameliorate Ca2+ dysregulation and associated AD pathologies and cognitive dysfunction synergistically.< Intellectual Property:
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Docket # 18-8664