Intranasal dantrolene effective treatment of neurodegenerative disease.

US: Dantrolene, an antagonist of the ryanodine receptor (RYR) calcium (Ca2+) channel, which is located in the membrane of the sarcoplasmic reticulum (SR) in muscle cells and the endoplasmic (ER) reticulum in neurons, is clinically used to treat muscle spasticity and malignant hyperthermia (MH) in patients, reducing MH mortality from 64% to 1.4%.

Dantrolene has been demonstrated to be neuroprotective for multiple neurodegenerative diseases. Recently, it has been demonstrated that both subcutaneous (SQ) and oral dantrolene have reduced amyloid pathology and memory loss in different Alzheimer's disease (AD) animal models. It seems that excessive Ca2+ release from the SR/ER plays an important role in inducing and/or aggravating cell stress and damage, leading to eventual muscle or neuronal damage. This could be ameliorated by dantrolene. However, dantrolene's limited penetration into the CNS hampers its effectiveness as a neuroprotective agent.

As an effort to uncover this, researchers at Perelman School of Medicine (PSOM) at the University of Pennsylvania showed that administering dantrolene through the nose increased its brain concentration and duration in a mouse model of Alzheimer's disease without causing obvious adverse side effects. The results were published today in Plos One.

The concentration of dantrolene in the brain and plasma was measured at 10, 20, 30, 50, 70, 120, 150 and 180 minutes after administration. Separate cohorts of mice were given intranasal dantrolene (5mg/kg) or vehicle, 3 times/ week, for either 3 weeks or 4 months, to examine potential adverse side effects on olfaction and motor coordination, respectively.

Following are the key findings of the study:

• Dantrolene concentrations were sustained in the brain after intranasal administration for 180 min, while concentrations fell to zero at 120 min for oral administration.

• Chronic use of intranasal dantrolene did not impair olfaction or motor function in these mice.

• Blood-brain barrier pump inhibitors did not further increase dantrolene peak concentrations in the brain.

Hence the results suggested that Intranasal administration of dantrolene is an effective route to increase its concentration and duration in the brain compared to the oral approach, without any obvious side effects on olfaction or motor function.

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https://doi.org/10.1371/journal.pone.0229156