Delivering the medication dantrolene through the nose rather than the mouth may help the medication penetrate the brain more effectively, potentially maximizing its therapeutic benefits in the treatment of neurodegenerative diseases, like Alzheimer’s disease.
In a first-of-its-kind study, researchers in the 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 findings represent a major step forward in addressing a question about the potential use of dantrolene–which is often used to treat patients with muscle spasms–in the treatment of neurodegenerative diseases.
Although research has shown dantrolene can inhibit or slow the progression of many neurodegenerative diseases in animal models, the medication–when given orally or intravenously–only has limited penetration into the central nervous system, hampering its effectiveness and viability as a long-term treatment option.
“We know the use of dantrolene in the treatment of Alzheimer’s disease or stroke would require chronic administration,” said the study’s corresponding author Huafeng Wei, MD, PhD, an associate professor of Anesthesiology and Critical Care at Penn.
“Rather than using high doses of the oral form, which could increase the risk of adverse side effects, we sought to test the effectiveness of the intranasal approach via pre-clinical studies in mice.”
In the United States, about 5.8 million people are living with Alzheimer’s disease, a degenerative brain disease and the sixth leading cause of death in the nation.
Previous studies involving cell and animal models have found that dantrolene can improve mental function and provide other therapeutic benefits in the treatment of Alzheimer’s, as well as other neurodegenerative diseases, such as Huntington’s disease, Amyotrophic Lateral Sclerosis (ALS), and stroke.
In this study, the Penn team examined two groups of mice–one group received the oral form of the medication, while the other received the intranasal form–to identify whether delivering dantrolene via the nose would yield increased penetration into the brain.
Researchers measured the concentration of dantrolene in the brain and blood at the eight intervals: 10, 20, 30, 50, 70, 120, 150 and 180 minutes following administration.
Additionally, the team gave separate groups of mice the intranasal form of dantrolene three times a week for either three weeks or four months to identify any potential adverse side effects associated with chronic use.
The findings represent a major step forward in addressing a question about the potential use of dantrolene–which is often used to treat patients with muscle spasms–in the treatment of neurodegenerative diseases.
Researchers found mice who received dantrolene through the nose had a much higher concentration of the medication in their brain–for a much longer period of time–compared to mice who received the oral form.
In fact, the medication was still in their brain at the 180-minute mark, whereas there was no trace of the medication at the 120-minute mark in mice that received the medication orally.
Chronic use of the medication did not appear to impair motor function or the ability to smell. However, researchers note additional studies are needed to compare the side effects and toxicity of the different methods.
The findings build on results from an earlier proof-of-concept study, conducted at Penn, that Wei presented at the 2019 Alzheimer’s Association International Conference.
That study showed that intranasal dantrolene treatment in mice provided better therapeutic effects on cognition and memory loss than administering the medication subcutaneously.
Researchers found the intranasal approach was particularly more effective in mice who had already experienced the onset of Alzheimer’s disease-like symptoms.
“While more research in animal models is needed to further evaluate the safety and effectiveness of this approach, our hope is that this will ultimately lead to a new therapeutic approach that can be studied in patients with various neurodegenerative diseases, including Alzheimer’s,” Wei said.
Additional Penn authors include Jintao Wang, MD, PhD, Yun Shi, MD, Shuchun Yu, MD, PhD, Yan Wang, MD, PhD, Qingcheng Meng, PhD, Ge Liang, MD and Maryellen F. Eckenhoff, PhD.
Funding: The research was supported, in part, by grants from the National Institute of General Medicine Science (R01GM084979) and the National Institute of Aging (R01AG061447).
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% [1, 2].
Dantrolene, in various animal models, has been shown to be neuroprotective in many neurodegenerative diseases, including cerebral ischemia [3, 4], Huntington’s disease [5], amyotrophic lateral sclerosis [6], trauma [7], and seizers [8].
Dantrolene has also been demonstrated to reduce mortality in an animal model of sepsis [9]. One early study of intraperitoneal injections of dantrolene in a familiar Alzheimer’s disease (FAD) animal model demonstrated improved neuropathology, but failed to examine cognition [10].
Recently, it has been demonstrated that both subcutaneous (SQ) and oral dantrolene have reduced amyloid pathology and memory loss in different Alzheimer disease (AD) animal models [11–13].
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.
Although dantrolene is a promising treatment for neurodegenerative diseases in various animal models, a major obstacle is the limited penetration of dantrolene into the CNS. Dantrolene has two properties, though, working in its favor to penetrate the CNS
It is both lipid soluble and has a molecular weight of 314 g/mol. Lipid soluble drugs and drugs with molecular weights under 400 g/mol are expected to penetrate the blood brain barrier (BBB) readily.
However, the ability of dantrolene to pass the BBB is still controversial with evidence for [14], and against [15] passage.
The use of dantrolene for the treatment of AD or stroke would require chronic administration. Due to the limited penetration of dantrolene into the CNS from the blood, oral administration requires high doses of dantrolene to reach the therapeutic concentration threshold in the CNS, making patients prone to first pass liver metabolism and drug toxicity.
Therefore, development of a method for elevating the dantrolene brain concentration for a longer duration is crucial to the future use of dantrolene as a treatment for Alzheimer’s and other neurodegenerative diseases.
The intranasal route for drug delivery is an emerging, viable, and non-invasive means for treating CNS disorders. Intranasal drugs have been shown to rapidly enter the brain along both the olfactory and trigeminal nerves via both intracellular and extracellular routes [16–18]. Intranasal drug delivery, targeted to the CNS, has been shown to reduce systemic exposure and adverse systemic side effects [19].
In this study, we have demonstrated that intranasal administration of dantrolene in mice significantly increased the concentration and duration of dantrolene in the brain, compared to oral administration. This may provide a new approach to maximize the potential neuroprotective effects of dantrolene in various neurodegenerative diseases, while minimizing its toxicity and side effects.
Source:
University of Pennsylvania
