Injecting tiny particles carrying adapalene — an activator of the retinoic acid signaling pathway — to the brain and spinal cord of mice with amyotrophic lateral sclerosis (ALS) can prolong animals’ survival, improve their motor function, and prevent neurodegeneration, a study shows.
The study, “Intravenously Administered, Retinoid Activating Nanoparticles Increase Lifespan and Reduce Neurodegeneration in the SOD1G93A Mouse Model of ALS,” was published in the journal Frontiers in Bioengineering and Biotechnology.
The retinoic acid (RA) signaling pathway plays a central role in the development and maintenance of the central nervous system (CNS, comprising the brain and spinal cord). In the adult CNS, this signaling cascade is involved in synaptic plasticity, learning, memory, neurogenesis, and regeneration.
Synaptic plasticity refers to the ability of synapses — the junction between two nerve cells that allows them to communicate — to strengthen or weaken over time; neurogenesis is the process by which new neurons are formed.
RA signaling also has been implicated in several neurodegenerative disorders, including ALS. In a previous study, the same group of researchers found the retinoic acid receptor beta (RAR-beta) was present at high levels in spinal cord motor neurons — the nerve cells responsible for controlling voluntary muscles — in post-mortem patient samples.
They also found that motor neurons that contained high levels of RAR-beta were negative for several markers of cell death, suggesting that RA signaling could be promoting neuron survival (neuroprotective role).
“We found that activation of retinoid signaling through the RAR-beta receptor significantly increased survival of primary motor neurons [cultured in a lab dish] in response to oxidative stress [cellular damage due to high levels of oxidant molecules]. Together, these data suggest that activation of retinoid signaling may be an adaptive, protective response to cell damage in ALS,” the researchers wrote.
Now, the team sought to explore the therapeutic potential of adapalene — a RAR-beta activator they previously had found to display neuroprotective properties in vitro — using a mouse model of ALS. Adapalene (brand names Differin, Plixda) is an FDA-approved medication for the topical treatment of acne and cervical neoplasia, due to its skin regenerative properties.
“Adapalene, like most retinoids, is poorly water soluble, which has thus far prevented effective drug delivery [in living organisms],” the researchers wrote.
To overcome this problem, the team used a nanoparticle composed of poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) to encapsulate adapalene. In addition to safely transporting adapalene to its final destination in the animals’ CNS, these nanoparticles were designed to allow the substance to be slowly released into the tissues.
The team administered the nanoparticles containing adapalene through an intravenous (into-the-vein) injection, three times weekly, starting when mice were 61 days old. In parallel, they also administered a matched concentration of nanoparticles that did not contain adapalene (placebo) to other animals that served as controls.
Intravenous administration of nanoparticles containing adapalene at a dose of 3 mg/kg led to a strong and widespread activation of RA signaling in the animals’ CNS, including in the cerebellum, cortex, and striatum. (The cerebellum is a brain region responsible for body balance; the striatum is a region involved in the control of body movements; and the cortex is a region that controls functions like speech, thought, and memory.)
Repeated intravenous injections of nanoparticles containing adapalene at the same dosage prolonged ALS mice’s median survival from 164 to 171 days. Maximum lifespan also was prolonged from 183 to 199 days in treated animals.
In addition, a battery of behavioral tests showed that treatment led to improvements in animals’ motor function compared to controls.
Importantly, compared to control animals, those treated with nanoparticles containing adapalene had a greater number of motor neurons in the spinal cord when they reached 104 and 143 days old, indicating treatment prevented neurodegeneration. They also found that treatment prevented denervation (loss of nerve supply), as well as atrophy (shrinkage) of muscle fibers to some extent.
In general, treatment was well-tolerated by the animals. No toxicity signals were observed at any point over the course of the study.
“Taking these results in sum, these studies simultaneously validate retinoid signaling as a therapeutic target and advance nanomedicine as a significant approach in the treatment of ALS,” the researchers wrote.
“Given the known biocompatibility of PLGA, including in nanoparticle form, and the early evidence for safety and efficacy described here, further development of this platform could advance Adap-NPs [adapalene nanoparticles] as a novel clinical approach for improved treatment of ALS,” they concluded.
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