Damaged nerve fibers (axons) in the peripheral nervous system can regenerate themselves, but complete functional recovery often doesn’t occur. That’s because the Schwann cells responsible for regeneration stop providing support after about three months. If the restoration of nerve function, called reinnervation, hasn’t happened in that time, the axonal injury often results in lifelong incomplete recovery and can lead to nerve or neuropathic pain.
Researchers from the University of Cologne in Germany used cnicin from the blessed thistle plant on cultured cells, including human cells, and live animals to see whether it sped up nerve regeneration and reduced pain.
Like many plants that have been used medicinally for centuries, cnicin has been the subject of much recent research. Traditionally used to treat stomach aches, studies from the last 10 years have found that it’s effective in treating lung inflammation in chronic obstruction pulmonary disease (COPD), impedes the viral replication of SARS-CoV-2, and can block the detection of painful stimuli by sensory nerves.
In the current study, the researchers crushed the sciatic nerve of mice, rats, and rabbits. They then gave the animals doses of either cnicin or parthenolide, a chemically similar compound from the same plant family (Asteraceae). Parthenolide, extracted from feverfew, has traditionally been used to treat a wide range of ailments. However, previous studies have found that parthenolide is poorly absorbed when taken orally, so it needs to be given as an intravenous injection.
Separately, sensory neurons from the animals were cultured and treated with cnicin. Eye (retinal) cells from mice and humans were cultured and treated to test whether cnicin promoted the regeneration of central nervous system (CNS) neurons as well.
The researchers found that cnicin significantly promoted axon growth in sensory neurons in different species. The effect was dependent on the dose given. As was seen in the sensory neurons, cnicin also increased the average length of outgrowths called neurites from the CNS neurons of mice and humans. Neurites ultimately grow into axons.
In animals with a crushed sciatic nerve, substantial axon regeneration was seen with doses of intravenous cnicin compared to the control groups. The researchers assessed muscle reinnervation following sciatic injury. Motor recovery was determined by calculating the static sciatic index (SSI), a way of assessing the recovery of function after sciatic nerve injury in animal models. Allodynia – pain due to a stimulus that wouldn’t usually cause pain, such as a light feather touch, common in neuropathy – was also measured to assess sensory recovery.
Daily repeated doses of cnicin significantly improved the SSI score and touch sensitivity compared to controls, with the first measurable improvements in motor function seen as early as four days post-injury. Improvements in sensory function were detectable seven days post-injury. Cnicin significantly enhanced skin and muscle innervation 10 days after the crush injury. Oral administration of cnicin also accelerated functional recovery with the same efficacy as intravenous injection, while oral parthenolide had no effect due to its poor bioavailability.
Cnicin-treated rats reached pre-injury SSI scores after 35 days, while the control group needed another seven days to achieve the same scores. Also, at 35 days, touch sensation in the treatment group had returned to pre-surgery levels, whereas the control group needed 49 days. Cnicin was well-tolerated and the animals showed no signs of toxicity.
The researchers tested whether delaying treatment with cnicin still promoted axon regeneration. They found that delaying treatment by five days meant that motor and sensory recovery was slower, but the effect was only slightly weaker than in rats that’d received cnicin for the first five days post-injury and placebo after that. The researchers concluded that while continuous treatment with cnicin showed the best results, delayed treatment was still effective.
“In conclusion, the current study underscores the potential of cnicin as a readily administered oral compound for augmenting axonal regeneration,” said the researchers. “It demonstrates a substantial in vivo and in vitro impact across multiple species, including an effect on cultured primary human nerve cells, even at remarkably low dosages. Consequently, cnicin is a promising candidate for further drug development to treat nerve damage and promote regeneration.”
The study was published in the journal Phytomedicine.
Source: University of Cologne
