Researchers have tested a synthetic and natural senolytic combination of RG-7112 and o-vanillin in mice with early-onset low back pain and disc degeneration. They observed reduced signs of back pain; decreased senescence and disc degeneration; and improvements in vertebral bone quality [1].
A painful global problem
Globally, low back pain is responsible for the most time that people spend living with some form of disability [2], reducing quality of life and losing billions of dollars a year due to its economic and health care costs [3, 4].
Low back pain is often caused by intervertebral disc degeneration (IVD), which, on the molecular level, is linked with the accumulation of senescent cells that produce the senescence-associated secretory phenotype (SASP). This creates a pro-inflammatory environment that further worsens IVD. Removing senescent cells, and thus ameliorating the SASP, may be a viable remedy for this.
In this study, the researchers used two senolytic drugs, the synthetic compound RG-7112 and the natural compound o-vanillin. This group has previously reported that RG-7112 and o-vanillin reduce senescence and SASP factors in intervertebral discs [5, 6]. In this study, they continued the exploration of these compounds’ anti-senescence and pain-reducing effects.
Mice with back pain
In human patients with low back pain, sparc gene expression and protein levels are reduced in degenerating intervertebral discs [7, 8]. Therefore, this study used a mouse model with a removed sparc gene. Those mice develop early-onset low back pain and disc degeneration, mainly in the lower back area, and they accumulate senescent cells in their intervertebral discs in a similar way as humans.
Gene expression analysis and a SASP factor release assay revealed many differentially expressed genes between the discs of wild-type mice and mice lacking the sparc gene. Many of those genes involved SASP factors or regulated senescence. Out of the 15 SASP factors that the researchers tested, 10 were increased in these modified mice. The researchers hypothesized that senolytics could be used to address these molecular changes, potentially leading to back pain reduction.
Relieving the pain
Reducing senescence is essential, but molecular changes must translate into actual pain reduction for the treatment to succeed. Therefore, the researchers tested pain reduction after 8 weeks of treatment.
Unlike wild-type mice, the animals without a functional sparc gene experienced low back pain, which worsened with time. Another sparc-less group received weekly oral doses of o-vanillin, RG-7112, or a combination at full or half doses.
Treatment improved low back discomfort, cold sensitivity, and radiating pain after just four weeks of treatment, and even more significant improvement was observed after eight weeks. The effects were enhanced in animals receiving drug combinations when at least one senotherapeutic was was administered at the full dose.
Reducing SASP and senescence
All of the 10 factors that were increased by the lack of a sparc gene were decreased by o-vanillin and RG-7112 treatment. The combination treatment of both senotherapeutics showed additive effects, but only when the senotherapeutics were used at the full, not half, dose.
The treatment also reduced the number of cells with senescence markers in intervertebral discs. The researchers observed around a 40% reduction in senescent cells for single-drug treatment. Combining drugs, with at least one taken at the full dose, increased the effect by around 25%.
Fixing bones and discs
Low back pain is complex, and several underlying problems might lead to it. One such possibility is low bone density (osteopenia). To assess bone health, the researchers focused on analyzing the trabecular part of the vertebrae, a segment at the end of the bone. Its structure is not solid; rather, it has many pores connected by rods and plates of bone tissue.
In the 9-month-old mice lacking the sparc gene, the bone density and thickness in the measured area was worse than in the wild-type mice. Single and combination of senotherapeutic treatments improved most measurements, suggesting that senolytic treatment enhances bone health, especially with combined drugs.
The researchers also assessed the health of intervertebral discs. The intervertebral disc volume of the 9-month-old mice lacking the sparc gene was around 34% lower than that of the wild-type mice. While single-compound treatment showed a trend toward improvements, combining the two at the full dose showed a significant improvement (~27%) in disc volume.
Treatment with o-vanillin and RG-7112 also improved the histological degeneration score of the discs, something that no drug had achieved before. Combining the drugs at their full doses showed an additive effect.
Pain mediators
The researchers also investigated the mediators of the pain sensation in the nervous system. They analyzed senescence markers in the spinal cord dorsal horn, which is the spinal cord area responsible for receiving sensory information, including pain, from the body and transmitting it to the brain. The dorsal horns of the mice lacking the sparc gene had significantly larger areas with senescence markers than the wild-type mice did.
Treatment with o-vanillin and RG-7112 led to a significant reduction (by 24 to 30%) of the senescent area, and the drug combination was even more effective (64% reduction compared to untreated mice without the sparc gene).
Previous research had also pointed to increased markers of spinal neuron activity and signalling in the dorsal horn of the spinal cord of mice lacking the sparc gene, possibly contributing to the pain. The treatment reduced the biomarker levels significantly, with the full-dose combination having an even higher effect, but drug combinations with lower doses varied in effect.
“These results suggest that senotherapeutics could be contributing to reducing back pain by decreasing pain-related neuroplasticity,” the researchers state, along with the fact that it could impact the activity of cells in the central nervous system.
Safe and effective, but needs testing in humans
This study has found that the senolytic drugs o-vanillin and RG- 7112 show promise as a treatment for low back pain or other painful disorders that involve senescent cells, especially when used in combination. The mouse results suggested “that o-vanillin, RG-7112, and their combination can slow or prevent IVD degeneration.”
The natural compound o-vanillin offers anti-inflammatory properties and a strong safety profile [9, 10]. RG-7112, when used in high doses for cancer treatment, has severe adverse effects [11]. However, the researchers used lower concentrations in this study and did not observe adverse effects. They point out that further studies should optimize their dosing and drug delivery strategies to minimize side effects.
Literature
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