Senolytics Alleviate Low Back Pain in Mice

Senolytics Decrease Low Back Pain in Mice

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 promising results that could pave the way for future treatments.

A Painful Global Problem

Globally, low back pain is responsible for the most time spent living with some form of disability, significantly reducing quality of life and costing billions of dollars annually due to economic and health care burdens.

• Low back pain is often attributed to intervertebral disc degeneration (IVD), which is linked with the accumulation of senescent cells.
• These senescent cells produce the senescence-associated secretory phenotype (SASP), creating a pro-inflammatory environment that exacerbates IVD.

Removing senescent cells to lessen the SASP might be a viable remedy for this ongoing issue.

Mice with Back Pain

In human patients experiencing low back pain, the expression and protein levels of the sparc gene are reduced in degenerating intervertebral discs. This study utilized a mouse model with a deleted sparc gene, a model that develops early-onset low back pain and disc degeneration akin to human conditions.

Gene expression analysis and a SASP factor release assay revealed a significant number of differentially expressed genes when comparing the discs of wild-type mice and those lacking the sparc gene. Notably, 10 out of the 15 SASP factors tested were elevated in these modified mice.

Relieving the Pain

The key to any treatment lies in translating molecular changes into palpable pain reduction. After an 8-week treatment period, results were promising:

• The mice lacking the sparc gene experienced progressive low back pain.
• A separate group received weekly doses of o-vanillin, RG-7112, or a combination of both at varying doses.
• After four weeks, treatment showed a marked improvement in low back discomfort, cold sensitivity, and radiating pain, with even more significant enhancements noted at the eight-week mark.

Reducing SASP and Senescence

All 10 of the SASP factors increased due to the absence of the sparc gene decreased post-treatment with o-vanillin and RG-7112. The combination of these senotherapeutics yielded additive effects, especially when used at full doses.

A significant reduction in senescent cells was noted, with a 40% decrease achieved with single-drug treatment and an additional 25% reduction when combining drugs.

Fixing Bones and Discs

Low back pain is multifaceted, often related to additional issues such as low bone density (osteopenia). The researchers focused on assessing the trabecular part of the vertebrae in 9-month-old mice lacking the sparc gene, finding detrimental effects on bone density and thickness compared to wild-type mice.

While treating these conditions, intervertebral disc volume was also assessed; results indicated that the volume in the sparc-deficient mice was approximately 34% lower than that in wild-type mice. Treatment with combinations of drugs showed significant improvements (around 27% increase in disc volume).

Pain Mediators

The researchers explored the mediators of pain sensation within the nervous system, focusing on the spinal cord dorsal horn, which transmits sensory information including pain to the brain. Mice without the sparc gene exhibited larger senescent areas in this region compared to wild-type counterparts.

• Treatment with o-vanillin and RG-7112 resulted in a 24% to 30% reduction of senescent areas, while the drug combination's effectiveness led to a 64% reduction.
• The combination also reduced biomarkers associated with spinal neuronal activity and signaling.

As stated by the researchers, “These results suggest that senotherapeutics could be contributing to reducing back pain by decreasing pain-related neuroplasticity.”

Safe and Effective, but Needs Testing in Humans

This study indicates that senolytic drugs o-vanillin and RG-7112 hold promise as treatments for low back pain and related disorders involving senescent cells. Moreover, the study suggests that these compounds may help to slow or prevent IVD degeneration.

While the natural compound o-vanillin is known for its anti-inflammatory properties and safety profile, RG-7112 has exhibited adverse effects when used in higher doses typically for cancer treatment. In this study, lower doses were applied without significant side effects. Future research should focus on optimizing dosing regimens and drug delivery methods to mitigate any potential side effects.

Literature Cited

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