Beta-caryophyllene for nerve pain after chemotherapy - a natural treatment for neuropathy?

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The publication we are discussing today focuses on beta-caryophyllene (BCP) – a natural compound found in hemp, which may help alleviate neuropathic pain, especially pain caused by chemotherapy.

https://pmc.ncbi.nlm.nih.gov/articles/PMC10604080/

Introduction Overview – What the Beginning of the Article Covers
In the introduction, the authors describe what chemotherapy-induced peripheral neuropathy (CIPN) is and the mechanisms that cause it.

What is chemotherapy-induced neuropathy, and what are its symptoms?
Peripheral neuropathy is a common side effect of cancer treatment with drugs such as platinum compounds (e.g., oxaliplatin), taxanes, and vinca alkaloids. It can occur in two forms:

• Acute neuropathy – develops quickly during treatment.
• Chronic neuropathy – can last for months or even years after treatment.

Common symptoms of neuropathy include:

• Pain upon touch (hyperalgesia)
• Tingling or numbness (paresthesia)
• Unpleasant sensations like burning or electric shock (dysesthesia)
• Sudden, stabbing pains (lancinating pain)

The symptoms usually affect the hands and feet, creating a characteristic “glove and sock” pattern.

How common is neuropathy after oxaliplatin?
The introduction highlights that oxaliplatin (OXA), used in colorectal cancer treatment, frequently causes neuropathy:

• 98% of patients treated with oxaliplatin experience acute neuropathy.
• In FOLFOX therapy (leucovorin, fluorouracil, oxaliplatin), 71% of patients report neuropathy symptoms.
• 84% of patients report worsened quality of life due to neuropathy even two years after completing treatment.

What happens in the nerves during oxaliplatin-induced neuropathy (OIPN)?
The authors explain that oxaliplatin-induced neuropathy has several causes:

• DNA damage in nerve cells:
  Oxaliplatin binds to DNA in nerve cells, both in the nucleus and mitochondria. This disrupts their function and leads to cell death.

• Oxidative stress:
  An excess of harmful molecules – reactive oxygen species (ROS) – forms, damaging nerve cells.

• Neuroinflammation:
  Inflammatory cytokines accumulate in the spinal cord, such as:

  • TNF (tumor necrosis factor)
  • IL-1 beta (interleukin-1 beta)
    This leads to nerve damage and increased pain sensitivity.

• Disrupted nerve signal transmission:
  Oxaliplatin interferes with the function of:

  • Calcium channels (Ca²⁺)
  • Potassium channels (K⁺)
  • Sodium channels (Na⁺)
    This results in excessive pain signal transmission.

Why are CB2 receptors important in treating neuropathic pain?
The introduction also describes the role of CB2 receptors, which are part of the endocannabinoid system:

• CB2 receptors are primarily found in immune cells such as:

  • B lymphocytes
  • Natural killer (NK) cells
  • Monocytes and neutrophils
    In the nervous system, they are present in microglia (immune cells of the brain).

• CB2 receptor activation:

  • Reduces inflammation
  • Provides pain relief
  • Protects nerve cells from oxidative stress

Importantly, CB2 receptor activation does not cause psychoactive effects, which are typical of CB1 receptors.

What is beta-caryophyllene, and why is it gaining interest?
The introduction notes that researchers focused on beta-caryophyllene (BCP), a natural compound found in:

• Hemp
• Oregano
• Cinnamon
• Cloves
• Black pepper

Why is beta-caryophyllene special?

• Selectively activates CB2 receptors, providing anti-inflammatory and pain-relieving effects without psychoactive effects.
• Does not bind to CB1 receptors, which cause intoxicating effects.
• Also influences PPARγ receptors, crucial for regulating inflammation and cell protection.
• Acts as an antioxidant, reducing harmful free radicals.

Study Objective – What Did the Authors Aim to Investigate?
In the summary of the introduction, the authors state that the study aimed to:

• Examine the effect of beta-caryophyllene (BCP) in relieving pain, inflammation, and oxidative stress in mice with oxaliplatin-induced neuropathy (OIPN).
• Investigate the role of CB2 receptors to confirm if they are responsible for BCP’s pain-relieving effects.
• Assess BCP’s impact on oxaliplatin’s anti-cancer efficacy, ensuring it does not weaken cancer treatment.
• Evaluate the safety of BCP by checking if it causes changes in blood morphology.

Results of the Beta-Caryophyllene (BCP) Experiment in the Oxaliplatin-Induced Neuropathy (OIPN) Model:

Agnes et al. (2023). Supplementary Figure S1. β-Caryophyllene Inhibits Oxaliplatin-Induced Peripheral Neuropathy in Mice
Source: Antioxidants (Basel). 2023;12(10):1893. doi:10.3390/antiox12101893.
License: CC BY 4.0 https://creativecommons.org/licenses/by/4.0/.

Conclusions – What Does the Study Show?

Continuing our discussion of the publication, we now move on to its conclusion, where the authors summarize their findings and key takeaways. The aim of the study was to investigate whether beta-caryophyllene (BCP) could serve as effective support in treating oxaliplatin-induced peripheral neuropathy (OIPN) and whether it impacts chemotherapy efficacy.

Can Beta-Caryophyllene Be an Effective Treatment for Oxaliplatin-Induced Neuropathy?

The authors indicate that their research demonstrates beta-caryophyllene (BCP) as a promising supportive treatment for neuropathy caused by oxaliplatin (OIPN). The therapeutic action of BCP is based on:

• Activation of CB2 receptors, which reduces pain and inflammation.
• Regulation of inflammation and reduction of oxidative stress in the spinal cord.

Does Beta-Caryophyllene Weaken the Effect of Chemotherapy?

A crucial conclusion from the study is that BCP does not reduce the effectiveness of oxaliplatin (OXA) in combating cancer. Experiments conducted on tumor-bearing mice allowed the researchers to:

• Confirm that BCP does not interfere with oxaliplatin’s antitumor effect.
• Demonstrate that BCP does not affect white blood cell counts, indicating that it does not weaken the immune system during chemotherapy.

Does Beta-Caryophyllene Work Only Preventively or Also Therapeutically?

The research showed that beta-caryophyllene has both:

• Preventive effects – When administered at the start of therapy, it prevented the onset of pain (both mechanical and cold-induced).
• Therapeutic effects – When administered after the onset of neuropathy, it reduced existing pain.

This indicates that BCP not only protects nerves from damage but also alleviates symptoms after they appear.

Does Beta-Caryophyllene Block the Harmful Effects of Oxaliplatin?

The authors explain that BCP does not act by blocking oxaliplatin's genotoxic effect on neurons (i.e., it does not prevent the DNA damage caused by platinum). Instead, it:

• Disrupts pain signaling mechanisms and reduces pain hypersensitivity.
• Reduces sensitivity to touch and cold through CB2 receptor activation.

How Do the Results Compare with Other Studies on CB2 Receptors?

The authors reference results from other studies on CB2 receptor agonists in chemotherapy-induced neuropathy and compare the effects of beta-caryophyllene (BCP) with other CB2 receptor agonists:

In a model of paclitaxel (taxoid)-induced neuropathy:

• Beta-caryophyllene (BCP): Reduced mechanical pain and cold-induced pain, demonstrating an effect similar to synthetic CB2 agonists.
• CB2 agonist AM1710: Reduced responses to touch and cold in a paclitaxel-induced neuropathy model.
• CB2 agonist MDA7: Improved mechanical pain response, reducing sensitivity to painful stimuli.
• Mixed CB1/CB2 agonist CP55,940: Alleviated mechanical pain, highlighting that activating both CB1 and CB2 receptors can have an analgesic effect.

In a model of cisplatin (platinum compound)-induced neuropathy:

• CB2 agonist JHW-133: Significantly reduced mechanical pain in the cisplatin-induced neuropathy model.

Conclusion from Comparisons:

Beta-caryophyllene (BCP) exhibits pain-relieving effects comparable to synthetic CB2 receptor agonists, confirming that CB2 receptors are a key therapeutic target for treating chemotherapy-induced neuropathic pain.

Is Beta-Caryophyllene's Pain-Relieving Effect Related to CB2 Receptors?

To confirm that BCP’s effect is mediated through CB2 receptor activation, the authors performed experiments using selective CB2 agonists and antagonists:

• CB2 receptor antagonist (SR144528):

  • Blocked the pain-relieving effect of BCP for mechanical pain.
  • This confirms that BCP’s reduction of mechanical pain is CB2 receptor-dependent.

• Selective CB2 receptor agonist (GW405538):

  • Reduced mechanical pain in a similar manner to BCP.
  • This further supports that CB2 receptor activation plays a key role in reducing neuropathic pain.

Conclusions from Receptor Studies:

• Mechanical pain: The analgesic effect of beta-caryophyllene depends on CB2 receptors.
• Cold-induced pain: The analgesic effect is independent of CB2 receptors, suggesting the involvement of another mechanism, possibly related to its antioxidant properties or interaction with PPARγ receptors.

Can Beta-Caryophyllene Help in Neuropathy Caused by Other Chemotherapy Drugs?

The authors highlight that their results, combined with findings from other studies on CB2 receptor agonists, suggest that beta-caryophyllene (BCP) may have broad potential for treating chemotherapy-induced neuropathic pain.

Potential Applications:

• Oxaliplatin-induced neuropathy (OIPN): The primary focus of this study, where BCP effectively reduced pain.
• Paclitaxel-induced neuropathy (taxoids): BCP’s action was comparable to synthetic CB2 agonists, showing cross-therapeutic potential.
• Cisplatin-induced neuropathy (platinum compounds): CB2 receptor activation was also proven effective in reducing pain in similar neuropathic models.

Conclusion from Potential Applications:

As a natural CB2 receptor agonist, BCP has the potential to:

• Provide broad pain relief across different types of chemotherapy-induced neuropathies.
• Serve as a safe, natural complementary therapy for oncology patients, without interfering with chemotherapy efficacy or the immune system.

Final Conclusions – Key Takeaways from the Study

Does Beta-Caryophyllene Effectively Treat Oxaliplatin-Induced Neuropathy?
The mouse model experiments demonstrated that beta-caryophyllene (BCP) effectively reduces:

• Mechanical pain (e.g., pain from touch) – in both preventive and therapeutic use.
• Cold-induced pain – reducing sensitivity to cold stimuli.

Is Beta-Caryophyllene’s Effect CB2 Receptor-Dependent?

• For mechanical pain: Yes, its relief is CB2 receptor-dependent, as proven by the blocking effect of the CB2 antagonist (SR144528) and the positive response to the CB2 agonist (GW405538).
• For cold-induced pain: No, here BCP works through a CB2-independent mechanism, likely involving its antioxidant properties or interaction with PPARγ receptors.

How Does Beta-Caryophyllene Reduce Inflammation and Oxidative Stress?

BCP demonstrated anti-inflammatory and antioxidant effects by:

• Reducing pro-inflammatory cytokines (e.g., TNF, IL-1β).
• Lowering reactive oxygen species (ROS) production, which causes nerve cell damage.
• Reducing oxidative damage in the spinal cord.

Does Beta-Caryophyllene Weaken Chemotherapy Effects?

The study showed that BCP does not interfere with oxaliplatin (OXA) chemotherapy:

• Antitumor efficacy remains intact: Tumor growth in the OXA and OXA+BCP groups was identical.
• No impact on blood morphology: BCP does not suppress the immune system during chemotherapy.

Is Beta-Caryophyllene a Promising Candidate for Neuropathy Treatment?

The authors emphasize that beta-caryophyllene (BCP) shows great potential as a supportive treatment for OIPN, acting through multiple mechanisms:

• Reduces mechanical pain via CB2 receptor activation.
• Relieves cold-induced pain through a CB2-independent mechanism.
• Protects nerve cells from oxidative and inflammatory damage.
• Does not interfere with chemotherapy efficacy and is safe for the immune system.

Final Summary:

The study confirms that beta-caryophyllene (BCP) is a promising candidate for further research on treating chemotherapy-induced neuropathic pain. Its:

• Efficacy,
• Safety, and
• Dual mechanism of action (CB2-dependent and CB2-independent)

position it as a potential complementary therapy for oncology patients.

References

1. Agnes, J. P., dos Santos, B., das Neves, R. N., Luciano, V. M. M., Benvenutti, L., Goldoni, F. C., Schran, R. G., Santin, J. R., Quintão, N. L. M., & Zanotto-Filho, A. (2023). β-Caryophyllene Inhibits Oxaliplatin-Induced Peripheral Neuropathy in Mice: Role of Cannabinoid Type 2 Receptors, Oxidative Stress and Neuroinflammation. Antioxidants (Basel), 12(10), 1893. https://doi.org/10.3390/antiox12101893

   https://pmc.ncbi.nlm.nih.gov/articles/PMC10604080/