The Role of Phytochemicals in Managing Neuropathic Pain: How Much Progress Have We Made?
Abstract
:1. Introduction
2. Phytochemicals: Definition and Classification
3. Epidemiology and Economic Burden of Neuropathic Pain
4. Mechanisms in Neuropathic Pain
4.1. Pathophysiology of Neuropathic Pain
4.2. Role of Inflammation and Oxidative Stress
4.3. Nociceptive Pathways and Pain Perception
5. Neuropathic Pain in Neurological Conditions
5.1. Guillain-Barré Syndrome (GBS)
Pathophysiology and Clinical Presentation of Pain in GBS
5.2. Multiple Sclerosis (MS)
Mechanisms of Neuropathic Pain in MS
5.3. Diabetic Polyneuropathy (DP)
Impact of Diabetes on Nerve Health
6. Neuropathic Pain Management
7. Phytochemicals in Neuropathic Pain Management
7.1. Flavonoides
7.2. Terpenoids
7.3. Alkaloids
7.4. Other Relevant Phytochemicals
8. Clinical Trials of Phytochemicals
9. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Phytochemical | Mechanism of Action | References | Structural Formula | Category | Type of Study | Study Results |
---|---|---|---|---|---|---|
Narirutin | Selectively inhibits Nav1.7 voltage-gated sodium channels | [79] | Flavonoid | In vivo | Mechanical withdrawal threshold: 10.5 ± 0.8 g (vs. 7.3 ± 0.5 g in control) Thermal withdrawal latency: 13.2 ± 0.5 s (vs. 10.6 ± 0.4 s in control) p < 0.05 | |
Diosmin | Reduces inflammation (NF-κB, TNF-α, COX-2), alleviates neuropathic pain via NO/cGMP/PKG/KATP pathway and spinal cytokine inhibition (IL-1β) | [80,81] | Flavonoid | In vivo | Inflammatory Markers: RF, TNF-α, ACPA, IL-17 decreased by 77%, 65%, 67%, and 72%, respectively; Oxidative Stress: LPO decreased by 38%; Western Blot: NF-κB p50/p65 down by 45%/38%, iNOS by 46%, Nrf2 up by 224% | |
Quercetin | Antioxidant, anti-inflammatory, modulates immune responses | [82,83] | Flavonoid | In vivo | Reduced Bax/Bcl-2 ratio, reduced Cyto. c expression; Caspase-3 activity reduced in cortex and hippocampus (p < 0.05); 8 mice/group for western blot, 5 mice/group for confocal microscopy; enhanced neuronal survival (p < 0.05) | |
6-Methoxyflavanone (6-MeOF) | Interacts with GABA-ergic and opioidergic systems | [6] | Flavonoid | In vivo | Significant attenuation of nociception at 10 and 30 mg/kg after 30 and 60 min | |
Berberine | Modulates glucose metabolism, inflammation, and lipid levels | [84] | Flavonoid | In vivo | Effect on Body Weight: 211 ± 0.8 g (20 mg/kg) and 250 ± 1.4 g (40 mg/kg) vs. Diabetic control (161 ± 1.0 g) Fasting Blood Glucose: Reduction in glucose (p < 0.001) vs. Diabetic control (421 ± 2.0 mg/dL) Serum Insulin Level: Increased to 11.73 ± 0.18 μIU/mL (20 mg/kg and 40 mg/kg) vs. Diabetic control (6.773 ± 0.07 μIU/mL) Thermal Hyperalgesia: Increased pain threshold (dose-dependent, p < 0.001) Mechanical Hyperalgesia: Increased pain threshold (dose-dependent, p < 0.001) Antioxidant Enzymes (GSH and SOD): GSH: 0.51 ± 0.02 μM/mg protein, SOD: 15.96 ± 0.15 U/mg protein Lipid Peroxidation (TBARS): Reduced to 3.16 ± 0.069 nmol/mg protein (vs. Diabetic control: 6.53 ± 0.15 nmol/mg protein) AGEs (Advanced Glycation End-products): Reduced to 2.48 ± 0.02 RFU/mg protein (vs. Diabetic control: 3.72 ± 0.02 RFU/mg protein) Nitrite Level: Significant reduction, but Gabapentin more effective | |
Alpha-Tocopherol | Antioxidant, protects cell membranes, modulates immune responses | [84] | Flavonoid | In vivo | Effect on Body Weight: 250 ± 1.4 g (1000 mg/kg) vs. Diabetic control (161 ± 1.0 g) Fasting Blood Glucose: Reduction in glucose (dose-dependent, p < 0.001) Serum Insulin Level: Increased to 11.73 ± 0.18 μIU/mL (20 mg/kg and 40 mg/kg) Thermal Hyperalgesia: Increased pain threshold (dose-dependent) Mechanical Hyperalgesia: Increased pain threshold Antioxidant Enzymes (GSH and SOD): GSH: 0.51 ± 0.02 μM/mg protein, SOD: 15.96 ± 0.15 U/mg protein Lipid Peroxidation (TBARS): Reduced to 3.16 ± 0.069 nmol/mg protein AGEs (Advanced Glycation End-products): Reduced to 2.48 ± 0.02 RFU/mg protein Nitrite Level: Significant reduction (dose-dependent) | |
Caryophyllene | Binds to CB2 receptors, modulates pain pathways | [88] | Terpenoid | In vivo | - BCP (1–100 μM) significantly increased IL-10 and decreased IFN-γ production - No change in IL-4 levels after MOG35–55 stimulation - CB2 selective antagonist AM630 (50 μM) blocked BCP’s immunomodulatory effect. - In EAE model, clinical score peaked at 3.5 on day 19 post-immunization - 25 mg/kg BCP reduced motor paralysis and weight loss. - BCP (50 mg/kg) significantly reduced mechanical hyperalgesia | |
Limonene | Interacts with serotonin and norepinephrine systems | [89,90] | Terpenoid | In vivo | BDNF: Decreased in Str (significantly lower than C, p < 0.05), increased in Str + Lim (higher than Str). IL-1β: 5.33 ± 0.42 (Str), 3.16 ± 0.41 (C), 2.85 ± 0.24 (Lim), 4.07 ± 0.1 (Str + Lim) − significantly reduced in Str + Lim compared to Str. Caspase-1: 0.55 ± 0.06 (Str + Lim), 0.32 ± 0.04 (Lim) − significantly higher in Str + Lim than Lim, p = 0.009. IL-6: No significant differences (p > 0.05). | |
Mycrene | Modulates cannabinoid receptors | [88,91] | Terpenoid | In vivo | - Nociception (secondary allodynia): 1 mg/kg dose improved nociception by 211.0 ± 17.93%; 5 mg/kg dose improved nociception by 269.3 ± 63.27%. - Blockade of CB receptors: CB1 antagonist AM281 blocked myrcene’s analgesic effect (p < 0.001), CB2 antagonist AM630 blocked it (p < 0.0001). - Leukocyte Rolling: Myrcene reduced leukocyte rolling at 60 min (p < 0.0001). - CB2 Antagonist Blockade: AM630 reduced leukocyte rolling (p < 0.05). - Chronic Pain: Repeated myrcene administration increased paw withdrawal threshold (p < 0.0001). | |
Pinene | Modulates cannabinoid receptors | [92] | Terpenoid | In vivo | IL-1β (skin): α-Pinene 1 mg/kg: 62.68 ± 4.54 α-Pinene 5 mg/kg: 45.74 ± 1.48 α-Pinene 10 mg/kg: 47.75 ± 4.44 TNF-α (skin): α-Pinene 1 mg/kg: 92.02 ± 4.84 α-Pinene 5 mg/kg: 56.36 ± 6.02 α-Pinene 10 mg/kg: 61.23 ± 3.25 SOD (skin): α-Pinene 1 mg/kg: 27.91 ± 2.88 α-Pinene 5 mg/kg: 41.49 ± 1.75 α-Pinene 10 mg/kg: 47.42 ± 3.02 | |
Capsaicin | Desensitizes TRPV1 receptors, modulates pain signaling | [95,96,97] | Alkaloid | In vivo | Axon reflex flare abolished during capsaicin, recovered to ~50% after 49 days. All sensations recovered completely within 7 weeks in healthy subjects. Analgesia lasted for months in spontaneous neuropathic pain patients treated with 8% capsaicin. | |
Tetrahydropalmatine (THP) | Modulates dopaminergic and serotonergic activity, decreases glutamate release | [98] | Alkaloid | In vivo In vitro | - THP (5 mg/kg, 10 mg/kg) alleviates mechanical allodynia and heat hyperalgesia in CFA-induced inflammatory pain rats (observed on Day 9) - 2.5 mg/kg did not significantly relieve pain - Gait parameters: THP treatment significantly reversed CFA-induced reductions in contact area and print length (Day 7) - 100 μM THP promoted significant apoptosis in astrocytes and microglia - 10 mg/kg THP reduced spinal cord inflammatory cytokines (TNF-α, IL-1β) and NF-κB activation - Significant reduction in p-NF-κB/NF-κB ratio after THP treatment | |
Matrine | Modulates neurotransmitter imbalances supports myelin restoration, and reduces pro-inflammatory cytokines | [99,100] | Alkaloid | In vivo | Paw withdrawal threshold: 0.88 ± 0.16 (Matrine) vs 0.18 ± 0.04 (CCI) Paw withdrawal latency: 7.01 ± 0.11 (Matrine) vs 4.62 ± 0.18 (CCI) Counts of paw withdrawal: 19.7 ± 1.15 (Matrine) vs 44.3 ± 2.99 (CCI) | |
Resveratrol | Modulates pro-inflammatory cytokines, oxidative stress, and neuroinflammatory responses | [101,102] | Phenolic Compound | In vivo | 40 mg/kg reduced thermal hyperalgesia and allodynia significantly. No effect at 5 mg/kg. Cytokine modulation: TNF-α, IL-1β, IL-6 decreased, IL-10 increased in a dose-dependent manner. Significant inhibition of TNF-α, IL-1β, IL-6 at 1, 2, and 5 μM. IL-10 secretion promoted. NO level reduced in Aβ-stimulated microglia. Significant pain relief from day 7 to day 21 after CCI, with maximal effect at day 21. | |
Curcumin | Modulates inflammation, oxidative stress, and ion channels | [103,104,105,106,107] | Phenolic Compound | In vivo | Cognitive Impairment (NOR Test): 3.16-fold and 2.07-fold increase in discrimination and preference indices (Curcumin) vs. 128% and 56.49% decrease (EAE) (p < 0.0001) Hippocampal Neurons (H and E Staining): 3.06-fold increase in intact neurons (Curcumin) vs. 69.42% decrease (EAE) (p < 0.0001) Motor Function: 3.33-, 2.40-, 2.36-, and 3.09-fold increase in distance traveled, mean speed, ambulation, and rearing frequencies (Curcumin) vs. 77.17%, 69.08%, 65.36%, and 76.77% decrease (EAE) (p < 0.0001) Protein Levels (AMPK/SIRT1 Pathway): 2.93-fold and 2.77-fold increase in p-AMPKThr172 and SIRT1 (Curcumin) vs. 71.67% and 69.09% decrease (EAE) (p < 0.0001) Demyelination (CREB/BDNF/MBP Pathway): 3.35-, 1.84-, and 2.21-fold increase in p-CREBSer133, BDNF, and MBP (Curcumin) vs. 73.27%, 51.90%, and 67.09% decrease (EAE) (p < 0.0001) |
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Sic, A.; Manzar, A.; Knezevic, N.N. The Role of Phytochemicals in Managing Neuropathic Pain: How Much Progress Have We Made? Nutrients 2024, 16, 4342. https://doi.org/10.3390/nu16244342
Sic A, Manzar A, Knezevic NN. The Role of Phytochemicals in Managing Neuropathic Pain: How Much Progress Have We Made? Nutrients. 2024; 16(24):4342. https://doi.org/10.3390/nu16244342
Chicago/Turabian StyleSic, Aleksandar, Aarish Manzar, and Nebojsa Nick Knezevic. 2024. "The Role of Phytochemicals in Managing Neuropathic Pain: How Much Progress Have We Made?" Nutrients 16, no. 24: 4342. https://doi.org/10.3390/nu16244342
APA StyleSic, A., Manzar, A., & Knezevic, N. N. (2024). The Role of Phytochemicals in Managing Neuropathic Pain: How Much Progress Have We Made? Nutrients, 16(24), 4342. https://doi.org/10.3390/nu16244342