Limonene, a food additive, and its active metabolite perillyl alcohol improve regeneration and attenuate neuropathic pain after peripheral nerve injury: Evidence for IL-1β, TNF-α, GAP, NGF and ERK involvement

• Published in: International immunopharmacology Vol. 86; p. 106766
• Main Authors: Araújo-Filho, Heitor G., Pereira, Erik W.M., Heimfarth, Luana, Souza Monteiro, Brenda, Santos Passos, Fabiolla Rocha, Siqueira-Lima, Pollyana, Gandhi, Sathiyabama R., Viana dos Santos, Márcio Roberto, Guedes da Silva Almeida, Jackson Roberto, Picot, Laurent, Grougnet, Raphaël, Almeida, Ray S., Douglas Melo Coutinho, Henrique, Quintans-Júnior, Lucindo J., Martins, Natália, Quintans, Jullyana S.S.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01-09-2020; Elsevier BV; Elsevier
• Subjects: Biochemistry; Biochemistry, Molecular Biology; D-limonene; Enzyme-linked immunosorbent assay; Extracellular signal-regulated kinase; Food additives; Gait; GAP-43 protein; Glial fibrillary acidic protein; Gliosis; IL-1β; Immunofluorescence; Inflammation; Life Sciences; Limonene; Medication; Metabolites; Monoterpenes; Muscle strength; Natural products; Nerve growth factor; Nerve regeneration; Neuropathic pain; Pain; Pain perception; Perillyl alcohol; Peripheral nerves; Peripheral neuropathy; Pharmaceutical sciences; Regeneration; Spinal cord; Tumor necrosis factor-α; NO; COX-2; POH; PNI; Akt; cAMP; Neuropathic pain; NPs; SNL; D-limonene; LIM; Perillyl alcohol; ERKs; ANOVA; Natural products; SFI; GAP-43; ROS; iNOS; TGF-β; Monoterpenes; pERK; Nerve regeneration; ELISA
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2020.106766

•POH and LIM improve the regeneration process.•POH and LIM improve the sensory and motor function recovery.•These effects are due the anti-inflammatory effect and upregulation of the neurotrophic process.
Limonene (LIM) and its main metabolite perillyl alcohol (POH) are ingredients found in food with promising chemical entities due to their pharmacological profile. In this study, we hypothesized that LIM and POH are two molecules capable of accelerating the regenerative process and alleviating neuropathic pain. Methods: Animals were treated daily (LIM, POH and saline) for 28 days and during this period evaluated for mechanical hyperalgesia, astrocyte participation by immunofluorescence for GFAP, and ELISA was used to quantify IL-1β and TNF-α in the spinal cord. Western blot analysis of the following proteins was also performed: GFAP, GAP-43, NGF and ERK. For motor deficit analysis, tests were performed to assess hind paw muscle strength and footprints through gait (SFI). Results: Both POH and LIM accelerated the regenerative process and improved motor deficits comparing to positive control; however, POH was more effective, particularly between the 2nd and 3rd week after the nerve injury, increasing GAP-43, NGF and the phosphorylated ERK immunocontent. Moreover, POH and LIM were able to reduce hyperalgesia and astrocytosis. Conclusions: Both substances, LIM and POH, improved the regeneration process and sensory and motor function recovery in the PNI model in mice by mitigating the inflammatory reactions and up-regulating the neurotrophic process.