Korean J Pain.  2020 Jan;33(1):13-22. 10.3344/kjp.2020.33.1.13.

Antinociceptive and neuroprotective effects of bromelain in chronic constriction injury-induced neuropathic pain in Wistar rats

• Bakare AO
• Owoyele BV

• KMID: 2506638
• DOI: http://doi.org/10.3344/kjp.2020.33.1.13

Abstract

Background
The continuous search for a novel neuropathic pain drug with few or no side effects has been a main focus of researchers for decades. This study investigated the antinociceptive and neuroprotective effects of bromelain in sciatic nerve ligation-induced neuropathic pain in Wistar rats.
Methods
Forty-eight Wistar rats randomly divided into eight groups comprised of six animals each were used for this study. Peripheral neuropathy was induced via chronic constriction of the common sciatic nerve. Thermal hyperalgesic and mechanical allodynia were assessed using a hotplate and von Frey filaments, respectively. The functional recovery and structural architecture of the ligated sciatic nerve were evaluated using the sciatic functional index test and a histological examination of the transverse section of the sciatic nerve. The neuroprotective effects of bromelain were investigated in the proximal sciatic nerve tissue after 21 days of treatment.
Results
Bromelain significantly (P < 0.05) attenuated both the thermal hyperalgesia and mechanical allodynic indices of neuropathic pain. There were improvements in sciatic function and structural integrity in rats treated with bromelain. These rats showed significant (P < 0.05) increases in sciatic nerve nuclear transcription factors (nuclear factor erythroid-derived-2-related factors-1 [NrF-1] and NrF-2), antioxidant enzymes (superoxide dismutase and glutathione), and reduced membranelipid peroxidation compared with the ligated control group.
Conclusions
This study suggest that bromelain mitigated neuropathic pain by enhancing the activities of nuclear transcription factors (NrF-1 and NrF-2) which increases the antioxidant defense system that abolish neuronal stress and structural disorganization.

Keyword

Antioxidants; Bromelain; Hyperalgesia; Neuralgia; Neuroprotection; NF-E2-Related Factor 2; NFI Transcription Factors; Nuclear Respiratory Factor 1; Rats; Wistar

Figure

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  Fig. 1 Bromelain reversed thermal hyperalgesia in sciatic nerve-induced neuropathic pain. (A) Presurgical hotplate test. (B) Third day post-surgery hotplate test. (C) Seventh day post-surgery hotplate test. (D) Fourteenth day post-surgery hotplate test. (E) Twenty first day post-surgery hotplate test. Each value represents the mean ± standard error of the mean of each group. PWL: paw withdrawal latency. a P < 0.05, aa P < 0.01, aaa P < 0.001 compared with unligated control (normal control); bb P < 0.01, bbb P < 0.001 compared with ligated control; and c P < 0.05, cc P < 0.01, ccc P < 0.001 compared with gabapentin (reference control).

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  Fig. 2 Bromelain reversed mechanical allodynia in sciatic nerve-induced neuropathic pain. aaa P < 0.001 compared with ligated control.

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  Fig. 3 Bromelain improved the SFI in sciatic nerve-ligated hind limb. SFI: sciatic functional index. a P < 0.05 compared with unligated control (normal control); b P < 0.05 compared with ligated control; and c P < 0.05 compared with gabapentin (reference control).

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  Fig. 4 Bromelain increases antioxidant enzymes and subdue lipid peroxidation and nitric oxide. (A) Reduced glutathione (GSH) concentration. (B) Super-oxide dismutase (SOD) activities. (C) Malondialdehyde (MDA) concentration. **P < 0.01, ***P < 0.001 compared with unligated control (normal control); ††† P < 0.001 compared with ligated control; and ‡‡‡ P < 0.001 compared with gabapentin (reference control).

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  Fig. 5 Effect of bromelain on transcription factors. (A) Nuclear factor erythroid-derived-2 related factor-1 (NrF-1). (B) NrF-2. *P < 0.05, **P < 0.01, ***P < 0.001 compared with ligated control; † P < 0.05 compared with gabapentin (reference control).

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  Fig. 6 Bromelain improved myelinated (white arrows) and unmyelinated nerve (black arrows) integrity. It attenuated swollen and degeneration of myelinated neurons (white arrows) and increases occurrence of Schwan’s cells. Arrowhead indicates swollen and deranged non-myelinated neurons while dashed arrows indicate reduced and swollen myelinated neurons (hematoxylin and eosin stain, ×400). (A) Normal control, (B) sham control, (C) ligated control, (D) reference control (30 mg/kg gabapentin), (E) low dose bromelain (30 mg/kg), (F) high dose bromelain (50 mg/kg), (G) pre-treated low dose bromelain (30 mg/kg), (H) pre-treated high dose bromelain.

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