Korean J Pain.  2022 Jul;35(3):271-279. 10.3344/kjp.2022.35.3.271.

Synergistic interaction between acetaminophen and L-carnosine improved neuropathic pain via NF-κB pathway and antioxidant properties in chronic constriction injury model

• Owoyele BV
• Bakare AO
• Olaseinde OF
• Ochu MJ
• Yusuff AM
• Ekebafe F
• Fogabi OL
• Roi T

• KMID: 2530982
• DOI: http://doi.org/10.3344/kjp.2022.35.3.271

Abstract

Background
Inflammation is known to underlie the pathogenesis in neuropathic pain. This study investigated the anti-inflammatory and neuroprotective mechanisms involved in antinociceptive effects of co-administration of acetaminophen and L-carnosine in chronic constriction injury (CCI)-induced peripheral neuropathy in male Wistar rats.
Methods
Fifty-six male Wistar rats were randomly divided into seven experimental groups (n = 8) treated with normal saline/acetaminophen/acetaminophen + L-carnosine. CCI was used to induce neuropathic pain in rats. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests, respectively. Investigation of spinal proinflammatory cytokines and antioxidant system were carried out after twenty-one days of treatment.
Results
The results showed that the co-administration of acetaminophen and Lcarnosine significantly (P < 0.001) increased the paw withdrawal threshold to thermal and mechanical stimuli in ligated rats compared to the ligated naïve group. There was a significant (P < 0.001) decrease in the levels of nuclear factor kappa light chain enhancer B cell inhibitor, calcium ion, interleukin-1-beta, and tumour necrotic factor-alpha in the spinal cord of the group coadministered with acetaminophen and L-carnosine compared to the ligated control group. Co-administration with acetaminophen and L-carnosine increased the antioxidant enzymatic activities and reduced the lipid peroxidation in the spinal cord.
Conclusions
Co-administration of acetaminophen and L-carnosine has anti-inflammatory effects as a mechanism that mediate its antinociceptive effects in CCIinduced peripheral neuropathy in Wistar rat.

Keyword

Acetaminophen; Anti-Inflammatory Agents; Antioxidants; Carnosine; Cytokines; Hyperalgesia; Lipid Peroxidation; Neuralgia; NF-kappa B; Spinal Cord

Figure

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  Fig. 1 Acetaminophen significantly increased paw withdrawal latency on the hotplate test. Data were represented as mean ± standard error of the mean (n = 8). aP < 0.05 vs. ligated control, bP < 0.05 vs. sham control.

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  Fig. 2 Acetaminophen + L-carnosine significantly increased paw withdrawal threshold to von Frey filament. Data were represented as mean ± standard error of the mean (n = 8). aP < 0.05 vs. ligated control, bP < 0.05 vs. sham control.

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  Fig. 3 Acetaminophen + L-carnosine mitigated proinflammatory mediators. Acetaminophen and L-carnosine significantly reduced proinflammatory mediators in the spinal lumbar neurons. (A) Acetaminophen + L-carnosine significantly inhibit tumour necrotic factor-alpha (TNF-α) concentration. (B) Acetaminophen + L-carnosine significantly reduced interleukin-1-beta (IL-1β) concentration. (C) Acetaminophen + L-carnosine significantly attenuated nuclear factor kappa light chain enhancer B cell inhibitor (NF-κB) concentration. (D) Acetaminophen + L-carnosine significantly inhibit calcium (Ca2+) ion concentration. Data were represented as mean ± standard error of the mean (n = 8). aP < 0.05 vs. ligated control, bP < 0.05 vs. sham control.

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  Fig. 4 Acetaminophen + L-carnosine improved neuroprotection of the neurons against oxidative stress. Combined treatment with acetaminophen and L-carnosine significantly increased antioxidant enzyme activities and reduced lipid peroxidation. (A) Acetaminophen + L-carnosine significantly reduced malondialdehyde (MDA) concentration. (B) Acetaminophen + L-carnosine significantly increased superoxide dismutase (SOD) activities. (C) Acetaminophen + L-carnosine significantly increased glutathione (GSH) concentration. Data were represented as mean ± standard error of the mean (n = 8). aP < 0.05 vs. ligated control, bP < 0.05 vs. sham control.

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  Fig. 5 Micrograph showing haematoxyline and eosin stained longitudinal section of the left sciatic nerve. Sciatic nerve ligation induces lost of myelinated (single broken yellow arrow) and unmyelinated (single broken black arrow), shrinkage and lost of nuclei of Schwann cell (single broken red arrow), vacuolarization (black arrow head). Acetaminophen + L-carnosine improved cytoarchitecture of the sciatic nerve by preserving the myelinated (double-broken yellow arrow) and unmyelinated (double-broken black arrow) fibres, nuclei of Schwann cell (red arrow head), regeneration of myelinated neuron (yellow arrow head), and reduces vacuolarization. Red arrow indicate normal Schwann cell, normal myelinated nerve fibre (yellow arrow), and normal unmyelinated nerve fibre (black arrow). (A) Unligated naïve group, (B) Sham group, (C) Ligated naïve group, (D) Post-treated acetaminophen group, (E) Pre-treated acetaminophen group, (F) Post-treated acetaminophen + L-carnosine group, (G) Pre-treated acetaminophen + L-carnosine group.

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