Table 6.

Effects of naringin on fibromyalgia-like symptoms.

First Author, Year [ref]	Experimental Design and Treatments	Results
Animal studies
Ben-Azu, 2019 [56]	Forced swim-induced FM-like model Male Swiss mice (n = 50) Treatments: vehicle (10 mL/kg BW, i.p.), naringin (2.5, 5 and 10 mg/kg BW, i.p.), diazepam (2 mg/kg BW, i.p.), donepezil (1 mg/kg BW, i.p.) and imipramine (15 mg/kg BW, i.p.) for 7 days	Compared to vehicle group, naringin groups:
		↑ locomotor activity
		↓ depressant and anxiety
		↑ % social preference
		↑ cognitive performance
		↓ AChE enzyme activity in brain
		↑ GSH, SOD, CAT levels in brain
		↓ MDA and nitrate levels in brain
Pinho-Ribeiro, 2016 [57]	Acetic acid- and PBQ-induced FM-like visceral pain model Male Swiss mice Treatments: vehicle, Nar (16.7–150 mg/kg p.o.) given 30 min before stimulus Formalin-induced FM-like pain model Male Swiss mice Treatments: vehicle, Nar (50 mg/kg, p.o.) given 30 min before stimulus Capsaicin- and CFA-induced overt FM-like pain models Male Swiss mice Treatments: vehicle, Nar (50 mg/kg, p.o.) given 30 min before nociceptive stimulus. Carrageenan-, CFA-, capsaicin-, and PGE2-induced mechanical hyperalgesia Male Swiss mice Treatments: vehicle, Nar p.o. given 30 min before stimulus	Compared to vehicle group, Nar groups:
		↑ antinociceptive effect induced by acid, formalin, and capsaicin- and CFA
		↓ mechanical hyperalgesia induced by carrageenan, capsaicin, CFA, and PGE2
		↑ NO/cGMP/PKG/ATP sensitive K+ channel signaling pathway
		↑ GSH production of plantar skin tissue
		↓ IL-33, TNF-α, IL-1β production, and NF-κB activation of paw skin tissues
Zamanian, 2016 [59]	Exercise-induced fatigue-induced FM model Female Wistar rats (n = 50) Treatments: control, vehicle, 40, 80, and 160 mg naringin/kg/day for 30 days	Compared to vehicle group, naringin groups:
		↑ exhaustion swimming time
		↓ LDH activity and serum MMP-9 levels
		↑ blood glucose levels
Xue, 2019 [60]	Hot plate-induced FM-like pain model	Compared to vehicle group, Nar groups:
	Acetic acid-, glutamate-, capsaicin-, capsaicin-, and formalin-induced FM-like pain models	↑ antinociceptive effect against thermal and chemical-induced pain
	Treatments: vehicles, Nar (25–75 mg/kg) p.o., before stimulus	↓ capsaicin-induced paw licking number
	Carrageenan-induced FM-like inflammatory model	↓ carrageenan-induced peritoneal leukocyte infiltration of paw edema
	Treatments: vehicles, Nar (25–75 mg/kg) p.o., given 30 min before stimulus	↓ TNF-α, IL-1β, and IL-6 levels of skin

Abbreviation: AChE, acetylcholine esterase; BW, body weight; CAT, catalase; CFA, complete Freud’s Adjuvant; FM, fibromyalgia; GSH, glutathione; IL-1β, interleukin-1β; IL-6, interleukin-6; i.p., intraperitoneal; i.pl., intraplantar; LDH, lactate dehydrogenase MDA, malondialdehyde; MMP-9, matrix metalloproteinases-9; NF-κB, nuclear factor kappa B; p.o., post oral; PBQ, phenyl-p-benzoquinone; PGE₂, prostaglandin E₂, TNF-α, tumor necrosis factor-α, NAR; naringenin; SOD, superoxide dismutase; ↑ increase; ↓ decrease; ↔ no difference.