Table 3.

Polyphenols in the treatment of diabetic neuropathy.

Polyphenols	Animal models	Duration	Dosage	Effects	References
Diosmin	STZ-induced diabetic rats	4 weeks	50 and 100 mg/kg/day	Increased tail-flick latency; decreased traveling duration; increased concentration of SOD and GSH; decreased levels of MDA and NO	[144]
Hydroxytyrosol	STZ-induced diabetic rats	6 weeks	10 and 100 mg/kg/day	Reduced thermal nociception; elevated paw withdrawal threshold and Na+/K+ ATPase activity; increased MNCV level	[145]
Kolaviron	STZ-induced diabetic rats	6 weeks	100 and 200 mg/kg/day	Reduced level of OS, IL-1β, TNF-α, MDA, and TBARS; elevated concentrations of GSH, CAT, and GPx	[146]
Carvacrol	STZ-induced diabetic rats	7 weeks	25, 50, and 100 mg/kg/day	Increased SOD level; decreased concentrations of IL-1β, MDA, and TNF-α	[147]
Naringenin	STZ-induced diabetic rats	5 weeks	25 and 50 mg/kg/day	Increased tail-flick latency and paw withdrawal; elevated NGF and IGF-1 in sciatic nerves; decreased IL-1β and TNF-α levels; increased concentrations of CAT, GSH, and GPx	[140]
Naringin	STZ-induced diabetic rats	4 weeks	40 and 80 mg/kg/day	Reduced mechanotactile allodynia, oxidative-nitrosative stress, and TNF-α level; increased tail-flick latency and nociceptive threshold; increased concentrations of MNCV and SOD	[141]
Curcumin	STZ-induced diabetic rats	6 weeks	100 mg/kg/day	Decreased thermal nociception, levels of TNF-α and IL-10; increased tail-flick latency and paw withdrawal threshold	[148]
	STZ-induced diabetic rats	3 weeks	200 mg/kg/day	Decreased mechanical allodynia and thermal hyperalgesia; increased paw withdrawal threshold; decreased AR, prostaglandin peroxidase, and COX levels	[149]
	STZ-induced diabetic rats	14 days	200 mg/kg/day	Increased paw withdrawal threshold and SOD level; decreased levels of MDA and H2O2 in the spinal cord	[143]
Curcumin and gliclazide	STZ-induced diabetic rats	5 weeks	100 mg/kg/day	Increased mechanical hyperalgesia threshold, hot-plate, and tail-flick latencies; decreased levels of peroxynitrite, LPO, and TNF-α	[150]
Curcumin and resveratrol	STZ-induced diabetic rats	4 weeks	Curcumin = 60 mg/kg/day; resveratrol = 20 mg/kg/day	Increased nociceptive threshold; decreased levels of brain nitrite and TNF-α	[151]
Astragaloside IV	STZ-induced diabetic rats	12 weeks	3, 6, and 12 mg/kg/day	Increased myelinated fiber density, myelinated fiber area, and segmental demyelination; decreased levels of HbA1C; increased levels of MNCV and GPx; decreased AR level in erythrocytes; increased activity of Na+/K+ ATPase in nerves and erythrocytes	[152]
Epigallocatechin gallate	STZ-induced diabetic rats	10 weeks	2 g/L/day	Decreased mechanical allodynia and thermal hyperalgesia; elevated paw withdrawal pressure; decreased 8-OHdG immunoreaction, numbers of Fos-immunoreacted neurons, and colocalization of 8-OHdG and Fos in laminae I–III	[153]
	STZ-induced diabetic rats	7 weeks	20 and 40 mg/kg/day	Increased nociceptive threshold and tail-flick latency; reduced formalin-mediated nociceptive behavior; decreased concentrations of nitrite, TBARS, and MDA; elevated SOD level	[154]
Grape seed proanthocyanidins	STZ-induced diabetic rats	16 weeks	125, 250, and 500 mg/kg/day	Increased hot-plate latency and nerve conduction velocity; decreased level of free Ca2+; elevated activities of ATPase in sciatic nerves	[155]
Bacosine	STZ-induced diabetic rats	30 days	5 and 10 mg/kg/day	Diabetes-linked cognitive impairment; decreased hyperalgesia; increased levels of MNCV and SOD; decreased levels of AGEs, ROS, MDA, TNF-α, and IL-1β	[156]
6-Methoxyflavanone	STZ-induced diabetic rats	—	10 and 30 mg/kg/day	Elevated paw withdrawal threshold and latency; reduced thermal nociception; involvement of GABA receptors; increased flinching response threshold and latency by a preference for the δ- and ĸ-opioid receptors	[157]
Chlorogenic acid	STZ-induced diabetic rats	14 days	100 mg/kg/day	Increased threshold of mechanical hyperalgesia; decreased formalin-mediated nociceptive behavior	[158]
7-Hydroxy-3,4-dihydrocadalin	STZ-induced diabetic rats and mice	—	0.3–30 and 30–300 mg/kg/day	Decreased mechanical hyperalgesia and allodynia and formalin-evoked hyperalgesia; increased withdrawal threshold; reduced level of MDA	[159]
Mulberry flavonoids	ALX-induced diabetic rats	8 weeks	0.3 and 0.1 g/kg/day	Reduced myelin breakdown and myelinated fiber cross-sectional area; decreased peripheral nerve injury and numbers of extramedullary fiber of sciatic nerves	[160]
Chromane	STZ-induced diabetic rats	30 days	5 and 10 mg/kg/day	Decreased mechanical allodynia and thermal hyperalgesia; increased paw withdrawal threshold and MNCV level; decreased levels of AGEs and ROS	[161]
Kaempferol	STZ-induced diabetic mice	3 weeks	25, 50, and 100 mg/kg/day	Decreased formalin-mediated nociceptive behavior in phases 1 and 2 and oedema size; reduced hyperalgesia; elevated thermal pain threshold; decreased levels of IL-1β, TNF-α, LPO, and nitrite	[162]
Oryzanol	STZ-induced diabetic rats	—	50 and 100 mg/kg/day	Increased pain threshold, hot-plate latency, and GSH; decreased flinching in diabetic rats during both quiescent phase and phase 2 but not in phase 1; reduced nitrite and MDA levels; attenuated activity of Na+-K+ ATPase	[163]
Pepino polyphenolic extract	STZ-induced diabetic mice	12 weeks	—	Decreased concentrations of IL-6, TNF-α, AGEs, and ROS; increased GSH and GPx levels; elevated fascicle with numerous small myelinated fibers	[164]
Quercetin	STZ-induced diabetic rats	2 weeks	40 mg/kg/day	Increased hot-plate, tail-withdrawal latency, and cold allodynia latency; reduced number of foot slips	[165]
	STZ-induced diabetic rats	8 weeks	10, 20, and 40 mg/kg/day	Reduced thermal hyperalgesia and mechanical allodynia; increased concentrations of MNCV, SOD, and GPx; decreased levels of TNF-α and IL-1β	[166]
	STZ-induced diabetic rats	4 weeks	10 mg/kg/day	Increased tail-flick latencies and nociceptive threshold in both diabetic and nondiabetic mice	[167]
	STZ-induced diabetic rats	4 weeks	10 mg/kg/day	Decreased thermal nociception; elevated tail withdrawal latencies and nociceptive threshold	[168]
Resveratrol	STZ-induced diabetic rats	2 weeks	10 and 20 mg/kg/day	Increased tail-flick latency and paw withdrawal pressure; elevated concentrations of MNCV and CAT; reduced MDA level	[169]
	STZ-induced diabetic rats	2 weeks	10 and 20 mg/kg/day	Increased MNCV level; decreased concentrations of p65, MDA, NF-κB, IκB-α, TNF-α, IL-6, and COX-2	[170]
	STZ-induced diabetic rats	6 weeks	20 mg/kg/day	Decreased cerebral MDA and COX-2; increased cerebral level of IL-4 and GSH	[171]
	STZ-induced diabetic rats	>6 weeks	10 mg/kg/day	Decreased concentrations of MDA, XO, and NO; increased level of GSH in the cortex, hippocampus, brain stem, cerebellum, and spinal cord	[142]
	STZ-induced diabetic rats	2 weeks	20 mg/kg/day	Elevated tail withdrawal threshold and latencies	[172]
Silymarin	STZ-induced diabetic rats	8 weeks	100 and 200 mg/kg/day	Elevated tail-flick latency; decreased nociceptive scores in both phases of the formalin test	[173]
Morin	STZ-induced diabetic rats	3 weeks	15 and 30 mg/kg/day	Increased paw withdrawal and tail-flick latency; elevated NGF and IGF-1 in sciatic nerves; decreased levels of IL-1β, TNF-α, and LPO	[174]

8-OHdG: 8-hydroxy-2′-deoxyguanosine; AGEs: advanced glycation end products; ALX: alloxan; AR: aldose reductase; CAT: catalase; COX: cyclooxygenase; DNP: diabetic neuropathy; GABA: gamma-aminobutyric acid; GPx: glutathione peroxidase; GSH: glutathione; HbA1C: hemoglobin A1c; IGF-1: insulin-like growth factor; IL-10: interleukin-10; IL-1β: interleukin 1 beta; LPO: lipid peroxidation; MDA: malondialdehyde; MNCV: motor nerve conduction velocity; NGF: nerve growth factor; NO: nitric oxide; NOS: nitric oxide synthase; OS: oxidative stress; ROS: reactive oxygen species; SOD: superoxide dismutase; STZ: streptozotocin; TBARS: thiobarbituric acid reactive substances; TNF-α: tumor necrosis factor-α; XO: xanthine oxidase.