Table 2.

Animal studies regarding the effect of phytochemicals in chemotherapy-induced neuropathy

Phytochemical & plant name	Animal model	Dosage	Outcome	Possible mechanisms	Reference
Curcumin from Curcumin longa	Cisplatin-induced neuropathy in Wistar rats	200 mg/kg, PO	↓Thermal hyperalgesia ↑MNCV in the 8thweek, but not in the 5th week No significant decrease in myelin thickness ↓neuron loss, nuclear & nucleolar atrophy	↓Oxidative stress	[34]
Xylopic acid from Xylopia aethiopica	Vincristine-induced neuropathy in Sprague-Dawley rats	10–100 mg/kg, PO	↓Tactile & cold allodynia, ↓static mechanical hyperalgesia & intermediate hyperalgesia	Inhibition of p38 &/or ERK1 & ERK2 pathways ↓NF-κB activation ↓pain stimuli propagation in the degenerated unmyelinated & myelinated C-, Aδ- & Aβ-fibers Ca2+ channel-blocking effect, Inhibition of NMDA, adrenergic (β & α) & protein kinase A/C pathways	[17]
Aucubin from Plantago sp.	Paclitaxel-induced allodynia in C57BL/6NCr mice	50 mg/kg, IP	↓Mechanical allodynia	Antioxidant activity	[20]
Thioctic acid	Vincristine- induced neuropathy in Sprague–Dawley rats	1, 5 & 10 mg/kg, IP	↓Tactile & cold allodynia	↓LPO, ↓IL-1β, TNF-α & NO	[35]
Curcumin	Cisplatin & oxaliplatin neuropathy in Wistar rats	10 mg/kg, PO	↓Neurotensin, insignificant decrease in platinum concentration, ↓demyelination	Anti-inflammatory, antiapoptotic & antioxidant	[36]
Euphol from Euphorbia tirucalli	PGE2-induced acute & persistent hypersensitivity in Swiss mice & Wistar Hanover rats, respectively	30 mg/kg, PO	↓Mechanical hypersensitivity ↓persistent hypersensitivity ↓hypersensitivity dose-dependently	↓PKCε ↓NF-ҡB & CREB ↓COX-2	[37]
	cAMP/PKA activation-induced mechanical hypersensitivity in Swiss mice		No inhibition
	PKCε activation-induced mechanical hypersensitivity in Wistar Hanover rats		↓Hyperalgesia
	Paclitaxel-induced neuropathy in Swiss mice		↓Mechanical hypersensitivity	↓PKCε
	Tumors-induced mechanical hypersensitivity in C57BL/6 mice		↓Mechanical hypersensitivity
Rutin,	Oxaliplatin-induced peripheral neuropathy in Swiss mice	Both: 25, 50 & 100 mg/kg	↓Mechanical & cold allodynia,	↓MDA in spinal cord ↓Fos, nitrotyrosine & LPS-induced iNOS,	[38]
Quercetin			Improvement of spinal morphological changes	↓ROS & LPO (Quercetin) ↑GSH
Matrine	Vincristine-induced neuropathy in mice	15, 30 & 60 mg/kg, IP	↓Mechanical & thermal hyperalgesia, ↓cold allodynia,	↑SNAP & SNCV, ↓MDA, total Ca2+, MPO, TNF-α, IL-6, ↑TAOC, Gpx, SOD, IL-10	[39]
Matrine	Vincristine-induced neuropathy in mice	15, 30 & 60 mg/kg, IP	↓Mechanical hyperalgesia by repeated dose, ↓cold allodynia, no significant deference in thermal hyperalgesia	Anti-inflammatory activity, ↓TNF-α, IL-1 & IL-6	[40]
Curcumin	Vincristine-induced neuropathy & formalin-induced nociception in Swiss albino mice	15, 30 & 60 mg/kg, PO	↑Pain threshold, ↓thermal allodynia, ↓Mechanical hyperalgesia, ↓SFI, ↓formalin-induced nociception in delayed phase, but not in acute phase ↓Total Ca ↑SOD, CAT, GPx, & GSH, ↓LPO, iNOS & NO	↓Pro-inflammatory cytokines, Involvement of monoamine pathway	[41]
Paeoniflorin	Paclitaxel-induced mechanical allodynia in C57BL/6NCr mice	0.1 & 1%, topical	↓Mechanical allodynia, time-dependently, ↓abnormal peripheral nerve activity, ↓demyelination & thinning, Involvement of A1 receptor, ↓CHOP	↓Cytosolic Ca2+ ↓ER stress in Schwann cells	[42]
Coumarin from Cinnamomum cassia	Oxaliplatin-induced neuropathy in Sprague-Dawley rats	10 mg/kg, PO	↑Mechanical threshold (insignificant), ↓cold allodynia	↓TNF & IL-1β	[27]

PO per oral, IP intraperitoneal, SFI sciatic functional index, LPO lipid peroxidation, MDA malondialdehyde, TNF tumor necrosis factor, NO nitric oxide, iNOS inducible nitric oxide synthase, IL interleukin, NF-ĸB nuclear factor ĸB, SOD superoxide dismutase, CAT catalase, GSH reduced glutathione, GPx glutathione peroxidase, ROS reactive oxygen species, COX cyclooxygenase, CHOP C/EBP homologous protein, ER endoplasmic reticulum, TAOC total antioxidant capacity, SNCV sensory nerve conduction velocity, SNAP sensory nerve action potential