Table 6.

Effects of different curcumin formulations on neuropathic pain.

Animals (Sex, Strain)	Dose (mg/kg), Route of Administration, Duration of Treatment	Effects			Reference
		Behavioral Evaluation/ Other Parameters	Electrophysiological/ Functional Evaluation	Histopathological/ Biochemical/Molecular Parameters
Diabetic Neuropathy
Curcumin Derivative
Female Swiss Webster mice or diabetic rats (strain and sex were not specified)	STZ − 90 mg/kg, i.p. STZ + phenyl hydrazide derivative J147 (10, 50 mg/kg, i.p. oral, 20 weeks)	↓ Blood glucose and HbA1c levels ↑ Paw thermal response (Hargreaves test) ↓ Tactile allodynia (von Frey) O Sensorimotor function (rotarod test)	↓ MNCV	↓ TNFR1, TNFR2, and type I diabetes mellitus signaling pathways ↑ AMPK, and ephrin receptor signaling pathways ↓ Protein levels of TNF-α, TSPO, iNOS or GFAP and peripheral inflammation marker C-reactive protein	[27]
Male SPF rats	STZ − 50 mg/kg, i.p. STZ + J147 (10 or 100 μM of at 10 mg/kg weight, 5 days) In vitro: J147 (10 and 100 μM)	↓ Mechanical withdrawal threshold (von Frey)		O Cell viability and apoptosis of RSC96 cells ↑ AMPK mRNA and protein expression levels ↓ TRPA1 mRNA and protein expression levels ↓ Calcium reaction level in AITCR treated RSC96 cells	[33]
Nanoparticle-Encapsulated Curcumin
Male Sprague-Dawley	STZ − 30 mg/kg, i.p. STZ + nanoparticle-encapsulated curcumin, 16 mg/kg, sublingual vein, 7th, and 8th week	↓ Mechanical (electronic mechanical stimulator) and thermal (thermal paw stimulator) hyperalgesia		Interacted perfectly with P2Y12 receptor agonist-binding pocket ↓ mRNA and protein expressions of P2Y12 in DRG ↓ Co-localization of glutamine synthetase (a marker of SGCs) in DRG ↓ mRNA and protein expression of IL-1β and Cx43 expressions in DRG X AKT activation	[28]
Self-Nano Emulsifying Drug Delivery System (SNEDDS) Curcumin
Male Sprague–Dawley rats	STZ − 55 mg/kg, i.p. STZ + naïve curcumin (30, 100 and 300 mg/kg, oral, 2 weeks) STZ + SNEDDS curcumin (30, 100 and 300 mg/kg, oral, 2 weeks)	O Body weight and plasma glucose level ✓ Thermal hyperalgesia (tail flick test) in both hot and cold immersion ✓ Mechanical hyperalgesia (von Frey and Randall Sellitto tests)	Naïve and SNEDDS ↓ MNCV and NBF	↓ MDA levels SNEDDS ↓ NF-κB protein expression SNEDDS X IKK-β phosphorylation expression SNEDDS ↓ Protein expression of NF-κB positive cells in nerves SNEDDS ↓ COX-2 and iNOS protein level Naïve and SNEDDS ↓ IL-6 level in sciatic nerves SNEDDS ↓ TNF-a level in sciatic nerves	[30]
CCI
Curcumin (Cur) Loaded with Lipid Nanocapsules (Cur@LNCs)
Female Sprague-Dawley rats	CCI + Cur@LNCs, 400 µL inject, 7 days	↓ Thermal hyperalgesia (hotplate)		↓ Sciatic nerve damages	[29]
Curcumin Prodrug-Curcumin Diglutaric Acid
Male ICR mice	CCI + curcumin diglutaric acid (CurDG) (25, 50, 100, and 200 mg/kg, oral, 14 days)	✓ Mechanical allodynia (von Frey), and thermal hyperalgesia (plantar test) O Motor performance (rotarod test)		↓ Overexpression of TNF-α and IL-6 levels in both sciatic nerve and spinal cord	[32]
Curcumin-Loaded Poly (d, l-lactide-co-glycolide) Nanovesicles
Male CD1 mice	CCI + curcumin (20 mg/kg, intravenous or 0.0005 and 0.025 mg, i.t.) CCI + PLGA CUR (0.045 mg curcumin/mg of nanoparticles, 20 mg/kg, intravenous) CCI + PLGA CUR (0.045 mg curcumin/mg of nanoparticles, 0.0005 and 0.025 mg, i.t.)	Low and high PLGA-CUR, i.t. ↓ Mechanical allodynia (dynamic plantar aesthesiometer test) and thermal hyperalgesia (plantar test) High curcumin, i.t. ↓ allodynia and hyperalgesia		High PLGA-CUR, i.t. ↓ IL-1β, IL-6,TNF-α and BDNF levels in spinal cord	[34]
Curcumin Derivative
Male ICR mice	Curcumin derivative KMS4034 (10 mg/kg, i.p., 120 min post-injection) In vitro: 10 µM KMS4034	↑ Mechanical thresholds (von Frey)	X ICAP and Iheat of TRPV1-expressing HEK293 cells	↓ CGRP expression in lamina I–II of lumbar dorsal horns	[31]

Behavioral modalities are mentioned within parentheses. ✓ = improve; ↑ = increase; ↓ = diminish/decrease/ameliorate; O = no effects/no changes; X = block/inhibit; AMPK = AMP-activated protein kinase; BDNF = brain-derived neurotrophic factor; Cox-2 = cyclooxygenase-2; Cur@LNCs = curcumin (Cur) loaded with lipid nanocapsules; Cx43 = connexin 43; DRG = dorsal root ganglion; GFAP = glial fibrillary acidic protein; ICR = institute of cancer research; IL-1β = interleukin-1β; interleukin 6; iNOS = inducible nitric oxide synthase; i.p. = intraperitoneal; i.t. = intrathecal; MDA = malondialdehyde; mRNA = messenger RNA; P2Y12 = purinergic receptor 12; PLGA-CUR = curcumin-loaded poly (d, l-lactide-co-glycolide) nanovesicles; SGC = satellite glial cells; SNEDDS = self-nano emulsifying drug delivery system; TNF-α = tumor necrosis factor alpha; NF-κB = nuclear factor kappa B; TNFR1 = tumor necrosis factor alpha receptor 1; TNFR2 = tumor necrosis factor alpha receptor 2; TSPO = translocator protein.