Antioxidant and Anti-inflammatory Mechanisms of Neuroprotection by Ursolic Acid: Addressing Brain Injury, Cerebral Ischemia, Cognition Deficit, Anxiety, and Depression

Table 1

Neuroprotective effects of ursolic acid in cellular and animal models.

Model	Procedure	Dosage	Main outcome	Reference
TBI	Wild-type and Nrf2^(−/−) mice	50, 100, or 150 mg/kg, i.p.	Neuroprotective in wild-type not Nrf2^(−/−) mice; increase the expression of Akt (in Nrf2 upstream signalling)	Ding et al. [18]
Subarachnoid haemorrhage (SH)	Endovascular puncture model in rats	25 or 50 mg/kg, i.p. at 0.5, 24, and 47 h after SH	Decrease the expressions of ICAM-1, TLR4, NF-κB P65, IL-1β, TNF-α, IL-6, iNOS, and MMP-9; ameliorate apoptosis (TUNEL method); attenuate early brain injury (brain oedema, BBB disruption, neural apoptosis, and neurological deficient)	Zhang et al. [19, 20]
Spinal cord injury (SCI)	C57BL/6J mice	100 or 200 mg/kg, p.o. 1 h after SCI and thereafter once daily for 6 weeks	Promote axonal regrowth and regaining of motor functions; suppress astrogliosis; decrease the levels of IL-6 and TNF-α; activate MAPK and PI3K/Akt/MTOR pathways at the SCI	Sahu et al. [21]
Focal cerebral ischemia	Transient MCAO in Nrf2(-/-) and wild-type mice	130 mg/kg, i.p.	Improve neurological deficit and reduce infarct size in wild-type mice; decrease lipid peroxidation; activate Nrf2; decrease TLR4 and NF-κB expression; no effect in Nrf2(-/-) mice	Li et al. [22]
Cerebral ischemia and reperfusion injury	MACO and reperfusion (MCAO/R) in rats	10 or 20 mg/kg, i.g. at 0.5, 24, and 47 h after reperfusion	Decrease neurological deficit scores, infarct volume, and apoptotic cells; suppress IL-1β, TNF-α, IL-6, TLR4 and HMGB1 levels, and NF-κB signalling	Wang et al. [29]
Cerebral ischemia and reperfusion injury	MCAO/R model in rats	5, 10, or 20 mg/kg, i.g. at 0.5, 24, and 47 h after reperfusion	Reduce the neurological deficit score, infarct volume; increase the number of intact neurons, PPARγ (protein), and PPARγ-positive cells; reduce (protein) MMP2, MMP9, and activated MAPKs; increase TIMP1; effect is dose-dependent	Wang et al. [32]
Radioprotection	Radiation with 5 Gy or fractionated exposure with 0.5 Gy continuously for 10 days in mice; open-field (locomotor) test; novel object recognition test; fear conditioning test; tail suspension test; forced swim test	25 mg/kg/daily, i.p. for 30 days after irradiation	Ameliorate irradiation-induced deficits in contextual learning and memory and in novel object recognition memory; exacerbate radiation-induced reduction of neurogenesis	Tang et al. [38]
Chemical-induced cognitive deficit	Domoic acid-induced cognitive deficit in mice—step-through passive avoidance task; Morris water maze (MWM) test	100 mg/kg, p.o. for 3 weeks	Attenuate the mitochondrial dysfunction and cognitive deficits through promoting Akt phosphorylation and FoxO1 nuclear exclusion in the hippocampus; LY294002, an inhibitor of PI3K/Akt signalling inhibit UA effect	Wu et al. [39]
Chemical-induced neuronal damage	Kainite-induced neuronal damage—primary neuronal cultures of cells isolated from the hippocampi of 7-day-old rats	Pretreatment with 5-15 μM	Suppress neuronal damages; reverse the decrease in mitochondrial membrane potential and free radical generation; effect is dose-dependent	Shih et al. [42]
Aging and chemical-induced neurotoxicity	D-Galactose-induced neurotoxicity in senescent mice; open-field test; Morris water maze	10 mg/kg, p.o. for 2 weeks	Reverse learning and memory impairment; increase the activity of CAT, SOD, GPx, and GR; reduce lipid peroxidation (MDA); inhibit caspase-3 activation	Lu et al. [43]
Aging	Antiaging biomarkers in the hypothalamus of mice	200 mg/kg, i.p. twice daily for 7 days	Increase protein levels of SIRT1 (∼ folds), SIRT-6 (∼ folds), α-Klotho (∼), and PGC-1β (∼ folds)	Bahrami and Bakhtiari [44]
Aging	Antiaging biomarkers in hepatic tissues of mice	200 mg/kg, i.p twice daily for 7 days	Increase protein levels of SIRT1 (~ folds), SIRT6 (~ folds), and PGC-1β (~ folds)	Gharibi et al. [49]
Inflammatory response in the mouse prefrontal cortex	D-Galactose-induced inflammatory in mice—step-through test and Morris water maze task	10 mg/kg, p.o. for 8 weeks	Decrease AGEs, ROS, and protein carbonyl levels; suppress microglia cells and astrocyte activation; decrease CD11b and glial fibrillary acidic protein expression; suppress iNOS, COX-2, IL-1β, IL-6, and TNF-α d levels in the prefrontal cortex; attenuate the AGE-induced RAGE expression and NF-κB p65 nuclear translocation	Lu et al. [50]
Cognition impairment	LPS-induced cognitive deficits in mice in open field, step-through passive avoidance, and Morris water maze task	10 or 20 mg/kg, i.p. for 12 weeks	Improve cognitive deficits; decrease the level of COX-2, iNOS, TNF-α, IL-1β, IL-2, and IL-6; inhibit the induced IκBα phosphorylation and degradation, NF-κB p65 nuclear translocation, and p38 activation	Wang et al. [51]
Obesity-induced cognitive impairments	C57/BL6J mice fed a HFD in both the step-through test and the Morris water maze task	10 mg/kg, p.o. for 20 weeks	Improve behavioral performance; inhibit ER stress and IκB kinase β/NF-κB signalling; restore insulin signalling and PI3K/Akt/mTOR pathway; effect inhibited by PI-103 (PI3K 110α inhibitor)	Lu et al. [52]
Insulin resistance and chronic restraint stress- (CRS-) induced behavioral alterations	Chronic restraint stress (CRS) in mice under insulin resistance—Morris water maze test	5 or 10 mg/kg, p.o. for 30 days	Improve cognitive impairment; decrease serum corticosterone and TNF-α levels; improve insulin sensitivity, learning, and cognitive performance; synergize with metformin	Mourya et al. [53]
β-Amyloid-induced memory impairment	Intracerebroventricularly administered Aβ(25-35) in mice—open-field test and Morris water maze test	10-40 mg/kg, p.o. for 11 days	Reverse learning and memory deficits; suppress MDA, IL-1β, IL-6, and TNF-α and increase GSH levels in the hippocampus	Liang et al. [54]
β-Amyloid-induced neurotoxicity	PC12 cells subjected to Aβ(25-35)-induced toxicity	Up to 250 μM	Inhibit the expression of iNOS and COX-2; block NF-κB nuclear translocation (p65 subunit); reduce IκBα, ERK1/2, p-38, and JNK phosphorylations; inhibit ROS generation and cell death	Yoon et al. [55]; Heo et al. [56]; Hong et al. [57]
β-Amyloid interactions with its receptor CD36		Up to 20 μM	Block the binding of Aβ to CHO-CD36 cells or Aβ to microglial cells; reduce subsequent ROS production	Wilkinson et al. [58]

Abbreviations: AGEs: advanced glycation end products; Akt; protein kinase B; BBB: blood-brain barrier; CAT: catalase; COX: cyclooxygenase; ER: endoplasmic reticulum; ERK: extracellular signal-regulated kinase; GPx: glutathione peroxidase; GR: glutathione reductase; GSH: glutathione; HMGB1: high-mobility group protein B1; ICAM-1: intercellular adhesion molecule-1; IκBα: nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor, alpha; IL-1β: interleukin-1β; IL-6, interleukin-6; iNOS: inducible nitric oxide synthase; i.g.: intragastric; i.p.: intraperitoneal; JNK: c-Jun N-terminal kinases; LPS: lipopolysaccharide; MACO: middle cerebral artery occlusion; MAPK: mitogen-activated protein kinase; MMP: matrix metalloproteinase; MDA: malondialdehyde; mTOR: mammalian target of rapamycin; Nrf2: nuclear factor-erythroid 2-related factor 2; NF-κB: nuclear factor-κB; PGC-1β: peroxisome proliferator-activated receptor-gamma coactivator-1β; PI3K: phosphoinositide 3-kinase; p.o.: per os or oral administration; PPARγ: peroxisome proliferator-activated receptor-γ; RAGE: receptor for advanced glycation end products; ROS: reactive oxygen species; SCI: spinal cord injury; SH: subarachnoid haemorrhage; SIRT: sirtuin; SOD: superoxide dismutase; TBI: traumatic brain injury; TLR4: toll-like receptor; TIMP1: tissue inhibitor of metalloproteinase 1; TNF-α: tumor necrosis factor-α.