Korean J Physiol Pharmacol.  2020 Jan;24(1):27-37. 10.4196/kjpp.2020.24.1.27.

Inhibitory effect of carvacrol on lipopolysaccharide-induced memory impairment in rats

• Lee B
• Yeom M
• Shim I
• Lee H
• Hahm DH

• KMID: 2466567
• DOI: http://doi.org/10.4196/kjpp.2020.24.1.27

Abstract

Neuroinflammation is an important process underlying a wide variety of neurodegenerative diseases. Carvacrol (CAR) is a phenolic monoterpene commonly used as a food additive due to its antibacterial properties, but it has also been shown to exhibit strong antioxidative, anti-inflammatory, and neuroprotective effects. Here, we sought to investigate the effects of CAR on inflammation in the hippocampus and prefrontal cortex, as well as the molecular mechanisms underlying these effects. In our study, lipopolysaccharide was injected into the lateral ventricle of rats to induce memory impairment and neuroinflammation. Daily administration of CAR (25, 50, and 100 mg/kg) for 21 days improved recognition, discrimination, and memory impairments relative to untreated controls. CAR administration significantly attenuated expression of several inflammatory factors in the brain, including interleukin-1β, tumor necrosis factor-α, and cyclooxygenase-2. In addition, CAR significantly increased expression of brain-derived neurotrophic factor (BDNF) mRNA, and decreased expression of Toll-like receptor 4 (TLR4) mRNA. Taken together, these results show that CAR can improve memory impairment caused by neuroinflammation. This cognitive enhancement is due to the anti-inflammatory effects of CAR medicated by its regulation of BDNF and TLR4. Thus, CAR has significant potential as an inhibitor of memory degeneration in neurodegenerative diseases.

Keyword

Brain-derived neurotrophic factor; Cytokines; Inflammation; Lipopolysaccharides; Memory

MeSH Terms

Animals
Brain
Brain-Derived Neurotrophic Factor
Cyclooxygenase 2
Cytokines
Discrimination (Psychology)
Food Additives
Hippocampus
Inflammation
Lateral Ventricles
Lipopolysaccharides
Memory*
Necrosis
Neurodegenerative Diseases
Neuroprotective Agents
Phenol
Prefrontal Cortex
Rats*
RNA, Messenger
Toll-Like Receptor 4
Brain-Derived Neurotrophic Factor
Cyclooxygenase 2
Cytokines
Food Additives
Lipopolysaccharides
Neuroprotective Agents
Phenol
RNA, Messenger
Toll-Like Receptor 4

Figure

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  Fig. 1 Experimental schedule of lesion generation, CAR administration, and behavioral tests in rats.CAR, carvacrol; LPS, lipopolysaccharide.

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  Fig. 2 Effects of CAR on body weight on the first day prior to LPS injection and on day 21 after LPS injection (n = 10–12/group).CAR, carvacrol; LPS, lipopolysaccharide; SAL, saline-treated; IBU, ibuprofen. **p < 0.01 vs. SAL group; #p < 0.05, ##p < 0.01 vs. LPS group.

• 

  Fig. 3 Effects of CAR on memory impairment in the ORT and MWM test.The ability to discriminate between familiar objects (A) and new objects (B) in the ORT. The MWM test was used to assess the effect of CAR on spatial learning and memory. The time taken to escape from water (latency) during acquisition trials using a submerged platform (C), the percentages of time spent in the target quadrant and the proportion of the total distance traversed in the target quadrant (D), and swimming speed (E) in the MWM test. Locomotor activity (counts) and total number of rearings (G) in the OFT (n = 10–12/group). CAR, carvacrol; ORT, object recognition test; MWM, Morris water maze; OFT, open field test; LPS, lipopolysaccharide; SAL, saline-treated; IBU, ibuprofen. *p < 0.05, **p < 0.01, ***p < 0.001 vs. SAL group; #p < 0.05, ##p < 0.05 vs. LPS group.

• 

  Fig. 4 Effects of CAR on depression-like and anxiety-like behaviors in the forced swimming test (FST) and elevated plus maze (EPM) test after LPS injection.Immobility time (A) in the FST, numbers of entries into the open and closed arms in the EPM test (B and C), and grip strength (D). CAR, carvacrol; LPS, lipopolysaccharide; SAL, saline-treated; IBU, ibuprofen. *p < 0.05 and **p < 0.01 vs. SAL group; #p < 0.05 vs. LPS group.

• 

  Fig. 5 Effects of CAR on inflammatory mediator concentrations in the hippocampus and prefrontral cortex of rats exposed to LPS.Interleukin (IL)-1β (A), IL-6 (B), tumor necrosis factor (TNF)-α (C), cyclooxygenase-2 (COX-2) (D), and nuclear factor-kappa B (NF-κB) (E) concentrations (n = 6/group). CAR, carvacrol; LPS, lipopolysaccharide; SAL, saline-treated; IBU, ibuprofen. *p < 0.05, **p < 0.01 vs. SAL group; #p < 0.05, ##p < 0.01 vs. LPS group.

• 

  Fig. 6 Effects of CAR on immune signaling molecules expression levels in the hippocampus of rats exposed to LPS.Inducible nitric oxide synthase (iNOS) (A), Toll-like receptor 4 (TLR4) (B), and brain-derived neurotrophic factor (BDNF) (C) mRNAs. PCR bands on agarose gels and relative intensities are shown in (D). The expression levels of iNOS, TLR4, and BDNF mRNAs were normalized to GAPDH mRNA as an internal control (n = 6/group). CAR, carvacrol; LPS, lipopolysaccharide; SAL, saline-treated; IBU, ibuprofen. *p < 0.05 and **p < 0.01 vs. SAL group; #p < 0.05 vs. LPS group.

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