Protective Effects of Phyllanthus amarus Against Lipopolysaccharide-Induced Neuroinflammation and Cognitive Impairment in Rats

Abstract

Background: Phyllanthus amarus (PA) is widely studied for its hepatoprotective properties but has recently received increasing attention due to its diverse anti-inflammatory effects. However, the effects of PA in modulating immune responses in the central nervous system leading to protection against functional changes remain unexplored. Therefore, we sought to examine the protective effects of 80% v/v ethanol extract of PA on lipopolysaccharide (LPS)-induced non-spatial memory impairment and neuroinflammation. Methods: Selected major phytoconstituents of PA extract were identified and quantified using high-performance liquid chromatography. Subchronic neurotoxicity was performed in male Wistar rats given daily oral administration of 100, 200, and 400 mg/kg of the PA extract. Their neurobehavioral activities (functional observation battery and locomotor activity) were scored, and the extracted brains were examined for neuropathological changes. Rats were treated orally with vehicle (5% Tween 20), PA extract (100, 200, and 400 mg/kg), or ibuprofen (IBF; 40 mg/kg) for 14 and 28 days before being subjected to novel object discrimination test. All groups were challenged with LPS (1 mg/kg) given intraperitoneally a day prior to the behavioral tests except for the negative control group. At the end of the behavioral tests, the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, nitric oxide (NO), inducible nitric oxide synthase (iNOS), CD11b/c integrin expression, and synaptophysin immunoreactivity were determined in the brain tissues. Results: Gallic acid, ellagic acid, corilagin, geraniin, niranthin, phyllanthin, hypophyllanthin, phyltetralin, and isonirtetralin were identified in the PA extract. Subchronic administration of PA extract (100, 200, and 400 mg/kg) showed no abnormalities in neurobehavior and brain histology. PA extract administered at 200 and 400 mg/kg for 14 and 28 days effectively protected the rodents from LPS-induced memory impairment. Similar doses significantly ( p < 0.05) decreased the release of proteins like TNF-α, IL-1β, and iNOS in the brain tissue. NO levels, CD11b/c integrin expression, and synaptophysin immunoreactivity were also reduced as compared with those in the LPS-challenged group. Conclusion: Pre-treatment with PA extract for 14 and 28 days was comparable with pre-treatment with IBF in prevention of memory impairment and alleviation of neuroinflammatory responses induced by LPS. Further studies are essential to identify the bioactive phytochemicals and the precise underlying mechanisms.

Phyllanthus amarus protects against spatial memory impairment induced by lipopolysaccharide in mice

“…Therefore, the present study sought to investigate the protective effects of a chemically characterized PA extract on spatial memory impairment induced by LPS in mice. This study is an extension of our recent work as described earlier [12].…”

“…Our previous study using the same PA extract given orally for 14 and 28 days has shown that the extract was able to protect against nonspatial memory deficits in rats, which resulted from inflammatory processes in the brain [12]. Indeed, the observed neuroprotective effects were possibly due to the suppression of inflammatory mediators like TNF-α, IL-1β, iNOS, NO, CD11b/c and an increased in synaptophysin marker through the inhibition of toll-like receptor 4 (TLR4) expression in LPS-induced rats [12]. In the present study, PA protected against impairment of spatial memory mediated by LPS in mice.…”

“…This improvement in cognition was suggested to be due to the reduction of oxidative stress, which increases brain anti-oxidant enzymes level [4][5][6][7][8][9]. Our previous study using the same PA extract given orally for 14 and 28 days has shown that the extract was able to protect against nonspatial memory deficits in rats, which resulted from inflammatory processes in the brain [12]. Indeed, the observed neuroprotective effects were possibly due to the suppression of inflammatory mediators like TNF-α, IL-1β, iNOS, NO, CD11b/c and an increased in synaptophysin marker through the inhibition of toll-like receptor 4 (TLR4) expression in LPS-induced rats [12].…”

“…Treatment with PA extract and phyllanthin were found to improve memory impairment and exhibited anti-cholinesterase activity in young and older mice [4,11]. In addition, we have demonstrated the protective effects of PA ©Biomedical Informatics (2019) against non-spatial memory impairment mediated by neuro inflammation [12]. However, studies on the effects of PA on different types of memory are scarce.…”

Phyllanthus amarus prevents LPS-mediated BV2 microglial activation via MyD88 and NF-κB signaling pathways

“…The methanol extract of P. amarus has been reported to possess antioxidant activity [25], inhibited phagocytosis [26] and has hepatoprotective properties [27]. The ethanol extract of P. amarus (EPA) has been shown to possess various biological properties including anticancer [28], recovery of peripheral nerve after injury [29] and immunosuppression [30,31]. Studies on anti-inflammatory activity of P. amarus within the field of neuroinflammation are currently limited.…”