Omarigliptin/galangin combination mitigates lipopolysaccharide-induced neuroinflammation in rats: Involvement of glucagon-like peptide-1, toll-like receptor-4, apoptosis and Akt/GSK-3β signaling

Jiang

BioMed Research International

et al. 2022

Postoperative cognitive dysfunction (POCD) in elderly patients undergoing general anesthesia is a major problem in the aging society. Sevoflurane is the most widely applied anesthetic in clinical practice. In this study, we investigated the effects of the GLP-1 analogue liraglutide on cognitive function in aged rats anesthetized by sevoflurane. Specifically, 48 Sprague-Dawley rats were divided into the control (C) group, the liraglutide (L) group, the sevoflurane (S) group, and the sevoflurane+liraglutide (SL) group, each group with 12 rats. In the S group and the SL group, the rats were injected subcutaneously with normal saline and liraglutide after inhalation of a mixture of 3% sevoflurane and pure oxygen. In the C group and the L group, normal saline and liraglutide were injected subcutaneously into the rats after inhalation of pure oxygen. Morris Water Maze Task was applied for the detection of spatial learning and memory in rats; HE and TUNEL for staining; and western blot for quantifying Bax, Bcl-2 expression, and examining caspase-3 activity in hippocampal tissues as well as for revealing the antiapoptotic mechanism. Besides, the accumulation of inflammatory factors NF-κB and IL-1β in the hippocampal tissue was quantitatively studied to reveal the anti-inflammatory mechanism. The protective effect of liraglutide on sevoflurane toxicity was the first to be confirmed in this study. Additionally, this study elucidated the mechanism of the above effect. The results of this study might be helpful to find an effective medical solution for the treatment of POCD caused by sevoflurane anesthesia.

Section: Discussionmentioning

confidence: 99%

GLP-1 Analog Alleviated Cognitive Dysfunction in Aged Rats Anaesthetized with Sevoflurane

Jiang

BioMed Research International

et al. 2022

“…Hence, the cytoprotective SIRT1 protein expression was examined. Meanwhile, the antioxidant Nrf2/HO-1 pathway and its downstream effector GPx were explored alongside the levels of lipid peroxides (MDA) [ 28 , 29 ]. Herein, statistical significance was detected among groups in the hippocampal levels of SIRT1 [F (3, 20) = 8.56, p = 0.0007], nuclear Nrf2 [F (3, 20) = 8.932, p = 0.0006], HO-1 [F (3, 20) = 12.11, p < 0.0001], GPx, [F (3, 20) = 8.52, p = 0.0008], and MDA [F (3, 20) = 34.51, p < 0.0001], as shown in Figure 5 A–E.…”

Section: Resultsmentioning

confidence: 99%

“…Hence, the cytoprotective SIRT1 protein expression was examined. Meanwhile, the antioxidant Nrf2/HO-1 pathway and its downstream effector GPx were explored alongside the levels of lipid peroxides (MDA) [28,29] 5A-E. In comparison to the vehicle-treated control group, rats intoxicated with cadmium showed significantly (p < 0.01) reduced levels of the cytoprotective SIRT1 by 50.9%.…”

Section: Topiramate Combats Hippocampal Redox Aberrations In Cadmium-...mentioning

confidence: 99%

Targeting Autophagy, Apoptosis, and SIRT1/Nrf2 Axis with Topiramate Underlies Its Neuroprotective Effect against Cadmium-Evoked Cognitive Deficits in Rats

Arab,

Eid,

Yahia

et al. 2023

Pharmaceuticals

Self Cite

Cadmium is an environmental toxicant that instigates cognitive deficits with excessive glutamate excitatory neuroactivity in the brain. Topiramate, a glutamate receptor antagonist, has displayed favorable neuroprotection against epilepsy, cerebral ischemia, and Huntington’s disease; however, its effect on cadmium neurotoxicity remains to be investigated. In this study, topiramate was tested for its potential to combat the cognitive deficits induced by cadmium in rats with an emphasis on hippocampal oxidative insult, apoptosis, and autophagy. After topiramate intake (50 mg/kg/day; p.o.) for 8 weeks, behavioral disturbances and molecular changes in the hippocampal area were explored. Herein, Morris water maze, Y-maze, and novel object recognition test revealed that topiramate rescued cadmium-induced memory/learning deficits. Moreover, topiramate significantly lowered hippocampal histopathological damage scores. Mechanistically, topiramate significantly replenished hippocampal GLP-1 and dampened Aβ42 and p-tau neurotoxic cues. Notably, it significantly diminished hippocampal glutamate content and enhanced acetylcholine and GABA neurotransmitters. The behavioral recovery was prompted by hippocampal suppression of the pro-oxidant events with notable activation of SIRT1/Nrf2/HO-1 axis. Moreover, topiramate inactivated GSK-3β and dampened the hippocampal apoptotic changes. In tandem, stimulation of hippocampal pro-autophagy events, including Beclin 1 upregulation, was triggered by topiramate that also activated AMPK/mTOR pathway. Together, the pro-autophagic, antioxidant, and anti-apoptotic features of topiramate contributed to its neuroprotective properties in rats intoxicated with cadmium. Therefore, it may be useful to mitigate cadmium-induced cognitive deficits.

“…Similar to human depression, the neuropathology of the CRS paradigm implicates aberrant activation of the HPA axis, resulting in escalating levels of plasma corticosterone in animals [ 2 , 6 ]. Consequently, multiple brain regions, including the hippocampus, experience excessive neuroinflammatory reactions and overshooting of the pro-inflammatory cytokines, e.g., interleukin 1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) [ 2 , 3 , 7 , 8 , 9 ]. Excessive pro-inflammatory cytokine production has been reported to activate the transcription of cyclo-oxygenase 2 (COX-2), the rate-limiting enzyme in prostaglandin E 2 (PGE 2 ) production, thereby intensifying neuroinflammation [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Meloxicam Targets COX-2/NOX1/NOX4/Nrf2 Axis to Ameliorate the Depression-like Neuropathology Induced by Chronic Restraint Stress in Rats

et al. 2023

Self Cite

Meloxicam has shown significant neuroprotection in experimental models of stroke, Alzheimer’s disease, and Parkinson’s disease. However, the potential of meloxicam to treat depression-like neuropathology in a chronic restraint stress (CRS) model and the associated molecular changes has been insufficiently explored. The current work aimed to explore the potential neuroprotective actions of meloxicam against CRS-evoked depression in rats. In the current experiments, animals received meloxicam (10 mg/kg/day; i.p.) for 21 days, and CRS was instigated by restraining the animals for 6 h/day during the same period. The sucrose preference test and the forced swimming test were used to explore the depression-linked anhedonia/despair, whereas the open-field test examined the animals’ locomotor activity. The current findings revealed that CRS elicited typical depression behavioral anomalies in the animals, including anhedonia, despair, and diminished locomotor activity; these findings were reinforced with Z-normalization scores. These observations were corroborated by brain histopathological changes and increased damage scores. In CRS-exposed animals, serum corticosterone spiked, and the hippocampi revealed decreased monoamine neurotransmitter levels (norepinephrine, serotonin, and dopamine). Mechanistically, neuroinflammation was evident in stressed animals, as shown by elevated hippocampal TNF-α and IL-1β cytokines. Moreover, the hippocampal COX-2/PGE2 axis was activated in the rats, confirming the escalation of neuroinflammatory events. In tandem, the pro-oxidant milieu was augmented, as seen by increased hippocampal 8-hydroxy-2′-deoxyguanosine alongside increased protein expression of the pro-oxidants NOX1 and NOX4 in the hippocampi of stressed animals. In addition, the antioxidant/cytoprotective Nrf2/HO-1 cascade was dampened, as evidenced by the lowered hippocampal protein expression of Nrf2 and HO-1 signals. Interestingly, meloxicam administration mitigated depression manifestations and brain histopathological anomalies in the rats. These beneficial effects were elicited by meloxicam’s ability to counteract the corticosterone spike and hippocampal neurotransmitter decrease while also inhibiting COX-2/NOX1/NOX4 axis and stimulating Nrf2/HO-1 antioxidant pathway. Together, the present findings prove the neuroprotective/antidepressant actions of meloxicam in CRS-induced depression by ameliorating hippocampal neuroinflammation and pro-oxidant changes, likely by modulating COX-2/NOX1/NOX4/Nrf2 axis.