Objective To explore the therapeutic effect and mechanism of Ganoderic acid A (GAA) on cerebral ischemia/reperfusion (I/R) injury in rats. Methods The I/R rat model was constructed by middle cerebral artery embolization. The I/R rats were divided into the model group, low-dose group (0.5 mg/kg GAA), medium-dose group (1 mg/kg GAA), high-dose group (2.5 mg/kg GAA) and the activator group (2.5 mg/kg GAA+0.1 mg/kg LPS), and the healthy SD rats were set as the sham operation group, with 15 rats in each group. The neurological function impairment of rats was scored, the volume of cerebral infarction was detected by TTC staining, brain tissue injury was detected by HE staining, neuronal injury was detected by Nissl staining, and neuronal apoptosis was detected by TUNEL staining. The levels of MDA, SOD, GSH-Px and ROS in rat brain tissues were detected by reagent kits. The protein expression levels of IL-1β, IL-18, TNF-α, NeuN, BDNF, TLR4, NF-κB, p-NF-κB and NLRP3 were detected by Western blot. Results Compared with the model group, the number of neurons and Nissl bodies, cerebral infarction volume fraction, neurological function score and neural cell apoptosis rate of rats in the low-dose, medium-dose and high-dose groups were all decreased, the protein levels of IL-1β, IL-18, TNF-α, TLR4, NLRP3 and p-NF-κB were all decreased, and the levels of NeuN and BDNF were all increased. The levels of SOD and GSH-Px were all increased, while the levels of MDA and ROS were all decreased. Compared with the high-dose group, activator treatment inhibited the therapeutic effect of high-dose GAA on I/R rats. Conclusion GAA has a good therapeutic effect on cerebral I/R injury in rats. GAA can reduce the apoptosis of nerve cells after cerebral I/R injury in rats, inhibit inflammation and oxidative stress responses, and alleviate brain injury. This effect may be related to the inhibition of the TLR4/NF-κB/NLRP3 signaling pathway.
Key words
cerebral ischemia/reperfusion (I/R) /
ganoderic acid A (GAA) /
neuronal injury /
inflammation /
oxidative stress /
TLR4/NF-κB/NLRP3 signaling pathway
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References
[1] ZHENG H, XIAO X, HAN Y, et al.Research progress of propofol in alleviating cerebral ischemia/reperfusion injury[J]. Pharmacol Rep, 2024, 76(5): 962-980.
[2] TÖRTELI A, TÓTH R, BERGER S, et al. Spreading depolarization causes reperfusion failure after cerebral ischemia[J]. J Cereb Blood Flow Metab, 2023, 43(5): 655-664.
[3] XU P, KONG L, TAO C, et al.Elabela-APJ axis attenuates cerebral ischemia/reperfusion injury by inhibiting neuronal ferroptosis[J]. Free Radic Biol Med, 2023, 196: 171-186.
[4] WIDIMSKY P, SNYDER K, SULZENKO J, et al.Acute ischaemic stroke: recent advances in reperfusion treatment[J]. Eur Heart J, 2023, 44(14): 1205-1215.
[5] LIU Y, ZHOU C, TAN J, et al.Ganoderic acid A slows osteoarthritis progression by attenuating endoplasmic reticulum stress and blocking NF-Κb pathway[J]. Chem Biol Drug Des, 2024, 103(1): e14382.
[6] MA F, WANG J, JIANG W, et al.Ganoderic Acid A: a potential natural neuroprotective agent for neurological disorders: a review[J]. Int J Med Mushrooms, 2024, 26(2): 11-23.
[7] ZHANG Y, WANG X, YANG X, et al.Ganoderic acid A to alleviate neuroinflammation of alzheimer's disease in mice by regulating the imbalance of the Th17/Tregs axis[J]. J Agric Food Chem, 2021, 69(47): 14204-14214.
[8] WANG D, CAI X, XU F, et al.Ganoderic Acid A alleviates the degeneration of intervertebral disc via suppressing the activation of TLR4/NLRP3 signaling pathway[J]. Bioengineered, 2022, 13(5): 11684-11693.
[9] TAO ZS, HU XF, WU XJ, et al.Ganoderic Acid A prevents bone loss in lipopolysaccharide-treated male rats by reducing oxidative stress and inflammatory[J]. Chem Biol Interact, 2024, 401: 111164.
[10] 胡哲, 赵军, 宋嵬, 等. 银杏叶提取物对脑缺血再灌注损伤模型大鼠的脑保护作用[J]. 中国比较医学杂志, 2022, 32(9): 55-61.
[11] BAO H, LI H, JIA Y, et al.Ganoderic acid A exerted antidepressant-like action through FXR modulated NLRP3 inflammasome and synaptic activity[J]. Biochem Pharmacol, 2021, 188: 114561.
[12] LONGA EZ, WEINSTEIN PR, CARLSON S, et al.Reversible middle cerebral artery occlusion without craniectomy in rats[J]. Stroke, 1989, 20(1): 84-91.
[13] TUO QZ, ZHANG ST, LEI P.Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications[J]. Med Res Rev, 2022, 42(1): 259-305.
[14] LI B, WANG W, LI Y, et al.cGAS-STING pathway aggravates early cerebral ischemia-reperfusion injury in mice by activating NCOA4-mediated ferritinophagy[J]. Exp Neurol, 2023, 359: 114269.
[15] CHEN Y, HE W, WEI H, et al.Srs11-92, a ferrostatin-1 analog, improves oxidative stress and neuroinflammation via Nrf2 signal following cerebral ischemia/reperfusion injury[J]. CNS Neurosci Ther, 2023, 29(6): 1667-1677.
[16] ZHAO P, LU Y, WANG Z.Naringenin attenuates cerebral ischemia/reperfusion injury by inhibiting oxidative stress and inflammatory response via the activation of SIRT1/FOXO1 signaling pathway in vitro[J]. Acta Cir Bras, 2023, 38: e380823.
[17] LI Y, LUO Y, WANG J, et al.Discovery of novel danshensu derivatives bearing pyrazolone moiety as potential anti-ischemic stroke agents with antioxidant activity[J]. Bioorg Chem, 2023, 131: 106283.
[18] LU Q, SHAO N, FANG Z, et al.The anti-Alzheimer's disease effects of ganoderic acid A by inhibiting ferroptosis-lipid peroxidation via activation of the NRF2/SLC7A11/GPX4 signaling pathway[J]. Chem Biol Interact, 2025, 412: 111459.
[19] AKHTAR W, MUAZZAM KHAN M, KUMAR S, et al.Pathophysiology of cerebral ischemia-reperfusion injury: An overview of oxidative stress and plant-based therapeutic approaches[J]. Brain Res, 2025, 1847: 149308.
[20] CHEN S, CHEN H, DU Q, et al.Targeting myeloperoxidase (MPO) mediated oxidative stress and inflammation for reducing brain ischemia injury: potential application of natural compounds[J]. Front Physiol, 2020, 11: 433.
[21] MIZUMA A, YENARI MA.Anti-inflammatory targets for the treatment of reperfusion injury in stroke[J]. Front Neurol, 2017, 8: 467.
[22] ZHAO Y, LIU B, XU L, et al.ROS-induced mtDNA release: the emerging messenger for communication between neurons and innate immune cells during neurodegenerative disorder progression[J]. Antioxidants (Basel), 2021, 10(12): 1917.
[23] LORENZANO S, ROST NS, KHAN M, et al.Early molecular oxidative stress biomarkers of ischemic penumbra in acute stroke[J]. Neurology, 2019, 93(13): e1288-e1298.
[24] LI R, ZHOU Y, ZHANG S, et al.The natural (poly) phenols as modulators of microglia polarization via TLR4/NF-κB pathway exert anti-inflammatory activity in ischemic stroke[J]. Eur J Pharmacol, 2022, 914: 174660.
[25] WANG N, LIU Y, JIA C, et al.Machine learning enables discovery of Gentianine targeting TLR4/NF-κB pathway to repair ischemic stroke injury[J]. Pharmacol Res, 2021, 173: 105913.
[26] PENG J, WANG H, GONG Z, et al.Idebenone attenuates cerebral inflammatory injury in ischemia and reperfusion via dampening NLRP3 inflammasome activity[J]. Mol Immunol, 2020, 123: 74-87.
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