Kaempferol Protects Against Cerebral Ischemia Reperfusion Injury Through Intervening Oxidative and Inflammatory Stress Induced Apoptosis

Abstract

The aim of this research is to investigate the potential neuro-protective effect of kaempferol which with anti-oxidant, anti-inflammatory, and immune modulatory properties, and understand the effect of kaempferol on reducing cerebral ischemia reperfusion (I/R) injury in vivo. Male adult Sprague Dawley (SD) rats were pretreated with kaempferol for one week via gavage before cerebral I/R injury operation. We found that kaempferol treatment can reduce the cerebral infarct volume and neurological score after cerebral I/R. Rats were sacrificed after 24 h reperfusion. We observed that kaempferol improved the arrangement, distribution, and morphological structure of neurons, as well as attenuated cell apoptosis in brain tissue via hematoxylin and eosin (H&E) staining, Nissl staining and TUNEL staining. Superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH) kit analysis, enzyme-linked immunosorbent (ELISA) assay, real-time PCR, Western blot, and immunohistochemical examination indicated that kaempferol mitigated oxidative and inflammatory stress via regulating the expression of proteins, p-Akt, p-GSK-3b, nuclear factor erythroid2-related factor 2 (Nrf-2), and p-NF-kB during cerebral I/R, thus increasing the activity of SOD and GSH, meanwhile decreasing the content of MDA in serum and brain tissue, as well as restoring the expression levels of tumor necrosis factor alpha (TNF-a), interleukin-1b (IL-1b), and IL-6 in vivo. Taken together, this study suggested that kaempferol protects against cerebral I/R induced brain damage. The possible mechanism is related with inhibiting oxidative and inflammatory stress induced apoptosis.

Interleukin-22 Plays a Protective Role by Regulating the JAK2-STAT3 Pathway to Improve Inflammation, Oxidative Stress, and Neuronal Apoptosis following Cerebral Ischemia-Reperfusion Injury

“…The inflammatory response plays a pivotal role in the pathophysiology of I/R-induced cerebral injury. After stroke, the interruption and reperfusion of blood flow in brain tissue trigger inflammatory cell infiltration and cause a robust inflammatory response, which induces neuronal apoptosis and death [ 43 , 44 ]. Multiple inflammatory-related cytokines are released in ischemic brain injury and participate in the damage and repair process of brain tissue, including ILs, TNF, interferon, and chemokines [ 45 , 46 ].…”

Neuroprotective effect of a new free radical scavenger HL-008 against ischemia-reperfusion injury

“…The tissue plasminogen activator, tPA dissolves thrombi and restores blood ow by promoting brinolysis. However, there is increasing evidence indicating that an ROS burst caused by reperfusion may aggravate brain injury [27][28][29]. Therefore, timely and effective ROS elimination in the I/R process is favorable for neuroprotection.…”

Merging the Multi-Target Effects of Phytochemicals in Neurodegeneration: From Oxidative Stress to Protein Aggregation and Inflammation

“…In the last decades, the search for an effective and potentially safe strategy to combat oxidative stress-mediated neuronal damage has increasingly prompted the investigation of naturally occurring compounds as antioxidant agents. The attenuation of oxidative stress by bioactive compounds belonging to different classes of phytochemicals including (i) flavonoids (quercetin, kaempferol and myricetin, scutellarin, baicalin, apigenin, catechins, epigallocatechin, and genistein) [ 52 , 61 , 81 , 82 , 83 , 88 , 94 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 ]; (ii) phenolic acids (syringic, gallic, caffeic, chlorogenic and salvianolic acids, and curcumin) [ 70 , 103 , 104 , 105 , 138 , 139 , 140 , 141 , 142 , 143 ]; (iii) flavonolignans (silymarin) [ 96 ]; (iv) stilbenes (resveratrol) [ 59 , 65 , 97 , 98 , 144 ]; (v) terpenes (bacosides/bacopasides, withanolides, and the carotenoids lutein and zeaxanthin) [ 7 , 110 , 113 , 115 , 145 , 146 , 147 ]; (vi) alkaloids (berberine and caffeine) [ 148 , 149 ]; (vii) glucosinolates (sulforaphane) and polyamines (spermine/spermidine) [ 123 , 124 ,…”

“…Roughly, the antioxidant mechanisms of phytochemicals consist of (1) promoting ROS scavenging and the suppression of intracellular ROS accumulation [ 82 , 130 , 136 , 137 , 145 ]; and/or (2) potentiation of antioxidant defense mechanisms [ 83 , 131 , 132 , 133 , 134 , 135 , 138 , 140 , 144 ]. A common molecular mechanism through which these natural compounds boost antioxidant defenses consists of activating the Nuclear factor (erythroid-derived 2)-like 2/antioxidant responsive element (Nrf2/ARE), which induces the expression of various ROS-dissipating and antioxidant enzymes [ 83 , 131 , 132 , 133 , 134 , 135 , 138 , 140 , 143 , 144 , 148 ]. These include heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase (NQO1), as well as γ-glutamyl-cysteine synthetase (GCS), which promotes the synthesis of endogenous glutathione (GSH), as well as GSH synthetase (GSS), GSH reductase (GSR), GSH peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), thioredoxin (THx), and cysteine-glutamate exchanger, the subunit of glutamate-cysteine ligase (GCL).…”

“…Moreover, some phytochemicals, such as quercetin, have been shown to induce paraoxonase 2 (PNO2), a ubiquitously expressed enzyme in the human brain, which is associated with neuroprotection and the suppression of oxidative stress owing to its strategic placement within mitochondria [ 76 , 151 ]. Phytochemicals also prevent ROS-mediated lipid peroxidation, which is known to exacerbate oxidative stress through lipid-derived radicals [ 81 , 132 , 134 , 137 , 140 , 145 ]. This is documented in various experimental models of neurodegeneration and neurotoxicity, where different phytochemicals can prevent the generation of malondialdehyde (MDA) and hydroxynonenal (HNE), the final products of peroxidation of unsaturated fatty acids [ 81 , 132 , 134 , 137 , 140 , 144 , 145 ].…”