Hexahydrocurcumin protects against cerebral ischemia/reperfusion injury, attenuates inflammation, and improves antioxidant defenses in a rat stroke model

Abstract

The purpose of the present experiment was to investigate whether hexahydrocurcumin (HHC) attenuates brain damage and improves functional outcome via the activation of antioxidative activities, anti-inflammation, and anti-apoptosis following cerebral ischemia/reperfusion (I/R). In this study, rats with cerebral I/R injury were induced by a transient middle cerebral artery occlusion (MCAO) for 2 h, followed by reperfusion. The male Wistar rats were randomly divided into five groups, including the sham-operated, vehicle-treated, 10 mg/kg HHC-treated, 20 mg/kg HHC-treated, and 40 mg/kg HHC-treated I/R groups. The animals were immediately injected with HHC by an intraperitoneal administration at the onset of cerebral reperfusion. After 24 h of reperfusion, the rats were tested for neurological deficits, and the pathology of the brain was studied by 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin and eosin (H&E) staining, and terminal deoxynucleotidyltransferase UTP nick end labeling (TUNEL) staining. In addition, the brain tissues were prepared for protein extraction for Western blot analysis, a malondialdehyde (MDA) assay, a nitric oxide (NO) assay, a superoxide dismutase (SOD) assay, a glutathione (GSH) assay, and a glutathione peroxidase (GSH-Px) assay. The data revealed that the neurological deficit scores and the infarct volume were significantly reduced in the HHC-treated rats at all doses compared to the vehicle group. Treatment with HHC significantly attenuated oxidative stress and inflammation, with a decreased level of MDA and NO and a decreased expression of NF-κB (p65) and cyclooxygenase-2 (COX-2) in the I/R rats. HHC also evidently increased Nrf2 (nucleus) protein expression, heme oxygenase-1 (HO-1) protein expression, the antioxidative enzymes, and the superoxide dismutase (SOD) activity. Moreover, the HHC treatment also significantly decreased apoptosis, with a decrease in Bax and cleaved caspase-3 and an increase in Bcl-XL, which was in accordance with a decrease in the apoptotic neuronal cells. Therefore, the HHC treatment protects the brain from cerebral I/R injury by diminishing oxidative stress, inflammation, and apoptosis. The antioxidant properties of HHC may play an important role in improving functional outcomes and may offer significant neuroprotection against I/R damage.

Inhibition of TIM‐4 protects against cerebral ischaemia‐reperfusion injury

“…To test this hypothesis, we es- Accumulating evidence shows that ischaemic injury and inflammation account for the pathogenic progression of stroke. 18,27 In the present study, we found that the level of the macrophage marker, CD68, and T cell marker, CD3, expression were lower in and TNF-α). It is known that stimulation with LPS or IFN-γ induces TIM-4 expression in macrophages.…”

“…10,12,22 TIM-4 expression is also increased in ischaemic stroke patients. 18,27 In the present study, we found that the level of the macrophage Although we have shown in mice that inhibiting TIM4 protects against reperfusion injury, there are still many limitations of our study. To test this hypothesis, we es- Accumulating evidence shows that ischaemic injury and inflammation account for the pathogenic progression of stroke.…”

“…16 Insufficient cerebral blood flow can cause hypoxia, inflammation, oxidative stress, glutamate excitatory toxicity and blood flow reperfusion can aggravate these symptoms, a process termed IRI. 18 The inflammatory reaction and apoptosis play an important role in cerebral IRI and are the main factors inducing nerve cell injury following IRI. 18 The inflammatory reaction and apoptosis play an important role in cerebral IRI and are the main factors inducing nerve cell injury following IRI.…”

The mechanism(s) of action of antioxidants: From scavenging reactive oxygen/nitrogen species to redox signaling and the generation of bioactive secondary metabolites

“…Hexahydrocurcumin ( 1a ) was also reported as a potent antioxidant in vivo such that a single intraperitoneal injection of 10 to 40 mg/kg dose significantly decreased the MDA and • NO levels and the expression of NF‐κB and COX‐2 in a rat stroke model. This same study found 1a to protect the rats' brain from ischaemia/reperfusion injury, and to reduce inflammatory response . Curcumin was also studied and found effective in a similar rat model, however at a much larger dose (300 mg/kg) .…”

“…This same study found 1a to protect the rats' brain from ischaemia/reperfusion injury, and to reduce inflammatory response. 79 Curcumin was also studied and found effective in a similar rat model, however at a much larger dose (300 mg/kg). 80 Unfortunately, this makes it difficult to draw any comparison between the efficacies of the two compounds.…”