Effects of Vitamin D3 on the NADPH Oxidase and Matrix Metalloproteinase 9 in an Animal Model of Global Cerebral Ischemia

Abstract

Decreased blood flow in the brain leads to a rapid increase in reactive oxygen species (ROS). NADPH oxidase (NOX) is an enzyme family that has the physiological function to produce ROS. NOX2 and NOX4 overexpression is associated with aggravated ischemic injury, while NOX2/4-deficient mice had reduced stroke size. Dysregulation of matrix metalloproteinases (MMPs) contributes to tissue damage. The active form of vitamin D3 expresses neuroprotective, immunomodulatory, and anti-inflammatory effects in the CNS. The present study examines the effects of the vitamin D3 pretreatment on the oxidative stress parameters and the expression of NOX subunits, MMP9, microglial marker Iba1, and vitamin D receptor (VDR), in the cortex and hippocampus of Mongolian gerbils subjected to ten minutes of global cerebral ischemia, followed by 24 hours of reperfusion. The ischemia/reperfusion procedure has induced oxidative stress, changes in the expression of NOX2 subunits and MMP9 in the brain, and increased MMP9 activity in the serum of experimental animals. Pretreatment with vitamin D3 was especially effective on NOX2 subunits, MMP9, and the level of malondialdehyde and superoxide anion. These results outline the significance of the NOX and MMP9 investigation in brain ischemia and the importance of adequate vitamin D supplementation in ameliorating the injury caused by I/R.

<p>Pristimerin Inhibits MMP-9 Expression and Cell Migration Through Attenuating NOX/ROS-Dependent NF-κB Activation in Rat Brain Astrocytes Challenged with LPS</p>

“…It has been reported that ROS generated by NOX can lead to MMP-9 expression challenged with various stimuli, including in vivo and ex vivo studies. 32,34 Our results of the present study showed that in RBA-1 cells, NOX-dependent ROS contributes to MMP-9 expression induced by LPS. Moreover, the results were confirmed by ChIP assay, pretreatment of APO, DPI, or edaravone can block the NF-κB p65 interaction with MMP-9 promoter element.…”

“… 27 Moreover, several reports have shown that scavenging ROS is a candidate for managing neurodegenerative diseases. 34 , 35 Triterpenoids have been found in a wide range of vegetable kingdom. This kind of compound has many effects on modulating cellular signaling networks including anti-oxidative stress.…”

Vitamin D Deficiency Aggravates Hepatic Oxidative Stress and Inflammation during Chronic Alcohol-Induced Liver Injury in Mice

“…However, the mechanism through which vitamin D deficiency promotes oxidative stress remains obscure. Several reports indicated that the protective effect of vitamin D3 against oxidative stress was associated with the regulation of NADPH oxidases and antioxidant enzymes [15,16,25,27]. Our previous study also found that vitamin D3 pretreatment alleviates LPS-induced real oxidative stress through regulating oxidant and antioxidant enzyme genes [28].…”

“…Another prospective study found that supplementation with vitamin D reduced the Child-Pugh score in patients with alcoholic liver cirrhosis [13]. Increasing data demonstrate that vitamin D has an antioxidant activity [14][15][16]. Several studies have considered its antioxidant potential to be even stronger than vitamin E and melatonin [17].…”

Pretreatment with Cholecalciferol Alleviates Renal Cellular Stress Response during Ischemia/Reperfusion-Induced Acute Kidney Injury

“…Several studies indicate that antioxidant enzymes, such as HO-1 and SOD, protect against I/R-evoked AKI [44–49]. A recent study showed that pretreatment with active VitD3 suppressed the NADPH oxidase NOX2 (also termed gp91phox) subunit during I/R-induced brain injury [50]. The present study found that the expression of renal gp91phox , p47phox , and nox4 , three NADPH oxidase subunits, was upregulated in I/R-induced AKI.…”