Z‐Guggulsterone attenuates astrocytes‐mediated neuroinflammation after ischemia by inhibiting toll‐like receptor 4 pathway

Abstract

Inflammatory damage plays a pivotal role in ischemic stroke pathogenesis and may represent one of the therapeutic targets. Z-Guggulsterone (Z-GS), an active component derived from myrrh, has been used to treat various diseases. The traditional uses suggest that myrrh is a good candidate for anti-inflammatory damage. This study was to investigate the anti-inflammatory and neuroprotective effects of Z-GS following cerebral ischemic injury, as well as the exact mechanisms behind them. Rat middle cerebral artery occlusion (MCAO) model and in vitro astrocytes oxygen-glucose deprivation (OGD) model were adopted to simulate ischemic stroke. Z-GS (30 or 60 mg/kg) was administered intraperitoneally immediately after reperfusion, while astrocytes were maintained in 30 or 60 μM Z-GS before OGD treatment. The results indicated that Z-GS significantly alleviated neurological deficits, infarct volume and histopathological damage in vivo, and increased the astrocytes viability in vitro. Moreover, the treatment of Z-GS inhibited the astrocytes activation and down-regulated the mRNA levels of pro-inflammatory cytokines. Furthermore, the activated TLR4-NF-κB signaling pathways induced by MCAO or OGD were significantly suppressed by Z-GS treatment, which was achieved via inhibiting the phosphorylation of JNK. Our results demonstrated that Z-GS exerted neuroprotective and anti-inflammatory properties through preventing activation of TLR4-mediated pathway in the activated astrocytes after ischemia injury. Therefore, Z-GS could be considered as a promising candidate for the treatment of ischemic stroke.

Z-Guggulsterone attenuates cognitive deficits and reduces amyloid-β levels in APPswe/PS1dE9 mice by inhibiting toll-like receptor 4 pathway

“…In recent years, the neuroprotective property of Z-GS has drawn increasing interest. Previous study has reported that Z-GS attenuates astrocytes-mediated neuroin ammation and protects the brain from acute damage induced by ischemia/reperfusion [13]. In addition, Z-GS was found to improve the scopolamine-induced memory impairments and ameliorate multiple sclerosis-related motor neuron dysfunctions in rodent models [14,15].…”

“…Each mouse with Z-GS treatment received Z-GS at a dosage of 30 mg/kg body weight via intraperitoneal injection once per day for 12 weeks, whereas each mouse with vehicle treatment was injected only with an equal volume of 5% DMSO/saline solution as control. The dosage of Z-GS was based upon previous studies in which 30 mg/kg Z-GS administered to mice yielded su cient concentrations in the brain [13,14,16]. Animals were housed under a 12 hours light/dark cycle and had free access to food and water.…”

Immune Cells in the BBB Disruption After Acute Ischemic Stroke: Targets for Immune Therapy?

“…TLR-NF-kB signaling is the initial step in astrocyte activation. By inhibiting TLR and NF-kB expression, cottonseed oil ( 308 ), Ginkgoaceae ( 309 ), metformin ( 310 ), ligustilide ( 252 ), Z -guggulsterone ( 311 ), IL-32a ( 314 ), microRNA-1906 ( 253 ), honokiol ( 313 ), and kaempferol glycosides ( 312 ), all reduced the number of reactive astrocytes and the levels of IL-1β, IL-6, and TNF-α, which significantly attenuated BBB disruption, brain edema, and functional neurological performance. NLRP3 inflammasome is an important signaling mechanism involved in the activation of A1 astrocytes.…”

A new cerebral ischemic injury model in rats, preventive effect of gallic acid and in silico approaches

“…The tissue damage occurs when there is a back flow of blood to the tissues, Cerebral ischemia–reperfusion injury (CIRI) which is very common in ischemic stroke. CIRI persuades oxidative stress which in turn triggers neuronal loss and cognitive impairment, circulation regeneration results in inflammation, and harmful oxidation effects ( Ritzel et al, 2015 ), hence inflammatory agents play a key role in damage of ischemic brain tissue ( Liu et al, 2018 ) along with antioxidant enzymes to modulate and provoke neuronal cell defence against toxic reactive oxygen species (ROS) ( Ding et al, 2015 , Farrell-Dillon et al, 2017 ) with this justification antioxidants have been advised in vitro and in vivo for a desirable pursuit for CIRI therapy, as the crucial role was played by oxidative stress. Globally 11% of total deaths are happened due to stroke when compared to all life-threatening diseases, especially in India the main cause for death is stroke according to the epidemiological statistics ( Banerjee and Das, 2016 , Kamalakannan et al, 2017 ) and cerebrovascular diseases are considered the second most common cause of expected deaths in 2020 ( Huang and McNamara, 2004 ).…”