Adenosine A2A Receptors in Bone Marrow-Derived Cells Attenuate Cognitive Impairment in Mice After Chronic Hypoperfusion White Matter Injury

Ran, Hong; Yuan, Jianmin; Huang, Jialu; Wang, Jie; Chen, Kangning; Zhou, Zhenhua

doi:10.1007/s12975-019-00778-9

Cited by 9 publications

(8 citation statements)

References 43 publications

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“…It was reported that the ADORA2A signaling pathway and the dopamine receptor signaling pathway could competitively regulate microglia-mediated inflammation and improve cognitive dysfunction in patients with Parkinson's disease by regulating the immune microenvironment (21). Our research team also confirmed that the activation of ADORA2A in bone marrow-derived cells could reduce white matter injury in the corpus callosum and improve the cognitive dysfunction caused by CCH (7,22). Because astrocytes are the most abundant cells in the CNS and are known to mediate inflammation in many diseases (23,24), they have received extensive attention in the clinical imaging diagnosis of cerebral small vessel disease (25).…”

Section: Discussionsupporting

confidence: 68%

“…A mouse model of chronic cerebral hypoperfusion (CCH) was established by referring to previously described methods ( 7 ). After placing the mouse under isoflurane inhalation anesthesia, the bilateral common carotid arteries were fully freed.…”

Section: Methodsmentioning

confidence: 99%

“…It has been reported that ADORA2A can regulate microglial remodeling in a mouse model of chronic anxiety, thereby reducing the anxiety-related behaviors in the mice ( 6 ). Our research group had previously demonstrated that bone marrow-derived ADORA2A could improve the cognitive functions of mice with chronic cerebral hypoperfusion (CCH)-induced white matter injury by inhibiting microglia-mediated inflammation ( 7 ). In recent years, many research groups have sought to clarify the role of the ADORA2A signaling pathway in astrocytes.…”

Section: Introductionmentioning

confidence: 99%

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Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions

et al. 2022

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White matter lesions are an important pathological manifestation of cerebral small vessel disease, with inflammation playing a pivotal role in their development. The adenosine A2a receptor (ADORA2A) is known to inhibit the inflammation mediated by microglia, but its effect on astrocytes is unknown. Additionally, although the level of YKL-40 (expressed mainly in astrocytes) has been shown to be elevated in the model of white matter lesions induced by chronic cerebral hypoperfusion, the specific regulatory mechanism involved is not clear. In this study, we established in vivo and in vitro chronic cerebral hypoperfusion models to explore whether the ADORA2A regulated astrocyte-mediated inflammation through STAT3/YKL-40 axis and using immunohistochemical, western blotting, ELISA, PCR, and other techniques to verify the effect of astrocytes ADORA2A on the white matter injury. The in vivo experiments showed that activation of the ADORA2A decreased the expression of both STAT3 and YKL-40 in the astrocytes and alleviated the white matter injury, whereas its inhibition had the opposite effects. Similarly, ADORA2A inhibition significantly increased the expression of STAT3 and YKL-40 in astrocytes in vitro, with more proinflammatory cytokines being released by astrocytes. STAT3 inhibition enhanced the inhibitory effect of ADORA2A on YKL-40 synthesis, whereas its activation reversed the phenomenon. These results suggest that the activation of ADORA2A in astrocytes can inhibit the inflammation mediated by the STAT3/YKL-40 axis and thereby reduce white matter injury in cerebral small vessel disease.

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Section: Discussionsupporting

confidence: 68%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions

et al. 2022

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“…The Morris water maze was used to evaluate spatial learning and memory at days 23–27 after GMH [ 36 ]. The water maze is made up of a plastic tub with an adjustable stand used as an escape for rats.…”

Section: Methodsmentioning

confidence: 99%

Activation of GPR40 attenuates neuroinflammation and improves neurological function via PAK4/CREB/KDM6B pathway in an experimental GMH rat model

Xiao

Cai

Fang

et al. 2021

J Neuroinflammation

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Background Germinal matrix hemorrhage (GMH) is defined by the rupture of immature blood vessels in the germinal matrix, where subsequent hemorrhage enters the subependymal zone and the cerebral lateral ventricles. The consequent blood clot has been identified as the causative factor of secondary brain injury, which triggers a series of complex parallel and sequential harmful mechanisms, including neuroinflammation. The orphan G-protein-coupled receptor 40 (GPR40), a free fatty acid (FFA) receptor 1, has been shown to exert anti-inflammatory effects when activated and improved outcomes in animal models of stroke. We aimed to investigate the anti-inflammatory effects of GPR40 and its underlying mechanisms after GMH. Methods GMH model was induced in 7-day-old rat pups by an intraparenchymal injection of bacterial collagenase. GPR40 agonist, GW9508, was administered intranasally 1 h, 25 h, and 49 h after GMH induction. CRISPR targeting GPR40, PAK4, and KDM6B were administered through intracerebroventricular injection 48 h before GMH induction. Neurologic scores, microglia polarization, and brain morphology were evaluated by negative geotaxis, right reflex, rotarod test, foot fault test, Morris water maze, immunofluorescence staining, Western blots, and nissl staining respectfully. Results The results demonstrated that GW9508 improved neurological and morphological outcomes after GMH in the short (24 h, 48 h, 72h) and long-term (days 21–27). However, the neuroprotective effects of treatment were abolished by GW1100, a selective GPR40 antagonist. GW9508 treatment increased populations of M2 microglia and decreased M1 microglia in periventricular areas 24 h after GMH induction. GW9508 upregulated the phosphorylation of PAK4, CREB, and protein level of KDM6B, CD206, IL-10, which was also met with the downregulation of inflammatory markers IL-1β and TNF-α. The mechanism study demonstrated that the knockdown of GPR40, PAK4, and KDM6B reversed the neuroprotective effects brought on by GW9508. This evidence suggests that GPR40/PAK4/CREB/KDM6B signaling pathway in microglia plays a role in the attenuation of neuroinflammation after GMH. Conclusions In conclusion, the present study demonstrates that the activation of GPR40 attenuated GMH-induced neuroinflammation through the activation of the PAK4/CREB/KDM6B signaling pathway, and M2 microglia may be a major mediator of this effect. Thus, GPR40 may serve as a potential target in the reduction of the inflammatory response following GMH, thereby improving neurological outcomes in the short- and long-term.

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“…At the 9th week after SCI, tissues from within 0.5 cm of the injury region were dissociated and immuno uorescence staining with reference to previously described methods 20 . The positive cells were counted using Image J.…”

Section: Immuno Uorescencementioning

confidence: 99%

Curcumin improves human umbilical cord derived mesenchymal stem cells survival and promotes motor outcome via ERK Signaling after spinal cord injury

Chen

et al. 2020

Preprint

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Abstract Background Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) transplantation are assumed as a promising strategy in spinal cord injury (SCI). However, the complex pathological microenvironment after SCI induces the apoptosis of hUC-MSCs, which limits the clinical application for the cell replacement therapy. Methods In this study, in order to investigate whether combined with curcumin could strengthen the therapeutic effects of hUC-MSCs transplantation for SCI, we mediated the apoptosis of hUC-MSCs with TNF-α and transplanted hUC-MSCs into SCI rats, followed by assessed the anti- apoptosis effect and mechanism of curcumin. Results LDH release test and flow cytometry demonstrated that TNF-α led to the hUC-MSCs apoptosis and curcumin increased survival rate of hUC-MSCs with dose-dependent. In addition, we showed that the phosphorylation levels of ERK, JNK and P38 were up-regulated in the hUC-MSCs apoptosis, while curcumin strengthened the phosphorylation of ERK, but not activated the JNK and P38, which was reversed by p42/44 antagonist U0126. Furthermore, we exhibited that the motor function scores and surviving HNA-positive cells were significantly increased after curcumin combined with hUC-MSCs transplantation therapy 8 weeks post SCI, while U0126 markedly attenuated these phenomenons. Conclusions The aforementioned data confirmed that curcumin suppressed the apoptosis of hUC-MSCs through ERK signal pathway and combined curcumin with hUC-MSCs treatment improved motor function after SCI in rats. The current research provides a strong basis for hUC-MSCs replacement therapy in conjunction with curcumin in the treatment and management of SCI in human.

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Adenosine A2A Receptors in Bone Marrow-Derived Cells Attenuate Cognitive Impairment in Mice After Chronic Hypoperfusion White Matter Injury

Cited by 9 publications

References 43 publications

Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions

Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions

Activation of GPR40 attenuates neuroinflammation and improves neurological function via PAK4/CREB/KDM6B pathway in an experimental GMH rat model

Curcumin improves human umbilical cord derived mesenchymal stem cells survival and promotes motor outcome via ERK Signaling after spinal cord injury

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