Mineralocorticoid receptor excessive activation involved in glucocorticoid-related brain injury

Chen, Yaxi; Yu, Yerong; Qiao, Jingtao; Zhu, Leilei; Xiao, Zhen

doi:10.1016/j.biopha.2019.109695

Cited by 10 publications

(4 citation statements)

References 41 publications

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“…To regulate the RAGE, MR, and NFκB pathway, we orally treated our aneurysm model rats for 6 weeks with a mineral corticoid receptor blocker, ESA, at 1 mg/kg (Fig. 4 A), based on previous studies [ 18 , 20 ]. ESA-treated rats showed a tendency for decreased blood pressure without changes in BW (Fig.…”

Section: Resultsmentioning

confidence: 99%

An imbalance between RAGE/MR/HMGB1 and ATP1α3 is associated with inflammatory changes in rat brain harboring cerebral aneurysms prone to rupture

Shikata

Miyamoto

Yamaguchi

et al. 2022

J Neuroinflammation

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Background and purpose An aneurysmal subarachnoid hemorrhage is a devastating event. To establish an effective therapeutic strategy, its pathogenesis must be clarified, particularly the pathophysiology of brain harboring intracranial aneurysms (IAs). To elucidate the pathology in brain harboring IAs, we examined the significance of the receptor for advanced glycation end-products (RAGE)/mineralocorticoid receptor (MR) pathway and Na+/K+-ATPase (ATP1α3). Methods Ten-week-old female rats were subjected to oophorectomy as well as hypertension and hemodynamic changes to induce IAs, and were fed a high-salt diet. Brain damage in these rats was assessed by inflammatory changes in comparison to sham-operated rats fed a standard diet. Results Six weeks after IA induction (n = 30), irregular morphological changes, i.e., an enlarged vessel diameter and vascular wall, were observed in all of the left posterior cerebral arteries (Lt PCAs) prone to rupture. Approximately 20% of rats had ruptured IAs within 6 weeks. In brain harboring unruptured IAs at the PCA, the mRNA levels of RAGE and MR were higher, and that of ATP1α3 was lower than those in the sham-operated rats (p < 0.05, each). Immunohistochemically, elevated expression of RAGE and MR, and decreased expression of ATP1α3 were observed in the brain parenchyma adjacent to the Lt PCA, resulting in increased Iba-1 and S100B expression that reflected the inflammatory changes. There was no difference between the unruptured and ruptured aneurysm rat groups. Treatment with the MR antagonist esaxerenone abrogated these changes, and led to cerebral and vascular normalization and prolonged subarachnoid hemorrhage-free survival (p < 0.05). Conclusions Regulation of the imbalance between the RAGE/MR pathway and ATP1α3 may help attenuate the damage in brain harboring IAs, and further studies are warranted to clarify the significance of the down-regulation of the MR/RAGE pathway and the up-regulation of ATP1α3 for attenuating the pathological changes in brain harboring IAs.

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Section: Resultsmentioning

confidence: 99%

An imbalance between RAGE/MR/HMGB1 and ATP1α3 is associated with inflammatory changes in rat brain harboring cerebral aneurysms prone to rupture

Shikata

Miyamoto

Yamaguchi

et al. 2022

J Neuroinflammation

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“…Zootec., v.75, n.5, p.831-842, 2023 meninges, indicating an involvement of these vessels in the pathogeny of the disease. An increase of marking of the collagen fibers in the basement membrane of blood vessels in the cerebral parenchyma is reported in cerebral injuries and occasionally in malformations in these vessels (Chen et al, 2020). According to Piera-Velazquez and Jimenez (2019), the endothelial cells may suffer conformational changes in some situations involving vascular, degenerative, inflammatory, and fibrotic diseases.…”

Section: Discussionmentioning

confidence: 99%

Histopathological features of the brain extracellular matrix from dogs with canine distemper

Oliveira,

Viscone,

Medeiros-Ronchi

et al. 2023

Arq. Bras. Med. Vet. Zootec.

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Canine distemper causes demyelinating leucoencephalitis, like human multiple sclerosis. The encephalic microenvironment, including the extracellular matrix, is an important key factor of this lesion, already described in multiple sclerosis but not proved in canine distemper. Thereby, the aim of this work is to characterize the extracellular matrix in the encephalon of dogs with canine distemper. Samples of cortex and cerebellum of 14 naturally infected dogs with canine distemper virus were collected after being sent for necropsy in the Animal Pathology Laboratory of the Veterinary Hospital of Uberlândia Federal University. The samples were processed as routine, stained with Hematoxylin and Eosin (H.E), Masson Trichrome (MT), Periodic Acid-Schiff (PAS) and Reticulin, and then described. Areas of demyelination and necrosis were quantified in percentage of stain. The TM samples showed blue stain around vessels and meninge, which indicates a higher deposition of collagen in lesioned areas. At necrotic areas, reticulin stain pointed to a disorganization in the vascular wall and PAS-stained pink granules in macrophages. We conclude that the extracellular matrix seems to participate in the pathogeny of canine distemper. More research should be done to better detail the involvement of these molecules in the course of this disease.

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“…Given that MRs are highly expressed in many brain tissues 38 and cerebral vessels 39 , we speculated that MR overactivation may also play a role in the brain structural abnormalities in Cushing's syndrome. In a latest animal research, we observed that MR and GR overactivation can cause brain atrophy and vascular apoptosis in a cortisol-excess animal model 40 . Further exploration of the cerebral molecular mechanisms underlying the detrimental effects of Cushing's disease could help prevent nervous system complications and cardiovascular disorders.…”

Section: Mineralocorticoid Receptor (Mr) Overactivation May Also Playmentioning

confidence: 90%

Detrimental effects of hypercortisolism on brain structure and related risk factors

Chen

Zhang

Tan

et al. 2020

Sci Rep

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Brain structural abnormalities are often observed on magnetic resonance imaging (MRI) scans of Cushing's syndrome patients, but the pathogenesis is not fully understood. To understand the relationship between brain structural abnormalities and potential risk factors in active Cushing's disease (CD) patients, a total of 101 treatment-naïve CD patients and 95 sex-, age-and education matched controls with non-functioning adenomas (NFA) underwent clinical evaluation and MRI investigation, and the relative risk factors were analyzed. 14 patients in sustained remission after transsphenoidal surgery were followed. Compared with the NFA subjects, the patients with CD had more cortical (P < 0.01) and subcortical atrophy (P < 0.01) and a higher prevalence of white matter hyperintensity (WMH) (P < 0.01). WMH severity in CD patients positively correlated with age (r = 0.532, P = 0.000), disease course (r = 0.257, P = 0.009), postprandial glucose (r = 0.278, P = 0.005), frequency of left ventricular hypertrophy (r = 0.398, P = 0.001) and hypothyroidism (r = 0.246, P = 0.014). The markers of cortical and subcortical atrophy (sylvian fissure ratio, bifrontal ratio, bicaudate ratio and third ventricle width) were positively associated with the progression of WMH in the CD patients. In the follow-up of 14 patients with CD, brain atrophy and WMH was partially reversible after correction of hypercortisolism. In conclusions, brain atrophy and WMH were more likely to appear in CD patients and were possibly partially reversible following correction of hypercortisolism. Cushing's syndrome results directly from chronic exposure to excess glucocorticoids. Alongside various physical symptoms, patients with Cushing's syndrome, whether endogenous or exogenous, display a wide variety of neuropsychiatric and cognitive symptoms, which are indicative of the involvement of the central nervous system 1,2. Brain structural abnormalities related to Cushing's syndrome have been repeatedly found, including smaller hippocampal volumes, enlarged ventricles, and cerebral atrophy 3. Brain imaging studies and neuropsychological studies have indicated that hypercortisolism or supraphysiological levels of exogenous glucocorticoids are especially deleterious to the hippocampus and frontal lobes, and there were specific correlations between hippocampal volume and verbal learning, recall and memory function scores 4,5. Although some of the deleterious effects of prolonged hypercortisolemia on cognitive functioning and brain volume are partly reversible after correction of hypercortisolism 6,7 , it remains unclear what pathophysiological processes are causing these reductions and reversibility, and we cannot draw conclusions concerning the underlying microstructural changes that are involved. Patients with Cushing's syndrome has persistent cardiovascular risk factors 8 , which is closely related to cerebrovascular injury including white matter hyperintensities (WMH) 9. Several recent studies examined white matter structural changes in Cushing's syndrome patient...

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Mineralocorticoid receptor excessive activation involved in glucocorticoid-related brain injury

Cited by 10 publications

References 41 publications

An imbalance between RAGE/MR/HMGB1 and ATP1α3 is associated with inflammatory changes in rat brain harboring cerebral aneurysms prone to rupture

An imbalance between RAGE/MR/HMGB1 and ATP1α3 is associated with inflammatory changes in rat brain harboring cerebral aneurysms prone to rupture

Histopathological features of the brain extracellular matrix from dogs with canine distemper

Detrimental effects of hypercortisolism on brain structure and related risk factors

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