Tauroursodeoxycholic acid attenuates neuronal apoptosis via the TGR5/ SIRT3 pathway after subarachnoid hemorrhage in rats

Abstract Background Neuronal apoptosis plays a critical event in the pathogenesis of early brain injury after subarachnoid hemorrhage (SAH). This study investigated the roles of Tauroursodeoxycholic acid (TUDCA) in attenuate neuronal apoptosis and underlying mechanisms after SAH. Methods Sprague–Dawley rats were subjected to model of SAH and TUDCA was administered via the internal carotid injection. Small interfering RNA (siRNA) for TGR5 were administered through intracerebroventricular injection 48 h before SAH. Neurological scores, brain water content, Western blot, TUNEL staining and immunofluorescence staining were evaluated. Results TUDCA alleviated brain water content and improved neurological scores at 24 h and 72 h after SAH. TUDCA administration prevented the reduction of SIRT3 and BCL-2 expressions, as well as the increase of BAX and cleaved caspase-3.Endogenous TGR5 expression were upregulated after SAH and treatment with TGR5 siRNA exacerbated neurological outcomes after SAH and the protective effects of TUDCA at 24 h after SAH were also abolished by TGR5 siRNA. Conclusions Our findings demonstrate that TUDCA could attenuated neuronal apoptosis and improve neurological functions through TGR5/ SIRT3 signaling pathway after SAH. TUDCA may be an attractive candidate for anti-apoptosis treatment in SAH.

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FGF10 Attenuates Experimental Traumatic Brain Injury through TLR4/MyD88/NF-κB Pathway

Cells Tissues Organs ◽

10.1159/000511381 ◽

2021 ◽

pp. 1-9

Author(s):

Qinhan Hou ◽

Hongmou Chen ◽

Quan Liu ◽

Xianlei Yan

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Protein Expression ◽

Water Content ◽

Neurological Deficit ◽

Neuronal Apoptosis ◽

Neuronal Damage ◽

Intraventricular Injection ◽

Brain Water Content ◽

Brain Water

Traumatic brain injury (TBI) can induce neuronal apoptosis and neuroinflammation, resulting in substantial neuronal damage and behavioral disorders. Fibroblast growth factors (FGFs) have been shown to be critical mediators in tissue repair. However, the role of FGF10 in experimental TBI remains unknown. In this study, mice with TBI were established via weight-loss model and validated by increase of modified neurological severity scores (mNSS) and brain water content. Secondly, FGF10 levels were elevated in mice after TBI, whereas intraventricular injection of Ad-FGF10 decreased mNSS score and brain water content, indicating the remittance of neurological deficit and cerebral edema in TBI mice. In addition, neuronal damage could also be ameliorated by stereotactic injection of Ad-FGF10. Overexpression of FGF10 increased protein expression of Bcl-2, while it decreased Bax and cleaved caspase-3/PARP, and improved neuronal apoptosis in TBI mice. In addition, Ad-FGF10 relieved neuroinflammation induced by TBI and significantly reduced the level of interleukin 1β/6, tumor necrosis factor α, and monocyte chemoattractant protein-1. Moreover, Ad-FGF10 injection decreased the protein expression level of Toll-like receptor 4 (TLR4), MyD88, and phosphorylation of NF-κB (p-NF-κB), suggesting the inactivation of the TLR4/MyD88/NF-κB pathway. In conclusion, overexpression of FGF10 could ameliorate neurological deficit, neuronal apoptosis, and neuroinflammation through inhibition of the TLR4/MyD88/NF-κB pathway, providing a potential therapeutic strategy for brain injury in the future.

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Effect of acute and chronic hyponatremia on brain buffering in rats

AJP Renal Physiology ◽

10.1152/ajprenal.1993.264.6.f968 ◽

1993 ◽

Vol 264 (6) ◽

pp. F968-F974

Author(s):

S. Adler ◽

J. G. Verbalis ◽

D. Williams

Keyword(s):

Water Content ◽

Recovery Period ◽

Brain Perfusion ◽

Receptor Activation ◽

Brain Water Content ◽

Sprague Dawley ◽

Chronic Hyponatremia ◽

Brain Ph ◽

Acute Hyponatremia ◽

Brain Water

The present studies evaluated whether previously observed impairments in brain buffering during acute hyponatremia were maintained during chronic hyponatremia as well and whether the impairment was due in part to changes in brain water, brain perfusion, or activation of arginine vasopressin (AVP) V1 receptors. Acute (1 and 2 day) and chronic (7 and 14 day) hyponatremia was induced in male Sprague-Dawley rats by constant desmopressin administration in combination with a liquid diet. Brain pH was determined by 31P nuclear magnetic resonance (NMR) in rats anesthetized with N2O and paralyzed with pancuronium. Brain buffering was evaluated by the response to CO2 loading, and brain perfusion was evaluated by 19F-NMR using trifluoromethane washout. Compared with normonatremic controls fed the same diet, brain pH in both acute and chronic hyponatremics was 0.12 pH units lower after 55 min ventilation with 20% CO2 despite identical decreases of approximately 0.35 units in all groups during the first 15 min. Moreover, in the recovery period brain pH overshot basal levels only in normonatremic controls. Brain water content in chronic hyponatremic rats was equal to controls, and brain perfusion was identical in the five groups during CO2 exposure. These results are analogous to those reported during acute hyponatremia induced with AVP and show that the impairment of active brain buffering is maintained during chronic hyponatremia and is unrelated to brain water content, perfusion, tissue catabolism, or AVP V1 receptor activation.

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Dexmedetomidine Inhibits Endoplasmic Reticulum Stress Response and Improves Neurological Function After Traumatic Brain Injury in Rats

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2019.2107 ◽

2019 ◽

Vol 9 (8) ◽

pp. 1038-1044

Author(s):

Hanqing Zang ◽

Jing Li ◽

Linxing Yang ◽

Wendong Sun ◽

Jing Han

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Water Content ◽

Neuronal Apoptosis ◽

Neurological Impairment ◽

Endoplasmic Reticulum Stress Response ◽

Brain Water Content ◽

Caspase 12 ◽

Group B ◽

Brain Water

Dexmedetomidine (DEX) can inhibit neuronal apoptosis. There are multiple secondary lesions following traumatic brain injury (TBI). Our study evaluated the application of DEX in TBI by observing neurological impairment score, brain edema, nerve cells apoptosis, and endoplasmic reticulum stress response (ERS). SD rats were selected to establish TBI model using modified Feeney method and then randomly divided into sham operation group (A), TBI group (B), TBI + DEX group (C), and TBI + DEX + endoplasmic reticulum stress inducer 2-deoxyglucose (2-DG) group (D). The neurological injury severity score (mNSS) was measured on day 1, 3, and 7 after injury. The water content of brain tissue was measured. The pathology of brain tissue was observed on the 7th day after craniocerebral injury. Caspase-12 and IRE-1 were determined by Western blot. Apoptosis was assessed by TUNEL assay. CHOP and Glucose Regulatory Protein 78 (GRP78) expressions were detected by immunohistochemistry (IHC). Compared with group A, mNSS scores, brain water content, and neuronal apoptosis were increased, and caspase-12, IRE-1, CHOP, and GRP78 proteins were upregulated in groups B, C, and D (P < 0.05). Compared to group B, the neurological function was improved, brain water content and neuronal apoptosis were decreased, and caspase-12, IRE-1, CHOP, and GRP78 protein expressions were reduced in group C (P < 0.05). Neurological impairment was aggravated, brain water content and nerve cell apoptosis were increased, and caspase-12, IRE-1, CHOP, and GRP78 protein expressions were upregulated in group D compared to group C (P < 0.05). DEX treatment can alleviate brain edema after TBI and inhibit neuronal apoptosis, which has neuroprotective effects. Its mechanism may be related to ERS after TBI inhibition.

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Atorvastatin ameliorates early brain injury through inhibition of apoptosis and ER stress in a rat model of subarachnoid hemorrhage

Bioscience Reports ◽

10.1042/bsr20171035 ◽

2018 ◽

Vol 38 (3) ◽

Cited By ~ 7

Author(s):

Wentao Qi ◽

Demao Cao ◽

Yucheng Li ◽

Aijun Peng ◽

Youwei Wang ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Water Content ◽

Caspase 3 ◽

Sham Group ◽

Early Brain Injury ◽

Brain Water Content ◽

Atorvastatin Group ◽

Related Proteins ◽

Brain Water

Aneurysmal subarachnoid hemorrhage (SAH) is a severe cerebrovascular disease with very poor prognosis. The aim of the present study was to evaluate the protective effects of atorvastatin on early brain injury (EBI) after SAH using a perforation SAH model. Male Sprague–Dawley rats were randomly divided into four groups: the sham group, the SAH group (model group), SAH + 10 mg.kg−1.day−1 atorvastatin (low atorvastatin group), and SAH + 20 mg.kg−1.day−1 atorvastatin (high atorvastatin group). Atorvastatin was administered orally by gastric gavage for 15 days before operation. At 24 h after SAH, we evaluated the effects of atorvastatin on brain water content, apoptosis by TUNEL assay and scanning electron microscope (SEM), and the expression of apoptosis-related proteins by immunofluorescence and Western blotting analysis. Compared with the sham group, we observed increased brain water content, significant apoptosis, and elevated levels of apoptosis-related proteins including caspase-3, CCAAT enhancer-binding protein homologous protein (CHOP), the 78-kDa glucose-regulated protein (GRP78), and aquaporin-4 (AQP4) in the SAH group. Atorvastatin administration under all doses could significantly reduce brain water content, apoptosis, and the expression levels of caspase-3, CHOP, GRP78, and AQP4 at 24 h after SAH. Our data show that early treatment with atorvastatin effectively ameliorates EBI after SAH through anti-apoptotic effects and the effects might be associated inhibition of caspase-3 and endoplasmic reticulum (ER) stress related proteins CHOP and GRP78.

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Brain Water as a Function of Age and Weight in Normal Rats

10.1101/2021.03.18.436025 ◽

2021 ◽

Author(s):

Allan Gottschalk ◽

Susanna Scafidi ◽

Thomas Toung

Keyword(s):

Water Content ◽

Aging Brain ◽

Normal Male ◽

Brain Water Content ◽

Sprague Dawley ◽

Age Related ◽

Injured Brain ◽

Allometric Functions ◽

Development And Aging ◽

Brain Water

Rats are frequently used to study water content of normal and injured brain, as well as changes in response to various osmotherapeutic regimens. Magnetic resonance imaging in humans has shown that brain water content declines with age as a result of progressive myelination. The purpose of this study was to quantify changes in brain water content during rat development and aging. Brain water content was measured by standard techniques in 129 normal male Sprague-Dawley rats that ranged in age (weight) from 13 to 149 days (18 to 759 g). Overall, the results demonstrated a decrease from 85.59% to 76.56% water content with increasing age (weight). Nonlinear allometric functions relating brain water to age and weight were determined. These findings provide age-related context for prior rat studies of brain water, emphasize the importance of using similarly aged controls in studies of brain water, and indicate that age-related changes in brain water content are not specific to humans.

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Activation of the Melanocortin-1 Receptor by NDP-MSH Attenuates Oxidative Stress and Neuronal Apoptosis through PI3K/Akt/Nrf2 Pathway after Intracerebral Hemorrhage in Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/8864100 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Siming Fu ◽

Xu Luo ◽

Xuan Wu ◽

Tongyu Zhang ◽

Linggui Gu ◽

...

Keyword(s):

Oxidative Stress ◽

Intracerebral Hemorrhage ◽

Water Content ◽

Neuronal Apoptosis ◽

Caspase 3 ◽

Neurological Deficits ◽

Enzyme Linked Immunosorbent Assay ◽

Brain Water Content ◽

Melanocortin 1 Receptor ◽

Brain Water

Oxidative stress and neuronal apoptosis play crucial roles in secondary brain injury (SBI) after intracerebral hemorrhage (ICH). Recently, Nle4-D-Phe7-α-melanocyte-stimulating hormone (NDP-MSH), a synthetic agonist of the melanocortin-1 receptor (Mc1r), has been proved to inhibit neuroinflammatory in several diseases. This study is aimed at exploring if NDP-MSH could reduce oxidative stress and neuronal apoptosis following ICH, as well as the potential mechanism. A mouse ICH model was induced by autologous blood injection. NDP-MSH was intraperitoneally injected at 1 h after ICH. Mc1r siRNA and PI3K inhibitor LY294002 were administrated to inhibit the expression of Mc1r and phosphorylation of PI3K, respectively. Neurological test, brain water content, enzyme-linked immunosorbent assay (ELISA), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), immunofluorescence, and Western blot analysis were utilized in this study. The results exhibited that Mc1r was mainly expressed in neurons, and its level in the ipsilateral hemisphere was significantly elevated after ICH. NDP-MSH treatment significantly attenuated the neurological deficits and brain water content 24 hours after ICH, which was accompanied by the inhibition of oxidative stress and neuronal apoptosis. The administration of NDP-MSH after ICH significantly promoted the expression of Mc1r, p-PI3K, p-Akt, and p-Nrf2, followed by an increase of Bcl-2 and reduction of cleaved caspase-3. Conversely, downregulating the expression of Mc1r and phosphorylation of PI3K aggravated the neurological deficits and brain edema at 24 hours after ICH, meanwhile, the effect of NDP-MSH on the expression of Mc1r, p-PI3K, p-Akt, p-Nrf2, Bcl-2, and cleaved caspase 3 was also abolished. In conclusion, our data suggest that the activation of Mc1r by NDP-MSH ameliorates oxidative stress and neuronal apoptosis through the PI3K/Akt/Nrf2 signaling pathway after ICH in mice.

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Attenuation of neurological injury with early baicalein treatment following subarachnoid hemorrhage in rats

Journal of Neurosurgery ◽

10.3171/2013.4.jns121919 ◽

2013 ◽

Vol 119 (4) ◽

pp. 1028-1037 ◽

Cited By ~ 15

Author(s):

Chang-Po Kuo ◽

Li-Li Wen ◽

Chun-Mei Chen ◽

Billy Huh ◽

Chen-Hwan Cherng ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Water Content ◽

Neuronal Degeneration ◽

Autologous Blood ◽

Glutamate Transporter ◽

Neurological Injury ◽

Brain Water Content ◽

Protein Activity ◽

Male Wistar Rats ◽

Brain Water

ObjectBaicalein has been shown to offer neuroprotection in the ischemic brain, but its effect in subarachnoid hemorrhage (SAH) is unknown. The authors used a double-hemorrhage model to study the role of early baicalein treatment in SAH.MethodsSubarachnoid hemorrhage was induced in male Wistar rats through a repeat injection of autologous blood at a 48-hour interval. Rats subjected or not subjected to SAH received a 30-mg/kg baicalein injection 3 hours after SAH and daily for 6 consecutive days, and results were compared with those obtained in vehicle-treated control rats. Mortality of the rats was recorded. Neurological outcome was assessed daily. Cerebrospinal fluid dialysates were collected and examined for glutamate concentrations. Cerebral vasospasm (CVS), brain water content, neuron variability, expression of glutamate transporter–1 (GLT-1), immunoreactivity of astrocyte, and level of malondialdehyde, activities of superoxide dismutase (SOD), and catalase in brain tissues content were determined on post-SAH Day 7.ResultsMortality rate, neuronal degeneration, brain water content, and CVS were decreased and neurological function improved in the baicalein-treated rats. Baicalein increased astrocyte activity and preserved GLT-1, which attenuated the glutamate surge after SAH. Baicalein also provided antioxidative stress by preserving activities of SOD and catalase and decreased malondialdehydelevel after SAH. The glutamate, body weight, neurological scores, and glial fibrillary acidic protein activity were significantly correlated. The CVS was correlated with neuronal degeneration, and GLT-1 was correlated with oxidative stress.ConclusionsEarly baicalein treatment attenuated CVS and limited neurological injury following SAH. These data may indicate clinical utility for baicalein as an adjunct therapy to reduce brain injury and improve patient outcomes.

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Brain water as a function of age and weight in normal rats

PLoS ONE ◽

10.1371/journal.pone.0249384 ◽

2021 ◽

Vol 16 (9) ◽

pp. e0249384

Author(s):

Allan Gottschalk ◽

Susanna Scafidi ◽

Thomas J. K. Toung

Keyword(s):

Water Content ◽

Aging Brain ◽

Normal Male ◽

Brain Water Content ◽

Sprague Dawley ◽

Age Related ◽

Injured Brain ◽

Allometric Functions ◽

Development And Aging ◽

Brain Water

Rats are frequently used for studying water content of normal and injured brain, as well as changes in response to various osmotherapeutic regimens. Magnetic resonance imaging in humans has shown that brain water content declines with age as a result of progressive myelination and other processes. The purpose of this study was to quantify changes in brain water content during rat development and aging. Brain water content was measured by standard techniques in 129 normal male Sprague-Dawley rats that ranged in age (weight) from 13 to 149 days (18 to 759 g). Overall, the results demonstrated a decrease in water content from 85.59% to 76.56% with increasing age (weight). Nonlinear allometric functions relating brain water to age and weight were determined. These findings provide age-related context for prior rat studies of brain water, emphasize the importance of using similarly aged controls in studies of brain water, and indicate that age-related changes in brain water content are not specific to humans.

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Inhibition of LRRK2-Rab10 Pathway Improves Secondary Brain Injury After Surgical Brain Injury in Rats

Frontiers in Surgery ◽

10.3389/fsurg.2021.749310 ◽

2022 ◽

Vol 8 ◽

Author(s):

Jie Li ◽

Muyao Wu ◽

Yating Gong ◽

Jiafeng Tang ◽

Jinchao Shen ◽

...

Keyword(s):

Brain Injury ◽

Water Content ◽

Neuronal Apoptosis ◽

Specific Inhibitor ◽

Secondary Brain Injury ◽

Brain Water Content ◽

Kinase Substrate ◽

Rab Protein ◽

Surgical Brain Injury ◽

Brain Water

Leucine-rich repeat kinase 2 (LRRK2) is considered as a potential target for the treatment of Parkinson's disease. This protein is expressed in the brain and has been associated with various diseases and lysosomal maintenance. Rab10 is a member of the Rab protein GTPase family that has been recently shown to be a kinase substrate of LRRK2. In addition, LRRK2 and its kinase substrate Rab10 constitute a key stress response pathway during lysosomal overload stress. This study aimed to investigate the potential role and mechanism underlying LRRK2 and its kinase substrate Rab10 involving surgical brain injury (SBI). One hundred and forty-four male Sprague-Dawley rats were examined using an SBI model, and some had received the LRRK2-specific inhibitor PF-06447475. Thereafter, western blotting, immunofluorescence, brain water content analysis, neuronal apoptosis assay, and neurological score analysis were conducted. The results showed that after SBI, LRRK2 and phosphorylated Rab10 (p-Rab10) expression in neuronal cells were upregulated, and administration of PF-06447475 significantly reduced neuronal apoptosis, neuroinflammation, and brain water content 12 h after SBI and improved neurological deficit 72 h after SBI, which is related to the decreased expression of LRRK2 and p-Rab10, and the lessening of lysosomal overload stress. Our research suggests that the inhibition of LRRK2 can effectively interfere with the role of p-Rab10 in promoting the secretion of lysosomal hydrolase in lysosomal overload stress after SBI, thereby reducing neuronal apoptosis and inflammation after SBI and playing a major role in brain protection.

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