Ischemic stroke in PAR1 KO mice: Decreased brain plasmin and thrombin activity along with decreased infarct volume

Shavit‐Stein, Efrat; Mindel, Ekaterina; Gofrit, Shany Guly; Chapman, Joab; Maggio, Nicola

doi:10.1371/journal.pone.0248431

Cited by 10 publications

(6 citation statements)

References 42 publications

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“…After model establishment, the mice were placed in a cage alone to observe their overall state and behavior. The neurological score [ 43 ] was calculated as follows: 0 points, normal behavior; 1 point, cannot fully extend the right front legs; 2 points, turning around in a circle; 3 points, falling onto the right side; 4 points, cannot move on own and loss of consciousness; 5 points, death.…”

Section: Methodsmentioning

confidence: 99%

The Aldose Reductase Inhibitor Epalrestat Maintains Blood–Brain Barrier Integrity by Enhancing Endothelial Cell Function during Cerebral Ischemia

Zhang

Xin-min

et al. 2023

Mol Neurobiol

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Excessive activation of aldose reductase (AR) in the brain is a risk factor for aggravating cerebral ischemia injury. Epalrestat is the only AR inhibitor with proven safety and efficacy, which is used in the clinical treatment of diabetic neuropathy. However, the molecular mechanisms underlying the neuroprotection of epalrestat remain unknown in the ischemic brain. Recent studies have found that blood–brain barrier (BBB) damage was mainly caused by increased apoptosis and autophagy of brain microvascular endothelial cells (BMVECs) and decreased expression of tight junction proteins. Thus, we hypothesized that the protective effect of epalrestat is mainly related to regulating the survival of BMVECs and tight junction protein levels after cerebral ischemia. To test this hypothesis, a mouse model of cerebral ischemia was established by permanent middle cerebral artery ligation (pMCAL), and the mice were treated with epalrestat or saline as a control. Epalrestat reduced the ischemic volume, enhanced BBB function, and improved the neurobehavior after cerebral ischemia. In vitro studies revealed that epalrestat increased the expression of tight junction proteins, and reduced the levels of cleaved-caspase3 and LC3 proteins in mouse BMVECs (bEnd.3 cells) exposed to oxygen–glucose deprivation (OGD). In addition, bicalutamide (an AKT inhibitor) and rapamycin (an mTOR inhibitor) increased the epalrestat-induced reduction in apoptosis and autophagy related protein levels in bEnd.3 cells with OGD treatment. Our findings suggest that epalrestat improves BBB function, which may be accomplished by reducing AR activation, promoting tight junction proteins expression, and upregulating AKT/mTOR signaling pathway to inhibit apoptosis and autophagy in BMVECs.

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Section: Methodsmentioning

confidence: 99%

The Aldose Reductase Inhibitor Epalrestat Maintains Blood–Brain Barrier Integrity by Enhancing Endothelial Cell Function during Cerebral Ischemia

Zhang

Xin-min

et al. 2023

Mol Neurobiol

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“…CD88, the C5a anaphylatoxin receptor, is expressed locally on presynaptic terminals of mossy fibers in the CA3 region of the adult rat hippocampus, possibly highlighting a role in synaptic plasticity [ 101 ]. PAR1 KO mice after occlusion of the middle cerebral artery display lower thrombin and plasmin activity, along with smaller infarcts [ 102 ]. Likewise, complement factors increase after ischemic strokes such as C1q and C3.…”

Section: The Complement and Coagulation Systems In Pathophysiologymentioning

confidence: 99%

Complement and Coagulation System Crosstalk in Synaptic and Neural Conduction in the Central and Peripheral Nervous Systems

et al. 2021

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Complement and coagulation are both key systems that defend the body from harm. They share multiple features and are similarly activated. They each play individual roles in the systemic circulation in physiology and pathophysiology, with significant crosstalk between them. Components from both systems are mapped to important structures in the central nervous system (CNS) and peripheral nervous system (PNS). Complement and coagulation participate in critical functions in neuronal development and synaptic plasticity. During pathophysiological states, complement and coagulation factors are upregulated and can modulate synaptic transmission and neuronal conduction. This review summarizes the current evidence regarding the roles of the complement system and the coagulation cascade in the CNS and PNS. Possible crosstalk between the two systems regarding neuroinflammatory-related effects on synaptic transmission and neuronal conduction is explored. Novel treatment based on the modulation of crosstalk between complement and coagulation may perhaps help to alleviate neuroinflammatory effects in diseased states of the CNS and PNS.

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“…Our previous studies demonstrated that the binding of PAR to HK‐1 results in glycolytic and bioenergetics defects in neural cells exposed to the DNA alkylating agent, N‐methyl‐N′‐nitro‐N′‐nitrosoguanidine (MNNG) 9 . PARP‐1 over‐activation plays a significant role in stroke‐induced neural death as PARP‐1 knockout (KO) mice or pharmacological inhibitors of PARPs are significantly protective in brain ischemia models 11–14 . Additionally, PARG KO mice have larger infarct lesions after middle cerebral artery occlusion, indicating that PAR likely plays a substantial role in the stroke pathophysiology 2,15 .…”

Section: Introductionmentioning

confidence: 99%

Poly(ADP‐ribose) mediates bioenergetic defects and redox imbalance in neurons following oxygen and glucose deprivation

Hossain,

Lee,

Gagné

et al. 2024

The FASEB Journal

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PARP‐1 over‐activation results in cell death via excessive PAR generation in different cell types, including neurons following brain ischemia. Glycolysis, mitochondrial function, and redox balance are key cellular processes altered in brain ischemia. Studies show that PAR generated after PARP‐1 over‐activation can bind hexokinase‐1 (HK‐1) and result in glycolytic defects and subsequent mitochondrial dysfunction. HK‐1 is the neuronal hexokinase and catalyzes the first reaction of glycolysis, converting glucose to glucose‐6‐phosphate (G6P), a common substrate for glycolysis, and the pentose phosphate pathway (PPP). PPP is critical in maintaining NADPH and GSH levels via G6P dehydrogenase activity. Therefore, defects in HK‐1 will not only decrease cellular bioenergetics but will also cause redox imbalance due to the depletion of GSH. In brain ischemia, whether PAR‐mediated inhibition of HK‐1 results in bioenergetics defects and redox imbalance is not known. We used oxygen–glucose deprivation (OGD) in mouse cortical neurons to mimic brain ischemia in neuronal cultures and observed that PARP‐1 activation via PAR formation alters glycolysis, mitochondrial function, and redox homeostasis in neurons. We used pharmacological inhibition of PARP‐1 and adenoviral‐mediated overexpression of wild‐type HK‐1 (wtHK‐1) and PAR‐binding mutant HK‐1 (pbmHK‐1). Our data show that PAR inhibition or overexpression of HK‐1 significantly improves glycolysis, mitochondrial function, redox homeostasis, and cell survival in mouse cortical neurons exposed to OGD. These results suggest that PAR binding and inhibition of HK‐1 during OGD drive bioenergetic defects in neurons due to inhibition of glycolysis and impairment of mitochondrial function.

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Ischemic stroke in PAR1 KO mice: Decreased brain plasmin and thrombin activity along with decreased infarct volume

Cited by 10 publications

References 42 publications

The Aldose Reductase Inhibitor Epalrestat Maintains Blood–Brain Barrier Integrity by Enhancing Endothelial Cell Function during Cerebral Ischemia

The Aldose Reductase Inhibitor Epalrestat Maintains Blood–Brain Barrier Integrity by Enhancing Endothelial Cell Function during Cerebral Ischemia

Complement and Coagulation System Crosstalk in Synaptic and Neural Conduction in the Central and Peripheral Nervous Systems

Poly(ADP‐ribose) mediates bioenergetic defects and redox imbalance in neurons following oxygen and glucose deprivation

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