A beacon of hope in stroke therapy—Blockade of pathologically activated cellular events in excitotoxic neuronal death as potential neuroprotective strategies

Hoque, Ashfaqul; Hossain, Mohammed Iqbal; Ameen, S. Sadia; C, Ang; Williamson, Nicholas A.; Ng, Dominic C.H.; Chüeh, Anderly C.; Roulston, Carli L; Cheng, Heung‐Chin

doi:10.1016/j.pharmthera.2016.02.009

Cited by 34 publications

(11 citation statements)

References 246 publications

(302 reference statements)

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“…Based on the importance of glutamate excitotoxicity as a contributing factor to many neurodegenerative diseases, it is not surprising that a great deal of effort has been devoted to the design of small-molecular-weight compounds that can potentially block or lessen the excitoxicity of extracellular glutamate. For example, blockers of ion channels associated with glutamate receptors have been effective in animal models of stroke [ 193 ]. Pharmacological activators of EAAT-2/GLT-1 have been explored for decades and are currently emerging as promising tools for protection in a wide variety of neurodegenerative diseases [ 194 , 195 , 196 ].…”

Section: Disruption Of Glutamate Homeostasis In Neurological Diseamentioning

confidence: 99%

Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain

2016

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Glutamate is present in the brain at an average concentration—typically 10–12 mM—far in excess of those of other amino acids. In glutamate-containing vesicles in the brain, the concentration of glutamate may even exceed 100 mM. Yet because glutamate is a major excitatory neurotransmitter, the concentration of this amino acid in the cerebral extracellular fluid must be kept low—typically µM. The remarkable gradient of glutamate in the different cerebral compartments: vesicles > cytosol/mitochondria > extracellular fluid attests to the extraordinary effectiveness of glutamate transporters and the strict control of enzymes of glutamate catabolism and synthesis in well-defined cellular and subcellular compartments in the brain. A major route for glutamate and ammonia removal is via the glutamine synthetase (glutamate ammonia ligase) reaction. Glutamate is also removed by conversion to the inhibitory neurotransmitter γ-aminobutyrate (GABA) via the action of glutamate decarboxylase. On the other hand, cerebral glutamate levels are maintained by the action of glutaminase and by various α-ketoglutarate-linked aminotransferases (especially aspartate aminotransferase and the mitochondrial and cytosolic forms of the branched-chain aminotransferases). Although the glutamate dehydrogenase reaction is freely reversible, owing to rapid removal of ammonia as glutamine amide, the direction of the glutamate dehydrogenase reaction in the brain in vivo is mainly toward glutamate catabolism rather than toward the net synthesis of glutamate, even under hyperammonemia conditions. During hyperammonemia, there is a large increase in cerebral glutamine content, but only small changes in the levels of glutamate and α-ketoglutarate. Thus, the channeling of glutamate toward glutamine during hyperammonemia results in the net synthesis of 5-carbon units. This increase in 5-carbon units is accomplished in part by the ammonia-induced stimulation of the anaplerotic enzyme pyruvate carboxylase. Here, we suggest that glutamate may constitute a buffer or bulwark against changes in cerebral amine and ammonia nitrogen. Although the glutamate transporters are briefly discussed, the major emphasis of the present review is on the enzymology contributing to the maintenance of glutamate levels under normal and hyperammonemic conditions. Emphasis will also be placed on the central role of glutamate in the glutamine-glutamate and glutamine-GABA neurotransmitter cycles between neurons and astrocytes. Finally, we provide a brief and selective discussion of neuropathology associated with altered cerebral glutamate levels.

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Section: Disruption Of Glutamate Homeostasis In Neurological Diseamentioning

confidence: 99%

Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain

2016

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“…; Hoque et al . ). These events initiate a complex sequence of signaling cascades that eventually result in neuronal dysfunction and cell death by necrosis or apoptosis (Radak et al .…”

Section: Discussionmentioning

confidence: 97%

“…Ischemic stroke is the most common form of stroke with high mortality and disability. After the onset of ischemia, the brain cells suffer depletion of energy supply, excessive accumulation of intracellular calcium, overproduction of free radicals, and potentiation of inflammatory responses (Li et al 2015a;Hoque et al 2016). These events initiate a complex sequence of signaling cascades that eventually result in neuronal dysfunction and cell death by necrosis or apoptosis (Radak et al 2017).…”

Section: Discussionmentioning

confidence: 99%

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

Liu

Zhang

et al. 2018

Journal of Neurochemistry

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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.

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“…Regarding the problem of pharmacological targets, the potential benefits of numerous compounds have been studied over the past 10–20 years: antioxidant compounds, acting as mere ROS scavengers or modulating Nrf2 signalling (Khan et al ., ); anti‐inflammatory agents capable of limiting glial reactivity and of inhibiting COX‐2, inducible NOS (iNOS) or the generation of cytokines (Baune, ); antagonists of glutamate receptors to limit excitotoxicity (Hoque et al ., ); caspase inhibitors to reduce apoptosis (Kudelova et al ., ); enhancers of autophagy to eliminate protein aggregates (Sarkar, ); neurotrophic factors to promote neuronal survival (Meldolesi, ); or other types of compounds that apparently favour neuronal preservation, rescue, repair and replacement and that may therefore possibly represent effective disease‐modifying therapies for neurodegenerative disorders (see Table for a summary of already or ongoing investigated neuroprotective agents). However, the results obtained have not been as positive as expected, with some of these compounds failing in cellular or animal models and others failing to reproduce their positive effects in humans (Berk et al ., ; Sampaio et al ., ; Athauda and Foltynie, ).…”

Section: The Failure In Developing Neuroprotective Therapiesmentioning

confidence: 99%

The biomedical challenge of neurodegenerative disorders: an opportunity for cannabinoid‐based therapies to improve on the poor current therapeutic outcomes

Fernández‐Ruiz

2018

British J Pharmacology

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At the beginning of the 21st century, the therapeutic management of neurodegenerative disorders remains a major biomedical challenge, particularly given the worldwide ageing of the population over the past 50 years that is expected to continue in the forthcoming years. This review will focus on the promise of cannabinoid-based therapies to address this challenge. This promise is based on the broad neuroprotective profile of cannabinoids, which may cooperate to combat excitotoxicity, oxidative stress, glia-driven inflammation and protein aggregation. Such effects may be produced by the activity of cannabinoids through their canonical targets (e.g. cannabinoid receptors and endocannabinoid enzymes) and also via non-canonical elements and activities in distinct cell types critical for cell survival or neuronal replacement (e.g. neurons, glia and neural precursor cells). Ultimately, the therapeutic events driven by endocannabinoid signalling reflect the activity of an endogenous system that regulates the preservation, rescue, repair and replacement of neurons and glia.

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A beacon of hope in stroke therapy—Blockade of pathologically activated cellular events in excitotoxic neuronal death as potential neuroprotective strategies

Cited by 34 publications

References 246 publications

Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain

Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain

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

The biomedical challenge of neurodegenerative disorders: an opportunity for cannabinoid‐based therapies to improve on the poor current therapeutic outcomes

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