Reduction of ischemic brain damage and increase of glutathione by a liposomal preparation of quercetin in permanent focal ischemia in rats

We examined the influence of type 4 metabotropic glutamate (mGlu4) receptors on ischemic brain damage using the permanent middle cerebral artery occlusion (MCAO) model in mice and the endothelin-1 (Et-1) model of transient focal ischemia in rats. Mice lacking mGlu4 receptors showed a 25% to 30% increase in infarct volume after MCAO as compared with wild-type littermates. In normal mice, systemic injection of the selective mGlu4 receptor enhancer, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-caboxamide (PHCCC; 10 mg/kg, subcutaneous, administered once 30 minutes before MCAO), reduced the extent of ischemic brain damage by 35% to 45%. The drug was inactive in mGlu4 receptor knockout mice. In the Et-1 model, PHCCC administered only once 20 minutes after ischemia reduced the infarct volume to a larger extent in the caudate/putamen than in the cerebral cortex. Ischemic rats treated with PHCCC showed a faster recovery of neuronal function, as shown by electrocorticographic recording and by a battery of specific tests, which assess sensorimotor deficits. These data indicate that activation of mGlu4 receptors limit the development of brain damage after permanent or transient focal ischemia. These findings are promising because selective mGlu4 receptor enhancers are under clinical development for the treatment of Parkinson's disease and other central nervous system disorders.

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Deletion of ubiquitin ligase Nedd4l exacerbates ischemic brain damage

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20943804 ◽

2020 ◽

pp. 0271678X2094380

Author(s):

TaeHee Kim ◽

Anil K Chokkalla ◽

Raghu Vemuganti

Keyword(s):

Brain Damage ◽

Cortical Neurons ◽

Focal Ischemia ◽

Artery Occlusion ◽

Motor Dysfunction ◽

Ischemic Brain Damage ◽

Ischemic Brain ◽

E3 Ligases ◽

Cerebral Artery Occlusion

Ubiquitination by Nedd4 (neuronally expressed developmentally downregulated 4) family of HECT type E3 ligases plays a key role in degrading misfolded and damaged proteins, and its disruption leads to neurodegeneration. Parkinson's disease-causing protein α-Synuclein (α-Syn) is ubiquitinated by the Nedd4 family and degraded by endosomes. Nedd4l is the only Nedd4 homolog that showed upregulation in post-stroke surviving cortical neurons where it correlated with neuroprotection. We tested the role of Nedd4l after stroke by subjecting the Nedd4l−/− mice to transient middle cerebral artery occlusion. Focal ischemia significantly increased Nedd4l expression and poly-ubiquitinated α-Syn levels, and knockout of Nedd4l reduced post-ischemic poly-ubiquitinated α-Syn that is majorly located in the peri-infarct neurons. Co-immunoprecipitation further shows that focal ischemia enhances the α-Syn-Nedd4l interaction resulting in increased ubiquitination of α-Syn. Nedd4l knockout mice ( n = 7 mice/group) showed exacerbated post-ischemic motor dysfunction manifested by decreased time on the rotarod and increased number of foot faults, and significantly increased ischemic brain damage. This suggests that Nedd4l might be a potential therapeutic target to minimize α-Syn-mediated toxicity after cerebral ischemia.

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Postischemic Administration of AK275, a Calpain Inhibitor, Provides Substantial Protection against Focal Ischemic Brain Damage

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1994.67 ◽

1994 ◽

Vol 14 (4) ◽

pp. 537-544 ◽

Cited By ~ 130

Author(s):

Raymond T. Bartus ◽

Keith L. Baker ◽

Angie D. Heiser ◽

Sean D. Sawyer ◽

Reginald L. Dean ◽

...

Keyword(s):

Brain Damage ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Focal Ischemia ◽

Artery Occlusion ◽

Calpain Inhibitor ◽

Ischemic Brain Damage ◽

Ischemic Brain ◽

Diastereomeric Mixture ◽

Cerebral Artery Occlusion

Experiments were conducted to determine whether a potent, reversible calpain inhibitor could reduce the cortical ischemic brain damage associated with focal ischemia in the rat. AK275 (Z-Leu–Abu–CONH–CH2CH3), the active isomer of the diastereomeric mixture, CX275, was employed in conjunction with a novel method of perfusing drug directly onto the infarcted cortical surface. This protocol reduced or eliminated numerous, nonspecific pharmacokinetic, hemodynamic, and other potentially confounding variables that might complicate interpretation of any drug effect. Focal ischemia was induced using a variation of the middle cerebral artery occlusion method. These studies demonstrated a reliable and robust neuroprotective effect of AK275 over the concentration range of 10 to 200 μ M (perfused supracortically at 4 μl/h for 21 h). Moreover, a 75% reduction in infarct volume was observed when initiation of drug treatment was delayed for 3 h postocclusion. Our data further support an important role of calpain in ischemia-induced neuropathology and suggest that calpain inhibitors may provide a unique and potentially powerful means of treating stroke and other ischemic brain incidents.

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Deletion of Mitochondrial Uncoupling Protein-2 Increases Ischemic Brain Damage after Transient Focal Ischemia by Altering Gene Expression Patterns and Enhancing Inflammatory Cytokines

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2010.52 ◽

2010 ◽

Vol 30 (11) ◽

pp. 1825-1833 ◽

Cited By ~ 49

Author(s):

Bryan A Haines ◽

Suresh L Mehta ◽

Serena M Pratt ◽

Craig H Warden ◽

P Andy Li

Keyword(s):

Brain Damage ◽

Inflammatory Cytokines ◽

Mitochondrial Membrane ◽

Focal Ischemia ◽

Wild Type ◽

Inner Mitochondrial Membrane ◽

Ischemic Brain Damage ◽

Ischemic Brain ◽

Transient Focal Ischemia

Mitochondrial hyperpolarization inhibits the electron transport chain and increases incomplete reduction of oxygen, enabling production of reactive oxygen species (ROS). The consequence is mitochondrial damage that eventually causes cell death. Uncoupling proteins (UCPs) are inner mitochondrial membrane proteins that dissipate the mitochondrial proton gradient by transporting H+ across the inner membrane, thereby stabilizing the inner mitochondrial membrane potential and reducing the formation of ROS. The role of UCP2 in neuroprotection is still in debate. This study seeks to clarify the role of UCP2 in transient focal ischemia (tFI) and to further understand the mechanisms of ischemic brain damage. Both wild-type and UCP2-knockout mice were subjected to tFI. Knocking out UCP2 significantly increased the infarct volume to 61% per hemisphere as compared with 18% in wild-type animals. Knocking out UCP2 suppressed antioxidant, cell-cycle, and DNA repair genes, including Sod1 and Sod2, Gstm1, and cyclins. Furthermore, knocking out UCP2 significantly upregulated the protein levels of the inflammatory cytokines, including CTACK, CXCL16, Eotaxin-2, fractalkine, and BLC. It is concluded that knocking out the UCP2 gene exacerbates neuronal death after cerebral ischemia with reperfusion and this detrimental effect is mediated by alteration of antioxidant genes and upregulation of inflammatory mediators.

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