Neuroprotection in Glaucoma Using Calpain-1 Inhibitors: Regional Differences in Calpain-1 Activity in the Trabecular Meshwork, Optic Nerve and Implications for Therapeutics

Govindarajan, B.; Laird, James; Sherman, Ronald A.; Salomon, Robert G.; Bhattacharya, Sanjoy K.

doi:10.2174/187152708784936644

Cited by 10 publications

(9 citation statements)

References 49 publications

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“…LGE 2 and their stereo isomers (isoLGE 2 ), as well as structural isomers, including iso[4]LGE 2 , exhibit extremely high reactivity toward proteins. They covalently bind to proteins within seconds [29], and their protein adducts are resistant to proteolytic degradation [30, 31]. Therefore, in contrast with other products of lipid oxidation, e.g., 4-HNE, MDA or isoprostanes, that are rapidly cleared, LG/isoLG-protein adducts accumulate in vivo [13].…”

Section: Discussionmentioning

confidence: 99%

“…Disease-related elevations of LG/isoLG-protein adducts are found in the plasma from patients with cardiovascular disease or end-stage renal disease [6, 8], in mouse plasma from a Candida-induced sepsis model of chronic inflammation [13], in the plaques of Alzheimer’s disease patients [32] and in the epicardial border zone and myocardium below the epicardium in the healing canine infracted heart [33, 34]. LG/isoLGs inhibit the activities of cellular proteins, including proteases such as calpain-1 [31, 35] and the proteasome [30, 31], as well as tubulin [36], and ion channels [5, 33]. The irreversible, covalent modification of myocardial ion channel proteins may contribute to ischemia-related conduction abnormalities and arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

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Formation of γ-ketoaldehyde–protein adducts during ethanol-induced liver injury in mice

Roychowdhury

McMullen

Pritchard

et al. 2009

Free Radical Biology and Medicine

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Ethanol metabolism promotes formation of a variety of reactive aldehydes in the liver. These aldehydes can rapidly form covalent protein adducts. Accumulating evidence indicates that these protein adducts may contribute to ethanol-mediated liver injury. Overproduction of γ-ketoaldehydes, levuglandins (LGs) and isolevuglandins (isoLGs), is implicated in the pathogenesis of several chronic inflammatory diseases. γ-ketoaldehydes can form protein adducts orders of magnitude more quickly than 4-hydroxynonenal (4-HNE) or malondialdehyde. We hypothesized that ethanol-induced oxidative stress in vivo results in overproduction of LGE 2 -and iso [4]LGE 2 -protein adducts in mouse liver. Female C57BL/6 mice were allowed free access to an ethanol containing diet for up to 39 days or pair-fed control diets. Pathological markers of ethanol-induced hepatic injury including serum alanine aminotransferase, hepatic triglyceride and CYP2E1 were elevated in response to ethanol feeding. Ethanol-induced formation of iso [4]LGE 2 , LGE 2 and 4-HNE-protein adducts in mouse liver was dependent on both dose and duration of ethanol feeding. Deficiency of cyclooxygenase 1 or 2 did not prevent ethanol-induced iso [4]LGE 2 or LGE 2 adducts in the liver, but adduct formation was reduced in both TNFR1 and CYP2E1 deficient mice. In summary, ethanol feeding enhanced γ-ketoaldehyde-protein adducts production via a TNFR1/CYP2E1-dependent, but cyclooxygenaseindependent, mechanism in mouse liver.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Formation of γ-ketoaldehyde–protein adducts during ethanol-induced liver injury in mice

Roychowdhury

McMullen

Pritchard

et al. 2009

Free Radical Biology and Medicine

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“…Upregulation of calpain-1 expression in a futile attempt to ameliorate the problem, exacerbates the pathology owing to efficient inactivation of the newly generated enzyme by adduction of isoLGs. In contrast, higher calpain-1 activity, which appears to be under translational control, was observed in glaucomatous optic nerve compared with control (32). Therapeutic neuroprotection strategies using calpain-1 inhibitors will require consideration of such anatomic differences in its activity and biosynthesis.…”

Section: Inhibition Of Proteolysis: Neurodegeneration and Glaucomamentioning

confidence: 95%

“…Thus, treatment of calpain-1 with iso [4]LGE 2 in vitro results in covalent modification, inactivation, the formation of high-molecular-weight aggregates, and resistance to proteasomal digestion. Iso [4]-LGE 2 -modified calpain-1 undergoes ubiquitination (32), and its loading impairs the cellular proteasome activity (31). Apparently, interference with proteasomal activity, owing to protein modification by isoLGs, contributes to glaucoma pathophysiology by decreasing the ability of the TM to modulate outflow resistance.…”

Section: Inhibition Of Proteolysis: Neurodegeneration and Glaucomamentioning

confidence: 99%

Isolevuglandin Adducts in Disease

Salomon

2015

Antioxidants & Redox Signaling

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Significance: A diverse family of lipid-derived levulinaldehydes, isolevuglandins (isoLGs), is produced by rearrangement of endoperoxide intermediates generated through both cyclooxygenase (COX) and free radicalinduced cyclooxygenation of polyunsaturated fatty acids and their phospholipid esters. The formation and reactions of isoLGs with other biomolecules has been linked to alcoholic liver disease, Alzheimer's disease, age-related macular degeneration, atherosclerosis, cardiac arythmias, cancer, end-stage renal disease, glaucoma, inflammation of allergies and infection, mitochondrial dysfunction, multiple sclerosis, and thrombosis. This review chronicles progress in understanding the chemistry of isoLGs, detecting their production in vivo and understanding their biological consequences. Critical Issues: IsoLGs have never been isolated from biological sources, because they form adducts with primary amino groups of other biomolecules within seconds. Chemical synthesis enabled investigation of isoLG chemistry and detection of isoLG adducts present in vivo. Recent Advances: The first peptide mapping and sequencing of an isoLG-modified protein present in human retina identified the modification of a specific lysyl residue of the sterol C27-hydroxylase Cyp27A1. This residue is preferentially modified by iso [4]LGE 2 in vitro, causing loss of function. Adduction of less than one equivalent of isoLG can induce COX-associated oligomerization of the amyloid peptide Ab 1-42 . Adduction of isoLGE 2 to phosphatidylethanolamines causes gain of function, converting them into proinflammatory isoLGE 2 -PE agonists that foster monocyte adhesion to endothelial cells. Future Directions: Among the remaining questions on the biochemistry of isoLGs are the dependence of biological activity on isoLG isomer structure, the structures and mechanism of isoLG-derived protein-protein and DNA-protein cross-link formation, and its biological consequences.

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“…Calpeptin, a calpain-specific inhibitor, has been shown in glaucoma experimental models to confer neuroprotection. [92] As other death processes such as autophagy and necrosis may also play a role in RGC death in glaucoma, inhibition of apoptosis alone may not completely prevent glaucoma progression. [76]…”

Section: Pharmacological Approachesmentioning

confidence: 99%

Neuroprotection in glaucoma

Vasudevan

Gupta

Crowston

2011

Indian J Ophthalmol

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Glaucoma is a neurodegenerative disease characterized by loss of retinal ganglion cells and their axons. Recent evidence suggests that intraocular pressure (IOP) is only one of the many risk factors for this disease. Current treatment options for this disease have been limited to the reduction of IOP; however, it is clear now that the disease progression continues in many patients despite effective lowering of IOP. In the search for newer modalities in treating this disease, much data have emerged from experimental research the world over, suggesting various pathological processes involved in this disease and newer possible strategies to treat it. This review article looks into the current understanding of the pathophysiology of glaucoma, the importance of neuroprotection, the various possible pharmacological approaches for neuroprotection and evidence of current available medications.

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Neuroprotection in Glaucoma Using Calpain-1 Inhibitors: Regional Differences in Calpain-1 Activity in the Trabecular Meshwork, Optic Nerve and Implications for Therapeutics

Cited by 10 publications

References 49 publications

Formation of γ-ketoaldehyde–protein adducts during ethanol-induced liver injury in mice

Formation of γ-ketoaldehyde–protein adducts during ethanol-induced liver injury in mice

Isolevuglandin Adducts in Disease

Neuroprotection in glaucoma

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