Calpain-Specific Proteolysis in Primate Retina: Contribution of Calpains in Cell Death

Nakajima, Emi; David, Larry L.; Bystrom, Cory; Shearer, Thomas R.; Azuma, Mitsuyoshi

doi:10.1167/iovs.06-0567

Cited by 49 publications

(37 citation statements)

References 32 publications

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“…In previous studies on rat and primate retinal organotypic cultures, hypoxia (95% N 2 /5% CO 2 without glucose) induced activation of calpains and proteolysis of their substrates, and these effects could be inhibited by a calpainspecific inhibitor (SJA6017), resulting in a prevention of cell death (Tamada et al, 2002;Nakajima et al, 2006). In the present study, RGC-5 cells clearly underwent cell death 24 h after oxygen-glucose deprivation (94% N 2 /1% O 2 /5% CO 2 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel Calpain Inhibitor, ((1S)-1-((((1S)-1-Benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic Acid 5-Methoxy-3-oxapentyl Ester (SNJ-1945), Reduces Murine Retinal Cell Death In Vitro and In Vivo

Shimazawa¹,

Suemori²,

Inokuchi³

et al. 2009

J Pharmacol Exp Ther

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We examined whether ((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester (SNJ-1945), a new orally available calpain inhibitor, might reduce retinal cell death in vivo and/or in vitro. Retinal cell damage was induced in vivo in mice by intravitreal injection of N-methyl-D-aspartate (NMDA), and SNJ-1945 was intraperitoneally or orally administered twice. NMDA-induced calpain activity (measured as the cleaved products of ␣-spectrin) and its substrate, p35 (a neuron-specific activator for cyclin-dependent kinase 5), in the retina were examined by immunoblotting. In RGC-5 (a rat retinal ganglion cell line) cell culture, cell damage was induced by a 4-h oxygenglucose deprivation (OGD) treatment followed by an 18-h reoxygenation period. In mouse retinas, SNJ-1945 (30 or 100 mg/kg i.p., 100 or 200 mg/kg p.o.) significantly inhibited the cell loss in the ganglion cell layer (GCL) and the thinning of the inner plexiform layer induced by NMDA. Furthermore, the number of positive cells for terminal deoxynucleotidyl transferase dUTP nick-end labeling was significantly reduced in the GCL and the inner nuclear layer of retinas treated with SNJ-1945 compared with vehicle-treated retinas 24 h after NMDA injection. Levels of cleaved ␣-spectrin products increased and p35 decreased 6 h after NMDA injection or later, and their effects were attenuated by SNJ-1945. In vitro, SNJ-1945 (10 and 100 M) inhibited the OGD stress-induced reduction in cell viability. In conclusion, SNJ-1945 may afford valuable neuroprotection against retinal diseases, because it was effective against retinal damage both in vitro and in vivo. Our results also indicate that calpain activation and subsequent p35 degradation may be involved in the mechanisms underlying retinal cell death.Retinal ganglion cell (RGC) death is a common feature of many ophthalmic disorders, including glaucoma, optic neuropathies, and various retinovascular diseases (diabetic retinopathy and retinal vein occlusions). Retinal ganglion cells are extremely sensitive to the effects of both glutamate and its analog N-methyl-D-aspartate (NMDA), both of which produce a dosedependent cell loss in vivo and in vitro. In addition, glutamate toxicity has been implicated in the pathophysiology of glaucoma (Dreyer, 1998). Activation of Ca 2ϩ -permeable NMDA receptors and the subsequent neuronal Ca 2ϩ overloading have been shown to mediate glutamate-induced neuron death (Choi, 1994). Induction of the Ca 2ϩ -activated neutral cysteine protease -calpain by micromolar concentrations of Ca 2ϩ occurs early in excitotoxic neuron death (Siman et al., 1989;Faddis et al., 1997). Similar to the caspases, -calpain cleaves a variety of cytoskeletal proteins, enzymes, and transcription factors and could also interfere with the proteolytic activity of the caspases (Croall and DeMartino, 1991).

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Section: Discussionmentioning

confidence: 99%

A Novel Calpain Inhibitor, ((1S)-1-((((1S)-1-Benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic Acid 5-Methoxy-3-oxapentyl Ester (SNJ-1945), Reduces Murine Retinal Cell Death In Vitro and In Vivo

Shimazawa¹,

Suemori²,

Inokuchi³

et al. 2009

J Pharmacol Exp Ther

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show abstract

“…Calpain activity has been shown in models of ocular hypertension, 20 NMDA excitotoxicity, 27 hypoxia, 21,26 and serum withdrawal, 25 and these reports demonstrate a degree of protection from various calpain inhibitors. Our study shows that after calcium influx and serum withdrawal in vitro, calpains are active and calpain inhibition affords protection.…”

Section: Discussionmentioning

confidence: 88%

“…18 Previous studies reported calpain activation in models of retinal cell apoptosis involving ocular hypertension 20 and hypoxia. 21 The purpose of our study was to examine the role of active calpains in RGC apoptosis and to examine the effect of calpain inhibitors. It has been suggested that excitotoxic death plays a role in glaucoma and is caused by glutamate-mediated calcium influx and that this death could be mimicked using the calcium ionophore A23187.…”

mentioning

confidence: 99%

A Key Role for Calpains in Retinal Ganglion Cell Death

McKernan

Guérin

O’Brien

et al. 2007

Invest. Ophthalmol. Vis. Sci.

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“…Calpain activation and retinal cell death has also been observed in retinitis pigmentosa [17,28]. Retinas from monkeys cultured under hypoxic conditions show increased cell death and leakage of lactate dehydrogenase [29]. Increased calpain expression and accumulation of α-spectrin have also been observed in hypoxic retinas.…”

Section: Introductionmentioning

confidence: 93%

“…In hypoxia there is an increase in calcium influx which may aid proteolysis of calpain specific substrates. Calpain inhibitor SJA6017 reduces the proteolysis of α-spectrinin hypoxic retinas [29]. Experiments performed on hypoxic rat retinas revealed elevated presence of calpain-1 and calpain-2 [30].…”

Section: Introductionmentioning

confidence: 97%

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

Govindarajan

Laird

Sherman

et al. 2008

CNSNDDT

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Glaucoma is a group of irreversible blinding eye diseases affecting over 70 million people worldwide. Systemic delivery of calpain-1 inhibitors was proposed as a neuroprotection strategy for the prevention of progressive optic nerve damage in glaucoma. We present a general review of calpain-1 and an account of vast differences in processing of calpain-1 in the trabecular meshwork (TM) and the optic nerve. Calpain-1 accumulates in the glaucomatous TM tissues in vivo. However, calpain-1 activity is substantially lower in the glaucomatous TM compared to controls, apparently owing to partial degradation, and modification by lipid oxidation products such as iso[4]levuglandin E2 (iso [4]LGE 2 ). Treatment of calpain-1 with iso [4]LGE 2 in vitro results in covalent modification, inactivation, and resistance to protease digestion. iso [4]LGE 2 -modified calpain-1 appeared to undergo ubiquitination in the TM by cellular degradation machinery mediated by ubch1-2, ubch5,6 and E6-AP, E2 and E3 enzymes respectively. In the TM, iso [4]LGE 2 -modified calpain-1 loading impairs the cellular proteasome activity consistent with competitive inhibition and formation of suicidal high molecular weight aggregates. In contrast, higher calpain-1 activity, that appears to be under translational control, was observed in glaucomatous optic nerve compared to control. Therapeutic neuroprotection strategies using calpain-1 inhibitors will require consideration of such anatomic differences in its activity and biosynthesis.

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Calpain-Specific Proteolysis in Primate Retina: Contribution of Calpains in Cell Death

Abstract: Taken together, these results suggested that calpain activation in primate retinas could play an important role in cell death during hypoxia caused by elevated IOP from glaucoma.

Cited by 49 publications

References 32 publications

A Novel Calpain Inhibitor, ((1S)-1-((((1S)-1-Benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic Acid 5-Methoxy-3-oxapentyl Ester (SNJ-1945), Reduces Murine Retinal Cell Death In Vitro and In Vivo

A Novel Calpain Inhibitor, ((1S)-1-((((1S)-1-Benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic Acid 5-Methoxy-3-oxapentyl Ester (SNJ-1945), Reduces Murine Retinal Cell Death In Vitro and In Vivo

A Key Role for Calpains in Retinal Ganglion Cell Death

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

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