A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain

Shields, Donald C.; Schaecher, Kurt E.; Saido, Takaomi C.; Banik, Naren L.

doi:10.1073/pnas.96.20.11486

Cited by 151 publications

(117 citation statements)

References 47 publications

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…Investigation of the production of specific breakdown products (FBDP) of substrates specific to calpain proteolysis has proved useful in detecting calpain activity in nervous and sensory tissues (Siman et al, 1984;Saido et al, 1993Saido et al, , 1994Blomgren et al, 1995;Shields et al, 1999;Rajgopal and Vemuri, 2002;Ladrech et al, 2004 among others). Among these substrates, fodrin, the neuronal form of spectrin, is a specific actin cross-linking protein that is cleaved by calpain to a greater extent than other substrates.…”

Section: Hal Author Manuscript Inserm-00145385 Versionmentioning

confidence: 99%

A novel dual inhibitor of calpains and lipid peroxidation (BN82270) rescues the cochlea from sound trauma

et al. 2007

View full text Add to dashboard Cite

Free radical and calcium buffering mechanisms are implicated in cochlear cell damage that has been induced by sound trauma. Thus in this study we evalua ted the therapeutic effect of a novel dual inhibitor of calpains and of lipid peroxidation (BN 82270) on the permanent hearing and hair cell loss induced by sound trauma.Perfusion of BN 82270 into the scala tympani of the guinea pig cochlea prevented the formation of calpain-cleaved fodrin, translocation of cytochrome c, DNA fragmentation and hair cell degeneration caused by sound trauma. This was confirmed by functional tests in vivo, showing a clear dose-dependent reduction of permanent hearing loss (ED 50 = 4.07 µM) with almost complete protection at 100 µM.Furthermore, BN82270 still remained effective even when applied onto the round window membrane after sound trauma had occurred, within a therapeutic window of 24hours. This indicates that BN 82270 may be of potential therapeutic value in treating the cochlea after sound trauma.

show abstract

Section: Hal Author Manuscript Inserm-00145385 Versionmentioning

confidence: 99%

A novel dual inhibitor of calpains and lipid peroxidation (BN82270) rescues the cochlea from sound trauma

et al. 2007

View full text Add to dashboard Cite

show abstract

“…This statement has been largely based on the protective effects exerted by synthetic protease inhibitors and by overexpression of calpastatin (35)(36)(37)(38)(39)(40). However, in these reports, the fact that a large excess of calpastatin is normally present in brain is not considered, and no explanation has been given on the possible ineffectiveness of the inhibitor under the experimental conditions used (31). It must also be considered that the severe and irreversible cell damage observed under these pathological conditions occurs in the presence of a massive Ca 2ϩ influx, associated with the collapse of the membrane potential.…”

mentioning

confidence: 97%

Regulation of Calpain Activity in Rat Brain with Altered Ca2+ Homeostasis

Averna

Stifanese

Tullio

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

The regulatory mechanism of calpain activity is primarily based on the physiological control of intracellular Ca 2ϩ homeostasis, predominantly exerted by the plasma membrane Ca 2ϩ -ATPase and, more specifically, by the expression in all mammalian cells of a natural protein inhibitor named calpastatin (1-7).Calpastatin is a protein endowed with peculiar molecular properties characterized by the presence of four identical inhibitory domains, each one possessing, in its free form, an inhibitory capacity almost equivalent to that expressed by the native calpastatin molecule (2-4, 8 -11). Moreover, calpastatin also behaves as a substrate of calpain, which is degraded to single inhibitory domains as well as to inactive products as a result of more extensive digestion (8,(12)(13)(14)(15)(16). Conservative fragmentation has been attributed to -calpain activity, and degradation to inactive peptides attributed to digestion by m-calpain (8, 16).Despite this information and the numerous reports on the structural properties of calpain (17-22), including the presence of different isoforms in various tissues (23-27), the biological function of this protease and the efficiency of its "in vivo" intracellular regulation remain uncertain.It is often suggested (28 -34) that in brain, calpain is directly implicated in neurodegeneration and neuronal cell death as a consequence of a massive Ca 2ϩ influx occurring under pathological conditions, such as hypoxia and ischemia. This statement has been largely based on the protective effects exerted by synthetic protease inhibitors and by overexpression of calpastatin (35-40). However, in these reports, the fact that a large excess of calpastatin is normally present in brain is not considered, and no explanation has been given on the possible ineffectiveness of the inhibitor under the experimental conditions used (31). It must also be considered that the severe and irreversible cell damage observed under these pathological conditions occurs in the presence of a massive Ca 2ϩ influx, associated with the collapse of the membrane potential. On the basis of these considerations, it seems therefore reasonable to assume that in brain cells, as well as in other cell types, a moderate alteration in Ca 2ϩ homeostasis, even prolonged for a long period of time, could evoke adaptive compensatory defense mechanisms capable of preserving cell integrity.To explore in vivo the existence in the brain of such mechanisms and to characterize their molecular aspects, we have treated normal normotensive Milan strain rats (NMS) 2 with a high salt (sodium) diet (HSD) known to promote elevation in blood pressure in response to a mild increase in intracellular free [Ca 2ϩ ] in vascular smooth muscle, via an alteration in the Na ϩ /Ca 2ϩ exchanger (41)(42)(43). A role of the exchanger in the alteration of calcium homeostasis in brain has been previously suggested (44,45). To amplify the effects of this treatment we have exposed hypertensive rats (HMS) of the same Milan strain (46) to the same diet, because these an...

show abstract

“…Calpain degrades all major myelin proteins, and there is increased calpain activity after neonatal cerebral HI in this model (19). Increased calpain activity has also been documented in brain tissue from patients with multiple sclerosis, and is implicated as a factor contributing to myelin degradation in multiple sclerosis (20).…”

mentioning

confidence: 99%

Hypoxic-Ischemic Oligodendroglial Injury in Neonatal Rat Brain

et al. 2002

View full text Add to dashboard Cite

Neonatal periventricular white matter injury is a major contributor to chronic neurologic dysfunction. In a neonatal rat stroke model, myelin basic protein (MBP) immunostaining reveals acute periventricular white matter injury. Yet, the extent to which myelin proteins can recover after neonatal hypoxicischemic injury is unknown. We developed a quantitative method to correlate the severity of the hypoxic-ischemic insult with the magnitude of loss of MBP immunostaining. Seven-day-old (P7) rats underwent right carotid ligation, followed by exposure to 8% oxygen for 1, 1.5, 2, or 2.5 h. On both P12 and P21, white matter integrity was evaluated by densitometric analysis of MBP immunostaining, and the amount of tissue injury was evaluated by morphometric measurements of cerebral hemisphere areas. The most severe hypoxic-ischemic insults (2.5 h) elicited marked reductions in MBP immunostaining ipsilaterally on both P12 and P21. In contrast, in mildly lesioned animals (1.5 h), MBP immunostaining was reduced ipsilaterally on P12, but 2 wk after lesioning, on P21, there was a substantial restoration of MBP immunostaining. The restoration in MBP immunostaining could reflect either functional recovery of injured oligodendroglia or proliferation and maturation of oligodendroglial precursors. Our data demonstrate that quantitative measurement of MBP immunostaining provides a sensitive indicator of acute oligodendroglial injury. Most importantly, we show that in this neonatal rodent stroke model, restoration of myelin proteins occurs after moderate, but not after more severe, cerebral hypoxia-ischemia. Considerable clinical and experimental data demonstrate that immature oligodendroglia are highly susceptible to HI injury (1-5). There is also growing recognition that oligodendroglial injury in the immature nervous system may have profound adverse effects on neuronal development (6). Among the mechanisms implicated as contributing to the vulnerability of immature oligodendroglia to HI are increased susceptibility to excitotoxicity (1, 7), oxidative stress (2), and inflammation (8 -9), and propensity for induction of apoptosis (10).In a widely used neonatal rat stroke model, elicited by unilateral carotid artery ligation and timed exposure to moderate hypoxia (8% oxygen) in 7-d-old (P7) rats, ipsilateral white matter injury occurs, together with more widespread tissue injury (11)(12)(13)(14)(15). In this model, lengthening the duration of hypoxic exposure results in a progressive increase in the severity of brain damage (12); the temporal threshold to elicit tissue injury is at approximately 1.5 h, and more prolonged HI (2-2.5 h) commonly elicits extensive neuronal loss in the ipsilateral cortex, hippocampus, striatum, and thalamus (13). Additional neuropathologic features of the HI lesion include an acute and sustained microglial and monocyte infiltrate (13, 14), reactive gliosis (13, 15), and the evolution of cortical cavitary infarcts (13).Although the original description of histopathology in this model documented the vulner...

show abstract

A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain

Cited by 151 publications

References 47 publications

A novel dual inhibitor of calpains and lipid peroxidation (BN82270) rescues the cochlea from sound trauma

A novel dual inhibitor of calpains and lipid peroxidation (BN82270) rescues the cochlea from sound trauma

Regulation of Calpain Activity in Rat Brain with Altered Ca2+ Homeostasis

Hypoxic-Ischemic Oligodendroglial Injury in Neonatal Rat Brain

Contact Info

Product

Resources

About