Pathophysiological role of calpain in experimental demyelination

Shields, Donald C.; Banik, Naren L.

doi:10.1002/(sici)1097-4547(19990301)55:5<533::aid-jnr1>3.0.co;2-8

Cited by 57 publications

(27 citation statements)

References 66 publications

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“…Several lines of evidence indicate that only p25 but not p35-bound cdk5 phosphorylates tau in vitro, thereby inducing pathological alterations in neurons (22-25, 40, 41). It is interesting to note that conversion of p35 to p25 is regulated by the calcium-dependent cysteine protease calpain as activation of calpain together with impaired calcium homeostasis has been observed in EAE and MS brains (42,43). It is therefore tempting to speculate that increased calcium influx might trigger a cascade of pathological events that lead to calpain activation, followed by conversion of p35 to p25 and increased and pathological tau phosphorylation at epitopes such as PHF-1, AT-8, and AT-100.…”

Section: Discussionmentioning

confidence: 99%

Hyperphosphorylation and Aggregation of Tau in Experimental Autoimmune Encephalomyelitis

Schneider

Araújo

Trajković

et al. 2004

Journal of Biological Chemistry

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Axonal damage is a major morphological correlate and cause of permanent neurological deficits in patients with multiple sclerosis (MS), a multifocal, inflammatory and demyelinating disease of the central nervous system. Hyperphosphorylation and pathological aggregation of microtubule-associated protein tau is a common feature of many neurodegenerative diseases with axonal degeneration including Alzheimer's disease. We have therefore analyzed tau phosphorylation, solubility and distribution in the brainstem of rats with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Tau was hyperphosphorylated at several sites also phosphorylated in Alzheimer's disease and became partially detergent-insoluble in EAE brains. Morphological examination demonstrated accumulation of amorphous deposits of abnormally phosphorylated tau in the cell body and axons of neurons within demyelinating plaques. Hyperphosphorylation of tau was accompanied by up-regulation of p25, an activator of cyclin-dependent kinase 5. Phosphorylation of tau, activation of cdk5, and axonal pathology were significantly reduced when diseased rats were treated with prednisolone, a standard therapy of acute relapses in MS. Hyperphosphorylation of tau was not observed in a genetic or nutritional model of axonal degeneration or demyelination, suggesting that inflammation as detected in the brains of rats with EAE is the specific trigger of tau pathology. In summary, our data provide evidence that axonal damage in EAE and possibly MS is linked to tau pathology.

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Section: Discussionmentioning

confidence: 99%

Hyperphosphorylation and Aggregation of Tau in Experimental Autoimmune Encephalomyelitis

Schneider

Araújo

Trajković

et al. 2004

Journal of Biological Chemistry

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“…In the acute Lewis rat model of EAE, calpain expression was correlated with T cell, macrophage, and neutrophil migration into the CNS [193]. Examination of the acute EAE spinal cord revealed that Ca 2+ influx and calpain expression correlated with axonal damage, mitochondrial damage, and loss of structural integrity of microtubules and filaments [187].…”

Section: Cytokine-based Immuno-interventionmentioning

confidence: 99%

Myelin Recovery in Multiple Sclerosis: The Challenge of Remyelination

et al. 2013

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Multiple sclerosis (MS) is the most common demyelinating and an autoimmune disease of the central nervous system characterized by immune-mediated myelin and axonal damage, and chronic axonal loss attributable to the absence of myelin sheaths. T cell subsets (Th1, Th2, Th17, CD8+, NKT, CD4+CD25+ T regulatory cells) and B cells are involved in this disorder, thus new MS therapies seek damage prevention by resetting multiple components of the immune system. The currently approved therapies are immunoregulatory and reduce the number and rate of lesion formation but are only partially effective. This review summarizes current understanding of the processes at issue: myelination, demyelination and remyelination—with emphasis upon myelin composition/architecture and oligodendrocyte maturation and differentiation. The translational options target oligodendrocyte protection and myelin repair in animal models and assess their relevance in human. Remyelination may be enhanced by signals that promote myelin formation and repair. The crucial question of why remyelination fails is approached is several ways by examining the role in remyelination of available MS medications and avenues being actively pursued to promote remyelination including: (i) cytokine-based immune-intervention (targeting calpain inhibition), (ii) antigen-based immunomodulation (targeting glycolipid-reactive iNKT cells and sphingoid mediated inflammation) and (iii) recombinant monoclonal antibodies-induced remyelination.

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“…Indeed, several laboratories have shown that degradation of cytoskeletal proteins occurs in experimental models of stroke (Aronowski et al, 1999;Hong et al, 1994;Liebetrau et al, 1999;RobertsLewis et al, 1994), TBI Kampf et al, 1996;Newcomb et al, 1997;Posmantur et al, 1996;Saatman et al, 1996a), spinal cord injury (Banik et al, 1997;Braughler and Hall, 1984;Ray et al, 1999), and experimental allergic encephalomyelitis (EAE), a model of the demyelinating disease, multiple sclerosis (for review, see Shields and Banik, 1999). While damage to cytoskeletal proteins (e.g., neurofilaments, microtubule-associated protein, a-spectrin) is evident within the first minutes following experimental TBI, the height of proteolytic activity appears to occur several hours after injury (Newcomb et al, 1997;Posmantur et al, 1994), and in the case of mild injury, occurs as late as several days (Saatman et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

The Novel Calpain Inhibitor SJA6017 Improves Functional Outcome after Delayed Administration in a Mouse Model of Diffuse Brain Injury

Kupina

Nath

Bernath

et al. 2001

Journal of Neurotrauma

103

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A principal mechanism of calcium-mediated neuronal injury is the activation of neutral proteases known as calpains. Proteolytic substrates for calpain include receptor and cytoskeletal proteins, signal transduction enzymes and transcription factors. Recently, calpain inhibitors have been shown to provide benefit in rat models of focal head injury and focal cerebral ischemia. The present study sought to investigate, in experiment 1, the time course of calpain-mediated cytoskeletal injury in a mouse model of diffuse head injury by measuring the 150- and 145-kDa alpha-spectrin breakdown products (SBDP). Secondly, in experiment 2, we examined the effect of early (20 min postinjury) administration of the novel calpain inhibitor SJA6017 on functional outcome measured 24 h following injury and its effect on posttraumatic alpha-spectrin degradation. Lastly, in experiment 3, we examined the effect of delayed (4 or 6 h postinjury) administration of SJA6017 on 24-h postinjury functional outcome. In experiment 1, isoflurane-anesthetized male CF-1 mice (18-22 g) were subjected to a 750 g-cm weight drop-induced injury and were sacrificed for SBDP analysis at postinjury times of 30 min, and 1, 2, 6, 24 and 48 h (plus sham). In experiments 2 and 3, mice were injured as described, and delivered a single tail vein injection of either SJA6017 (0.3, 1, or 3 mg/kg) or vehicle (administered immediately, 4 or 6 h postinjury [3 mg/kg]). Functional outcome was evaluated in both studies, and, in experiment 2, 24-h postinjury assessment of SBDPs was determined. Following injury, the level of SBDP 145 was significantly different from sham at 24 and 48 h in cortical and at 24 h in the hippocampal tissues and at 48 h in the striatum. Immediate postinjury administration of SJA6017 resulted in a dose-related improvement in 24-h functional outcome (p < 0.05 at 3 mg/kg). Significance was maintained after a 4-h delay of the 3 mg/kg, but was lost after a 6-h delay. Despite improvement in functional outcome at 24 h, SJA6017 did not reduce spectrin breakdown in cortical or hippocampal tissues. These results support a role for calpain-mediated neuronal injury and the potential for a practical therapeutic window for calpain inhibition following traumatic brain injury. However, measurements of regional spectrin degradation may not be the most sensitive marker for determining the effects of calpain inhibition.

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Pathophysiological role of calpain in experimental demyelination

Cited by 57 publications

References 66 publications

Hyperphosphorylation and Aggregation of Tau in Experimental Autoimmune Encephalomyelitis

Hyperphosphorylation and Aggregation of Tau in Experimental Autoimmune Encephalomyelitis

Myelin Recovery in Multiple Sclerosis: The Challenge of Remyelination

The Novel Calpain Inhibitor SJA6017 Improves Functional Outcome after Delayed Administration in a Mouse Model of Diffuse Brain Injury

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