Activation of Calpain and Caspase Pathways in Demyelination and Neurodegeneration in Animal Model of Multiple Sclerosis

Das, Arabinda; Guyton, M. Kelly; Butler, Jonathan T.; Ray, Swapan K.; Banik, Naren L.

doi:10.2174/187152708784936699

Cited by 41 publications

(33 citation statements)

References 77 publications

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“…30 Calpains are implicated in the demyelination associated with multiple sclerosis, and calpain inhibitors protect the white matter in animal models of this disorder. 31,32 Thus, the white matter sparing observed with LVCapn1-shRNA is thought to reflect protection of oligodendrocytes after SCI.…”

Section: Discussionmentioning

confidence: 99%

Calpain 1 Knockdown Improves Tissue Sparing and Functional Outcomes after Spinal Cord Injury in Rats

Raza

et al. 2013

Journal of Neurotrauma

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To evaluate the hypothesis that calpain 1 knockdown would reduce pathological damage and functional deficits after spinal cord injury (SCI), we developed lentiviral vectors encoding calpain 1 shRNA and eGFP as a reporter (LV-CAPN1 shRNA). The ability of LV-CAPN1 shRNA to knockdown calpain 1 was confirmed in rat NRK cells using Northern and Western blot analysis. To investigate the effects on spinal cord injury, LV-CAPN1shRNA or LV-mismatch control shRNA (LV-control shRNA) were administered by convection enhanced diffusion at spinal cord level T10 in Long-Evans female rats (200-250 g) 1 week before contusion SCI, 180 kdyn force, or sham surgery at the same thoracic level. Intraspinal administration of the lentiviral particles resulted in transgene expression, visualized by eGFP, in spinal tissue at 2 weeks after infection. Calpain 1 protein levels were reduced by 54% at T10 2 weeks after shRNA-mediated knockdown (p < 0.05, compared with the LV-control group, n = 3 per group) while calpain 2 levels were unchanged. Intraspinal administration of LV-CAPN1shRNA 1 week before contusion SCI resulted in a significant improvement in locomotor function over 6 weeks postinjury, compared with LV-control administration (p < 0.05, n = 10 per group). Histological analysis of spinal cord sections indicated that pre-injury intraspinal administration of LV-CAPN1shRNA significantly reduced spinal lesion volume and improved total tissue sparing, white matter sparing, and gray matter sparing ( p < 0.05, n = 10 per group). Together, results support the hypothesis that calpain 1 activation contributes to the tissue damage and impaired locomotor function after SCI, and that calpain1 represents a potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Calpain 1 Knockdown Improves Tissue Sparing and Functional Outcomes after Spinal Cord Injury in Rats

Raza

et al. 2013

Journal of Neurotrauma

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“…Thus, recent studies have shown that in an animal model of multiple sclerosis the activation of caspase-and calpain-mediated pathways contributed to apoptotic death of oligodendrocytes and neurons, promoting the pathological events leading to neurological deficits. Apoptosis is also involved in the disease-regulating as well as in the disease-promoting processes in experimental autoimmune encephalomyelitis (EAE) [12], a widely recognized animal model of multiple sclerosis [14]. Apoptotic cell death occurs in the course of HD, a devastating neurodegenerative disorder caused by a mutation of huntingtin, which is crucial for normal development and may be regarded as a cell survival gene, whereas mutant huntingtin results in neuronal death [15].…”

Section: Neurodegenerative Disorders and Cell Deathmentioning

confidence: 99%

Mitochondria as targets for chemotherapy

2009

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Mitochondrial malfunctioning is implicated in the pathogenesis of a variety of disorders, including cancer and multiple neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. Disturbance of mitochondrial vital functions, e.g., production of ATP, calcium buffering capacity, and generation of reactive oxygen species, can be potentially involved in disease pathogenesis. Neurological disorders caused by mitochondrial deterioration are often associated with cell loss within specific brain regions. In contrast, mitochondrial alterations in tumor cells and the "Warburg effect" might lead to cell survival and resistance of tumor cells to chemotherapy. This review is devoted to the role of mitochondria in neurodegeneration and tumor formation, and describes how targeting of mitochondria can be beneficial in the therapy of these diseases, which affect a large human population.

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“…Since plasma VEGF is significantly increased in InfEPO mice this does not seem plausible in this experimental model. Calpain activity can be induced by both hypoxia and inflammatory conditions (47, 48) and thus blocking this pathway directly may be more promising as adjunct therapy against CM.…”

Section: Discussionmentioning

confidence: 99%

Systemic and Cerebral Vascular Endothelial Growth Factor Levels Increase in Murine Cerebral Malaria along with Increased Calpain and Caspase Activity and Can be Reduced by Erythropoietin Treatment

et al. 2014

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The pathogenesis of cerebral malaria (CM) includes compromised microvascular perfusion, increased inflammation, cytoadhesion, and endothelial activation. These events cause blood–brain barrier disruption and neuropathology and associations with the vascular endothelial growth factor (VEGF) signaling pathway have been shown. We studied this pathway in mice infected with Plasmodium berghei ANKA causing murine CM with or without the use of erythropoietin (EPO) as adjunct therapy. ELISA and western blotting was used for quantification of VEGF and relevant proteins in brain and plasma. CM increased levels of VEGF in brain and plasma and decreased plasma levels of soluble VEGF receptor 2. EPO treatment normalized VEGF receptor 2 levels and reduced brain VEGF levels. Hypoxia-inducible factor (HIF)-1α was significantly upregulated whereas cerebral HIF-2α and EPO levels remained unchanged. Furthermore, we noticed increased caspase-3 and calpain activity in terminally ill mice, as measured by protease-specific cleavage of α-spectrin and p35. In conclusion, we detected increased cerebral and systemic VEGF as well as HIF-1α, which in the brain were reduced to normal in EPO-treated mice. Also caspase and calpain activity was reduced markedly in EPO-treated mice.

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Activation of Calpain and Caspase Pathways in Demyelination and Neurodegeneration in Animal Model of Multiple Sclerosis

Cited by 41 publications

References 77 publications

Calpain 1 Knockdown Improves Tissue Sparing and Functional Outcomes after Spinal Cord Injury in Rats

Calpain 1 Knockdown Improves Tissue Sparing and Functional Outcomes after Spinal Cord Injury in Rats

Mitochondria as targets for chemotherapy

Systemic and Cerebral Vascular Endothelial Growth Factor Levels Increase in Murine Cerebral Malaria along with Increased Calpain and Caspase Activity and Can be Reduced by Erythropoietin Treatment

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