Mechanisms of Calpain Proteolysis Following Traumatic Brain Injury: Implications for Pathology and Therapy: A Review and Update

Kampfl, A.; Posmantur, Rand; Zhao, Xiurong; Schmutzhard, Erich; Clifton, Guy L.; Hayes, Ronald L.

doi:10.1089/neu.1997.14.121

Cited by 184 publications

(99 citation statements)

References 116 publications

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“…Proteolysis of ABCC1 by serine proteases is inhibited by GSH. 49 Given the potential role of cysteine and serine proteases after TBI, [50][51][52] it is tempting to speculate that protease activation after TBI may modulate ABCB1 and/or ABCC1 transporter expression and/or function. Further study including identification of these peptide bands using mass spectroscopy and functional assays ex vivo appear justified.…”

Section: Abcc1 and Abcb1 In Human Brain After Severe Tbimentioning

confidence: 99%

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans

Willyerd

Empey

Philbrick

et al. 2016

Journal of Neurotrauma

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Adenosine triphosphate-binding cassette (ABC) transport proteins ABCC1 and ABCB1 (also known as multidrug resistance-associated protein 1 and p-glycoprotein, respectively), are key membrane efflux transporters of drugs and endogenous substrates, including in the brain. The impact of traumatic brain injury (TBI) on ABCC1 and ABCB1 expression in humans is unknown. We hypothesized that ABCC1 and ABCB1 expression would be altered in brain tissue from patients acutely after severe TBI. Archived TBI samples (n = 10) from our Brain Trauma Research Center and control samples (n = 7) from our Alzheimer Disease Research Center were obtained under Institutional Review Board approval. Protein was extracted from fresh frozen cortical brain tissue for Western blot analysis and sections were obtained from fixed cortical tissue for immunohistochemistry. Relative abundance of ABCC1 was increased in samples from TBI versus controls (2.8 -2.5 fold; p = 0.005). ABCC1 immunohistochemistry was consistent with Western blot data, with increased immunoreactivity in cerebral blood vessel walls, as well as cells with the morphological appearance of neurons and glia in TBI versus controls. Relative abundance of ABCB1 was similar between TBI and controls ( p = 0.76), and ABCB1 immunoreactivity was primarily associated with cerebral blood vessels in both groups. These human data show that TBI increases ABCC1 expression in the brain, consistent with possible implications for both patients receiving pharmacological inhibitors and/or substrates of ABCC1 after TBI.

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Section: Abcc1 and Abcb1 In Human Brain After Severe Tbimentioning

confidence: 99%

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans

Willyerd

Empey

Philbrick

et al. 2016

Journal of Neurotrauma

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“…Pathological calpain activation is known to be triggered by excessive intracellular Ca ++ accumulation (Bartus et al, 1995) (Kampfl et al, 1997), which is associated with the glutamate release and sustained NMDA activation, as well as depolarization-induced opening of voltage-dependent Ca ++ channels immediately after CNS trauma. Preferred substrates for calpain include cytoskeletal proteins, membrane-associated proteins, signaling transduction proteins and transcription factors (Carafoli and Molinari, 1998);Wang, 2000a).…”

Section: Temporal Characteristics Of Calpain-mediated Cytoskeletal Damentioning

confidence: 99%

Temporal relationship of peroxynitrite-induced oxidative damage, calpain-mediated cytoskeletal degradation and neurodegeneration after traumatic brain injury

Deng

Thompson

Gao

et al. 2007

Experimental Neurology

133

171

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We assessed the temporal and spatial characteristics of PN-induced oxidative damage and its relationship to calpain-mediated cytoskeletal degradation and neurodegeneration in a severe unilateral controlled cortical impact (CCI) traumatic brain injury (TBI) model. Quantitative temporal time-course studies were performed to measure two oxidative damage markers: 3-nitrotyrosine (3NT) and 4-hydroxynonenal (4HNE) at 30 min, 1, 3, 6, 12, 24, 48, 72 hrs, 7 days after injury in ipsilateral cortex of young adult male CF-1 mice. Secondly, the time course of Ca ++ -activated, calpain-mediated proteolysis was also analyzed using quantitative western-blot measurement of breakdown products of the cytoskeletal protein α-spectrin. Finally, the time course of neurodegeneration was examined using de Olmos silver staining. Both oxidative damage markers increased in cortical tissue immediately after injury (30 min) and elevated for the first 3-6 hrs before returning to baseline. In the immunostaining study, the PN-selective marker, 3NT, and the lipid peroxidation marker, 4HNE, were intense and overlapping in the injured cortical tissue. α-Spectrin breakdown products, which was used as biomarker for calpain-mediated cytoskeletal degradation, were also increased after injury, but the time course lagged behind the peak of oxidative damage and did not reach its maximum until 24 hrs post-injury. In turn, cytoskeletal degradation preceded the peak of neurodegeneration which occurred at 48 hrs post-injury. These studies have led us to the hypothesis that PN-mediated oxidative damage is an early event that contributes to a compromise of Ca ++ homeostatic mechanisms which causes a massive Ca ++ overload and calpain activation which is a final common pathway that results in post-traumatic neurodegeneration.

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“…Specific activation of the intracellular Ca 2ϩ -dependent protease calpain by excitatory amino acid signaling confers selective activitydependent cleavage of synaptic substrates and thus plays a pivotal role in regulating neuronal plasticity Siman and Noszek, 1988;Denny et al, 1990;Wu and Lynch, 2006;Liu et al, 2008). Calpain is activated by intracellular Ca 2ϩ and by the neurotrophic factor BDNF and its receptor TrkB, which leads to specific cleavage of synaptic substrates in response to intense synaptic activity under physiological (Zadran et al, 2010a,b) as well as pathophysiological conditions (Kampfl et al, 1997;Zhou and Baudry, 2006), including seizures (Sierra-Paredes et al, 1999;Fujikawa, 2005). Notably, an increased calpain expression has been recently reported in cortical tissue of patients with drug-resistant temporal lobe epilepsy (Feng et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Activity-Dependent Cleavage of the K-Cl Cotransporter KCC2 Mediated by Calcium-Activated Protease Calpain

et al. 2012

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The K-Cl cotransporter KCC2 plays a crucial role in neuronal chloride regulation. In mature central neurons, KCC2 is responsible for the low intracellular Cl Ϫ concentration ([Cl Ϫ ] i ) that forms the basis for hyperpolarizing GABA A receptor-mediated responses. Fast changes in KCC2 function and expression have been observed under various physiological and pathophysiological conditions. Here, we show that the application of protein synthesis inhibitors cycloheximide and emetine to acute rat hippocampal slices have no effect on total KCC2 protein level and K-Cl cotransporter function. Furthermore, blocking constitutive lysosomal degradation with leupeptin did not induce significant changes in KCC2 protein levels. These findings indicate a low basal turnover rate of the total KCC2 protein pool. In the presence of the glutamate receptor agonist NMDA, the total KCC2 protein level decreased to about 30% within 4 h, and this effect was blocked by calpeptin and MDL-28170, inhibitors of the calcium-activated protease calpain. Interictal-like activity induced by incubation of hippocampal slices in an Mg 2ϩ -free solution led to a fast reduction in KCC2-mediated Cl Ϫ transport efficacy in CA1 pyramidal neurons, which was paralleled by a decrease in both total and plasmalemmal KCC2 protein. These effects were blocked by the calpain inhibitor MDL-28170. Taken together, these findings show that calpain activation leads to cleavage of KCC2, thereby modulating GABAergic signaling.

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Mechanisms of Calpain Proteolysis Following Traumatic Brain Injury: Implications for Pathology and Therapy: A Review and Update

Cited by 184 publications

References 116 publications

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans

Temporal relationship of peroxynitrite-induced oxidative damage, calpain-mediated cytoskeletal degradation and neurodegeneration after traumatic brain injury

Activity-Dependent Cleavage of the K-Cl Cotransporter KCC2 Mediated by Calcium-Activated Protease Calpain

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