Calpain Activation and Cytoskeletal Protein Breakdown in the Corpus Callosum of Head-Injured Patients

McCracken, Eileen; Hunter, Andrea; Patel, Shyam A.; Graham, David I.; Dewar, Deborah

doi:10.1089/neu.1999.16.749

Cited by 100 publications

(69 citation statements)

References 49 publications

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“…Proteolysis of structural axonal proteins such as neurofilament and APP is probably important in the occurrence of white matter damage. 27,28 In the present study, the neurological findings in animals with lacunar infarction were not always correlated with the morphological findings. Obvious signs of neurological deficit were seen with the maximum score at 12 hours after the ischemic insult and were maintained during the first 24 hours.…”

Section: Discussioncontrasting

confidence: 72%

Experimental Model of Lacunar Infarction in the Gyrencephalic Brain of the Miniature Pig

Tanaka

Imai

Konno

et al. 2008

Stroke

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Background and Purpose-Lacunar infarction accounts for 25% of ischemic strokes, but the pathological characteristics have not been investigated systematically. A new experimental model of lacunar infarction in the miniature pig was developed to investigate the pathophysiological changes in the corticospinal tract from the acute to chronic phases. Methods-Thirty-five miniature pigs underwent transcranial surgery for permanent anterior choroidal artery occlusion.Animals recovered for 24 hours (nϭ7), 2 (nϭ5), 3 (nϭ2), 4 (nϭ2), 6 (nϭ1), 7 (nϭ7), 8 (nϭ2), and 9 days (nϭ1), 2 weeks (nϭ2), 4 weeks (nϭ3), and more than 4 weeks (nϭ3). Neurology, electrophysiology, histology, and MRI were performed. Seven additional miniature pigs underwent transient anterior choroidal artery occlusion to study muscle motor-evoked potentials and evaluate corticospinal tract function during transient anterior choroidal artery occlusion. Results-The protocol had a 91.4% success rate in induction of internal capsule infarction 286Ϯ153 mm 3 (meanϮSD). Motor-evoked potentials revealed the presence of penumbral tissue in the internal capsule after 6 to 15 minutes anterior choroidal artery occlusion. Total neurological deficit scores of 15.0 (95% CI, 13.5 to 16.4) and 3.4 (0.3 to 6.4) were recorded for permanent anterior choroidal artery occlusion and sham groups, respectively (PϽ0.001, maximum score 25) with motor deficit scores of 3.4 (95% CI, 2.9 to 4.0) and 0.0 (CI, 0.0 to 0.0), respectively (PϽ0.001, maximum score 9). Histology revealed that the internal capsule lesion expands gradually from acute to chronic phases. Conclusions-This

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Section: Discussioncontrasting

confidence: 72%

Experimental Model of Lacunar Infarction in the Gyrencephalic Brain of the Miniature Pig

Tanaka

Imai

Konno

et al. 2008

Stroke

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“…Cytoskeletal damage was assessed by measuring the calpainmediated spectrin breakdown product BDP N , a sensitive precursor to neuronal pathology in animal models of excitotoxic insults (Lee et al, 1991;Saido et al, 1993;Roberts-Lewis et al, 1994;Bahr et al, 1995Bahr et al, , 2002Saatman et al, 1996;Munirathinam et al, 2002;Zhu et al, 2005) and human brain injury (McCracken et al, 1999). AM374/AM404 reduced the excitotoxic damage induced in the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects against Excitotoxicity

Karanian¹,

Brown²,

Makriyannis³

et al. 2005

J. Neurosci.

111

109

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The endocannabinoid system has been suggested to elicit signals that defend against several disease states including excitotoxic brain damage. Besides direct activation with CB 1 receptor agonists, cannabinergic signaling can be modulated through inhibition of endocannabinoid transport and fatty acid amide hydrolase (FAAH), two mechanisms of endocannabinoid inactivation. To test whether the transporter and FAAH can be targeted pharmacologically to modulate survival/repair responses, the transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) and the FAAH inhibitor palmitylsulfonyl fluoride (AM374) were assessed for protection against excitotoxicity in vitro and in vivo. AM374 and AM404 both enhanced mitogen-activated protein kinase (MAPK) activation in cultured hippocampal slices. Interestingly, combining the distinct inhibitors produced additive effects on CB 1 signaling and associated neuroprotection. After an excitotoxic insult in the slices, infusing the AM374/AM404 combination protected against cytoskeletal damage and synaptic decline, and the protection was similar to that produced by the stable CB 1 agonist AM356 (R-methanandamide). AM374/ AM404 and the agonist also elicited cytoskeletal and synaptic protection in vivo when coinjected with excitotoxin into the dorsal hippocampus. Correspondingly, potentiating endocannabinoid responses with the AM374/AM404 combination prevented behavioral alterations and memory impairment that are characteristic of excitotoxic damage. The protective effects mediated by AM374/AM404 were (1) evident 7 d after insult, (2) correlated with the preservation of CB 1 -linked MAPK signaling, and (3) were blocked by a selective CB 1 antagonist. These results indicate that dual modulation of the endocannabinoid system with AM374/AM404 elicits neuroprotection through the CB 1 receptor. The transporter and FAAH are modulatory sites that may be exploited to enhance cannabinergic signaling for therapeutic purposes.

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“…McCreacken and colleagues provided evidence in TBI patients that calpain-mediated breakdown of the cytoskeleton may contribute to axonal delayed damage after head injury (McCracken et al, 1999). Although a proportion of axons become severed at the time of injury-the so-called primary axotomy-many axons undergo secondary or delayed axotomy (Graham and Gennarelli, 1997;Maxwell et al, 1997), distinct from the irreversible axonal damage that occurs at the moment of injury (Gennarelli, 1996;Povlishock and FIG.…”

Section: Fig 2 Receiver-operating Characteristic (Roc) Curves and Amentioning

confidence: 99%

αII-Spectrin Breakdown Products (SBDPs): Diagnosis and Outcome in Severe Traumatic Brain Injury Patients

Mondello

Robicsek

Gabrielli

et al. 2010

Journal of Neurotrauma

187

139

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In this study we assessed the clinical utility of quantitative assessments of aII-spectrin breakdown products (SBDP145 produced by calpain, and SBDP120 produced by caspase-3) in cerebrospinal fluid (CSF) as markers of brain damage and outcome after severe traumatic brain injury (TBI). We analyzed 40 adult patients with severe TBI (Glasgow Coma Scale [GCS] score 8) who underwent ventriculostomy. Patients requiring CSF drainage for other medical reasons served as controls. CSF samples were taken at admission and every 6 h thereafter for a maximum of 7 days and assessed using novel quantitative fragment-specific ELISAs for SBDPs. Outcome was assessed using the 3-month Glasgow Outcome Scale. Mean CSF levels of SBDPs were significantly higher in TBI patients than in controls at all time points examined. Different temporal release patterns of CSF SBDP145 and SBDP120 were observed. SBDP145 provided accurate diagnoses at all time points examined, while SBDP120 release was more accurate 24 h after injury. Within 24 h after injury, SBDP145 CSF concentrations significantly correlated with GCS scores, while SBDP120 levels correlated with age. SBDP levels were significantly higher in patients who died than in those who survived. SBDP145 levels (>6 ng/mL) and SBDP120 levels (>17.55 ng/mL) strongly predicted death (odds ratio 5.9 for SBDP145, and 18.34 for SBDP120). The time course of SBDPs in nonsurvivors also differed from that of survivors. These results suggest that CSF SBDP levels can predict injury severity and mortality after severe TBI, and can be useful complements to clinical assessment.

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Calpain Activation and Cytoskeletal Protein Breakdown in the Corpus Callosum of Head-Injured Patients

Cited by 100 publications

References 49 publications

Experimental Model of Lacunar Infarction in the Gyrencephalic Brain of the Miniature Pig

Experimental Model of Lacunar Infarction in the Gyrencephalic Brain of the Miniature Pig

Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects against Excitotoxicity

αII-Spectrin Breakdown Products (SBDPs): Diagnosis and Outcome in Severe Traumatic Brain Injury Patients

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