A calpain inhibitor attenuates cortical cytoskeletal protein loss after experimental traumatic brain injury in the rat

Posmantur, Rand; Kampfl, A.; Siman, Robert; Liu, S.J; Zhao, Xiurong; Clifton, Guy L.; Hayes, Ronald L.

doi:10.1016/s0306-4522(96)00483-6

Cited by 168 publications

(119 citation statements)

References 71 publications

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“…A likely offtarget candidate may be inhibition of the calpains, which are known TBI drug targets, 43 because calpain-1 KO studies have validated as such. 44 Brain calpain activity spikes within 24 h of trauma, [45][46][47] and E64d administration has been shown to reduce calpain activity and provide neuroprotection after trauma. 48,49 Thus, whereas the cathepsin B KO studies here show that E64d acts primarily by inhibition of cathepsin B, some additional benefits may occur in TBI treatment through E64d inhibition of other proteases, especially calpains.…”

Section: E64d Improves Traumatic Brain Injurymentioning

confidence: 99%

The Cysteine Protease Cathepsin B Is a Key Drug Target and Cysteine Protease Inhibitors Are Potential Therapeutics for Traumatic Brain Injury

Hook

Sipes

et al. 2014

Journal of Neurotrauma

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There are currently no effective therapeutic agents for traumatic brain injury (TBI), but drug treatments for TBI can be developed by validation of new drug targets and demonstration that compounds directed to such targets are efficacious in TBI animal models using a clinically relevant route of drug administration. The cysteine protease, cathepsin B, has been implicated in mediating TBI, but it has not been validated by gene knockout (KO) studies. Therefore, this investigation evaluated mice with deletion of the cathepsin B gene receiving controlled cortical impact TBI trauma. Results indicated that KO of the cathepsin B gene resulted in amelioration of TBI, shown by significant improvement in motor dysfunction, reduced brain lesion volume, greater neuronal density in brain, and lack of increased proapoptotic Bax levels. Notably, oral administration of the small-molecule cysteine protease inhibitor, E64d, immediately after TBI resulted in recovery of TBI-mediated motor dysfunction and reduced the increase in cathepsin B activity induced by TBI. E64d outcomes were as effective as cathepsin B gene deletion for improving TBI. E64d treatment was effective even when administered 8 h after injury, indicating a clinically plausible time period for acute therapeutic intervention. These data demonstrate that a cysteine protease inhibitor can be orally efficacious in a TBI animal model when administered at a clinically relevant time point post-trauma, and that E64d-mediated improvement of TBI is primarily the result of inhibition of cathepsin B activity. These results validate cathepsin B as a new TBI therapeutic target.

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Section: E64d Improves Traumatic Brain Injurymentioning

confidence: 99%

The Cysteine Protease Cathepsin B Is a Key Drug Target and Cysteine Protease Inhibitors Are Potential Therapeutics for Traumatic Brain Injury

Hook

Sipes

et al. 2014

Journal of Neurotrauma

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“…30 male adult healthy SpragueDawley (SD) rats were anesthetized with 10% chloral hydrate (0.32 mL/100g) administered intraperitoneally (i.p.). A controlled cortical impact device was used to induce the injury (Dixon et al, 1991;Postmantur et al, 1997). Rats were placed in a stereotactic frame, and two craniotomies were performed adjacent to the central suture, midway between lambda and bregma.…”

Section: Tbi Rats and Sci Monkeys Modelsmentioning

confidence: 99%

Tracking Induced Pluripotent Stem Cells–Derived Neural Stem Cells in the Central Nervous System of Rats and Monkeys

Sha

Sun

et al. 2013

Cellular Reprogramming

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Despite of the immense breakthroughs of induced pluripotent stem cells (iPSCs), clinical application of iPSCs and their derivates remains hampered by a lack of definitive in vivo studies. Here, we attempted to track iPSCsderived neural stem cells (NSCs) in the rodent and primate central nervous system (CNS) and explore their therapeutic viability for stem cell replacement in traumatic brain injury (TBI) rats and monkeys with spinal cord injury (SCI). Superparamagnetic iron oxide (SPIO) particles were used to label iPSCs-derived NSCs in vitro. Labeled NSCs were implanted into TBI rats and SCI monkeys 1 week after injury, and then imaged using gradient reflection echo (GRE) sequence by 3.0T magnetic resonance imaging (MRI) scanner. MRI analysis was performed at 1, 7, 14, 21, and 30 days, respectively, following cell transplantation. Pronounced hypointense signals were initially detected at the cell injection sites in rats and monkeys and were later found to extend progressively to the lesion regions, demonstrating that iPSCs-derived NSCs could migrate to the lesion area from the primary sites. The therapeutic efficacy of iPSCs-derived NSCs was examined concomitantly through functional recovery tests of the animals. In this study, we tracked iPSCs-derived NSCs migration in the CNS of TBI rats and SCI monkeys in vivo for the first time. Functional recovery tests showed obvious motor function improvement in transplanted animals. These data provide the necessary foundation for future clinical application of iPSCs for CNS injury.

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“…Several studies in cerebral ischemia and trauma have also implicated calcium-induced calpain-mediated proteolysis in the pathogenesis (Bartus et al, 1995;Buki et al, 1999a;Buki et al, 1999b;Hong et al, 1994;Posmantur et al, 1997;Saatman et al, 1996) of injury. The substrates for calpain effects have been shown to include many cytoskeletal proteins, membrane proteins, and various regulatory and signaling proteins.…”

Section: Cell Death Mechanismsmentioning

confidence: 99%

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Bramlett

Dietrich

2004

J Cereb Blood Flow Metab

562

358

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Summary: Current knowledge regarding the pathophysiology of cerebral ischemia and brain trauma indicates that similar mechanisms contribute to loss of cellular integrity and tissue destruction. Mechanisms of cell damage include excitotoxicity, oxidative stress, free radical production, apoptosis and inflammation. Genetic and gender factors have also been shown to be important mediators of pathomechanisms present in both injury settings. However, the fact that these injuries arise from different types of primary insults leads to diverse cellular vulnerability patterns as well as a spectrum of injury processes. Blunt head trauma produces shear forces that result in primary membrane damage to neuronal cell bodies, white matter structures and vascular beds as well as secondary injury mechanisms. Severe cerebral ischemic insults lead to metabolic stress, ionic perturbations, and a complex cascade of biochemical and molecular events ultimately causing neuronal death. Similarities in the pathogenesis of these cerebral injuries may indicate that therapeutic strategies protective following ischemia may also be beneficial after trauma. This review summarizes and contrasts injury mechanisms after ischemia and trauma and discusses neuroprotective strategies that target both types of injuries.

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A calpain inhibitor attenuates cortical cytoskeletal protein loss after experimental traumatic brain injury in the rat

Cited by 168 publications

References 71 publications

The Cysteine Protease Cathepsin B Is a Key Drug Target and Cysteine Protease Inhibitors Are Potential Therapeutics for Traumatic Brain Injury

The Cysteine Protease Cathepsin B Is a Key Drug Target and Cysteine Protease Inhibitors Are Potential Therapeutics for Traumatic Brain Injury

Tracking Induced Pluripotent Stem Cells–Derived Neural Stem Cells in the Central Nervous System of Rats and Monkeys

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

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