Targeted Gene Inactivation of Calpain-1 Suppresses Cortical Degeneration Due to Traumatic Brain Injury and Neuronal Apoptosis Induced by Oxidative Stress

Yamada, Kaori; Kozlowski, Dorothy A.; Seidl, Stacey E.; Lance, Steven; Wieschhaus, Adam J.; Sundivakkam, Premanand; Tiruppathì, Chinnaswamy; Chishti, Imran; Herman, Ira M.; Kuchay, Shafi; Chishti, Athar H.

doi:10.1074/jbc.m111.302612

Cited by 63 publications

(34 citation statements)

References 56 publications

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“…Of particular interest is the family of calcium-dependent neutral proteases known as calpains. Involvement of calpains has been reported in animal models of SCI, TBI, and ischemic stroke (Bartus et al, 1994; Sribnick et al, 2007; Yamada et al, 2012). Recent experimental evidence suggests that calpain may activate p53 following induction of direct DNA damage in primary cortical neurons in vitro (Sedarous et al, 2003).…”

Section: Effects Of Dna Damage On Neuronal Viabilitymentioning

confidence: 99%

Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration

Smith¹,

Park²,

Krause³

et al. 2013

Neurochemistry International

148

100

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Oxidative stress has been identified as an important contributor to neurodegeneration associated with acute CNS injuries and diseases such as spinal cord injury (SCI), traumatic brain injury (TBI), and ischemic stroke. In this review, we briefly detail the damaging effects of oxidative stress (lipid peroxidation, protein oxidation, etc.) with a particular emphasis on DNA damage. Evidence for DNA damage in acute CNS injuries is presented along with its downstream effects on neuronal viability. In particular, unchecked oxidative DNA damage initiates a series of signaling events (e.g. activation of p53 and PARP-1, cell cycle re-activation) which have been shown to promote neuronal loss following CNS injury. These findings suggest that preventing DNA damage might be an effective way to promote neuronal survival and enhance neurological recovery in these conditions. Finally, we identify the telomere and telomere-associated proteins (e.g. telomerase) as novel therapeutic targets in the treatment of neurodegeneration due to their ability to modulate the neuronal response to both oxidative stress and DNA damage.

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Section: Effects Of Dna Damage On Neuronal Viabilitymentioning

confidence: 99%

Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration

Smith¹,

Park²,

Krause³

et al. 2013

Neurochemistry International

148

100

View full text Add to dashboard Cite

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“…They play functional roles in numerous physiological processes, including cytoskeletal reorganization, cell motility, apoptosis, neuronal biogenesis and haemostasis [1,2]. Genome sequencing has identified at least 14 members of the calpain superfamily.…”

Section: Introductionmentioning

confidence: 99%

Calpain-1 knockout reveals broad effects on erythrocyte deformability and physiology

Wieschhaus

Khan

Zaidi

et al. 2012

Biochemical Journal

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Pharmacological inhibitors of cysteine proteases have provided useful insights into the regulation of calpain activity in erythrocytes. However, the precise biological function of calpain activity in erythrocytes remains poorly understood. Erythrocytes express calpain-1, an isoform regulated by calpastatin, the endogenous inhibitor of calpains. In the present study, we investigated the function of calpain-1 in mature erythrocytes using our calpain-1-null [KO (knockout)] mouse model. The calpain-1 gene deletion results in improved erythrocyte deformability without any measurable effect on erythrocyte lifespan in vivo. The calcium-induced sphero-echinocyte shape transition is compromised in the KO erythrocytes. Erythrocyte membrane proteins ankyrin, band 3, protein 4.1R, adducin and dematin are degraded in the calcium-loaded normal erythrocytes but not in the KO erythrocytes. In contrast, the integrity of spectrin and its state of phosphorylation are not affected in the calcium-loaded erythrocytes of either genotype. To assess the functional consequences of attenuated cytoskeletal remodelling in the KO erythrocytes, the activity of major membrane transporters was measured. The activity of the K+–Cl− co-transporter and the Gardos channel was significantly reduced in the KO erythrocytes. Similarly, the basal activity of the calcium pump was reduced in the absence of calmodulin in the KO erythrocyte membrane. Interestingly, the calmodulin-stimulated calcium pump activity was significantly elevated in the KO erythrocytes, implying a wider range of pump regulation by calcium and calmodulin. Taken together, and with the atomic force microscopy of the skeletal network, the results of the present study provide the first evidence for the physiological function of calpain-1 in erythrocytes with therapeutic implications for calcium imbalance pathologies such as sickle cell disease.

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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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Targeted Gene Inactivation of Calpain-1 Suppresses Cortical Degeneration Due to Traumatic Brain Injury and Neuronal Apoptosis Induced by Oxidative Stress

Cited by 63 publications

References 56 publications

Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration

Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration

Calpain-1 knockout reveals broad effects on erythrocyte deformability and physiology

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

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