The Effects of Cathepsin B Inhibition in the Face of Diffuse Traumatic Brain Injury and Secondary Intracranial Pressure Elevation
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals
2.2. Drug Preparation
2.3. Whisker Nuisance Task
2.4. Surgical Preparation, Injury Induction, and Drug Infusion
2.5. Tissue Processing for Molecular Analysis
2.6. Tracer Infusion and Tissue Processing for Histological Analysis
2.7. Quantification of Cathepsin B Activity
2.8. Western Blotting
2.9. Membrane Disruption and Total Cell Count Analysis
2.10. Cellular Cathepsin B Localization Analysis
2.11. Statistics
3. Results
3.1. Cathepsin B Activity Was Decreased in the Left and Right Cortex after 2w of Continuous CA-074Me Infusion
3.2. Protein Expression of Cathepsin B and Signaling Partners Bcl-XL, Bak, and AIF
3.3. Elevation of ICP and/or Infusion of CA-074Me Did Not Impact the Number of Neurons in the Lateral Neocortex Following CFPI
3.4. Neuronal Membrane Disruption Was Not Significantly Altered Following CFPI in the Presence of 10% DMSO or CA-074Me Regardless of ICP Elevation
3.5. Cathepsin B Re-Localizes from Lysosomes to Cytosol in Disrupted Neurons at 2w Following Injury
3.6. Secondary ICP Elevation Exacerbates Somatosensory Sensitivity at 2w Post-CFPI, Which Is Ameliorated with CA-074Me Infusion
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Maas, A.I.R.; Menon, D.K.; Manley, G.T.; Abrams, M.; Åkerlund, C.; Andelic, N.; Aries, M.; Bashford, T.; Bell, M.J.; Bodien, Y.G.; et al. Traumatic Brain Injury: Progress and Challenges in Prevention, Clinical Care, and Research. Lancet Neurol. 2022, 21, 1004–1060. [Google Scholar] [CrossRef] [PubMed]
- Taylor, C.A.; Bell, J.M.; Breiding, M.J.; Xu, L. Traumatic Brain Injury–Related Emergency Department Visits, Hospitalizations, and Deaths—United States, 2007 and 2013. MMWR Surveill. Summ. 2017, 66, 1–16. [Google Scholar] [CrossRef]
- James, S.L.; Theadom, A.; Ellenbogen, R.G.; Bannick, M.S.; Montjoy-Venning, W.; Lucchesi, L.R.; Abbasi, N.; Abdulkader, R.; Abraha, H.N.; Adsuar, J.C.; et al. Global, Regional, and National Burden of Traumatic Brain Injury and Spinal Cord Injury, 1990–2016: A Systematic Analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019, 18, 56–87. [Google Scholar] [CrossRef]
- Dams-O’Connor, K.; Juengst, S.B.; Bogner, J.; Chiaravalloti, N.D.; Corrigan, J.D.; Giacino, J.T.; Harrison-Felix, C.L.; Hoffman, J.M.; Ketchum, J.M.; Lequerica, A.H.; et al. Traumatic Brain Injury as a Chronic Disease: Insights from the United States Traumatic Brain Injury Model Systems Research Program. Lancet Neurol. 2023, 22, 517–528. [Google Scholar] [CrossRef] [PubMed]
- Farahvar, A.; Gerber, L.M.; Chiu, Y.-L.; Carney, N.; Härtl, R.; Ghajar, J. Increased Mortality in Patients with Severe Traumatic Brain Injury Treated without Intracranial Pressure Monitoring. J. Neurosurg. 2012, 117, 729–734. [Google Scholar] [CrossRef]
- Miller, J.D.; Becker, D.P.; Ward, J.D.; Sullivan, H.G.; Adams, W.E.; Rosner, M.J. Significance of Intracranial Hypertension in Severe Head Injury. J. Neurosurg. 1977, 47, 503–516. [Google Scholar] [CrossRef] [PubMed]
- Lafrenaye, A.D.; Krahe, T.E.; Povlishock, J.T. Moderately Elevated Intracranial Pressure after Diffuse Traumatic Brain Injury Is Associated with Exacerbated Neuronal Pathology and Behavioral Morbidity in the Rat. J. Cereb. Blood Flow Metab. 2014, 34, 1628–1636. [Google Scholar] [CrossRef]
- Lafrenaye, A.D.; McGinn, M.J.; Povlishock, J.T. Increased Intracranial Pressure after Diffuse Traumatic Brain Injury Exacerbates Neuronal Somatic Membrane Poration but Not Axonal Injury: Evidence for Primary Intracranial Pressure-Induced Neuronal Perturbation. J. Cereb. Blood Flow Metab. 2012, 32, 1919–1932. [Google Scholar] [CrossRef]
- Cullen, D.K.; Vernekar, V.N.; LaPlaca, M.C. Trauma-Induced Plasmalemma Disruptions in Three-Dimensional Neural Cultures Are Dependent on Strain Modality and Rate. J. Neurotrauma 2011, 28, 2219–2233. [Google Scholar] [CrossRef]
- Farkas, O.; Lifshitz, J.; Povlishock, J.T. Mechanoporation Induced by Diffuse Traumatic Brain Injury: An Irreversible or Reversible Response to Injury? J. Neurosci. 2006, 26, 3130–3140. [Google Scholar] [CrossRef]
- Geddes, D.M.; Cargill, R.S.; LaPlaca, M.C. Mechanical Stretch to Neurons Results in a Strain Rate and Magnitude-Dependent Increase in Plasma Membrane Permeability. J. Neurotrauma 2003, 20, 1039–1049. [Google Scholar] [CrossRef] [PubMed]
- Geddes, D.M.; LaPlaca, M.C.; Cargill, R.S. Susceptibility of Hippocampal Neurons to Mechanically Induced Injury. Exp. Neurol. 2003, 184, 420–427. [Google Scholar] [CrossRef] [PubMed]
- Harris, J.P.; Mietus, C.J.; Browne, K.D.; Wofford, K.L.; Keating, C.E.; Brown, D.P.; Johnson, B.N.; Wolf, J.A.; Smith, D.H.; Cohen, A.S.; et al. Neuronal Somatic Plasmalemmal Permeability and Dendritic Beading Caused by Head Rotational Traumatic Brain Injury in Pigs–An Exploratory Study. Front. Cell. Neurosci. 2023, 17, 1055455. [Google Scholar] [CrossRef] [PubMed]
- Keating, C.E.; Browne, K.D.; Duda, J.E.; Cullen, D.K. Neurons in Subcortical Oculomotor Regions Are Vulnerable to Plasma Membrane Damage after Repetitive Diffuse Traumatic Brain Injury in Swine. J. Neurotrauma 2020, 37, 1918–1932. [Google Scholar] [CrossRef]
- LaPlaca, M.C.; Lessing, M.C.; Prado, G.R.; Zhou, R.; Tate, C.C.; Geddes-Klein, D.; Meaney, D.F.; Zhang, L. Mechanoporation Is a Potential Indicator of Tissue Strain and Subsequent Degeneration Following Experimental Traumatic Brain Injury. Clin. Biomech. 2019, 64, 2–13. [Google Scholar] [CrossRef] [PubMed]
- LaPlaca, M.C.; Thibault, L.E. Dynamic Mechanical Deformation of Neurons Triggers an Acute Calcium Response and Cell Injury Involving the N-Methyl-D-Aspartate Glutamate Receptor. J. Neurosci. Res. 1998, 52, 220–229. [Google Scholar] [CrossRef]
- Prado, G.R.; LaPlaca, M.C. Neuronal Plasma Membrane Integrity Is Transiently Disturbed by Traumatic Loading. Neurosci. Insights 2020, 15, 263310552094609. [Google Scholar] [CrossRef]
- Singleton, R.H.; Povlishock, J.T. Identification and Characterization of Heterogeneous Neuronal Injury and Death in Regions of Diffuse Brain Injury: Evidence for Multiple Independent Injury Phenotypes. J. Neurosci. 2004, 24, 3543–3553. [Google Scholar] [CrossRef]
- Wofford, K.L.; Harris, J.P.; Browne, K.D.; Brown, D.P.; Grovola, M.R.; Mietus, C.J.; Wolf, J.A.; Duda, J.E.; Putt, M.E.; Spiller, K.L.; et al. Rapid Neuroinflammatory Response Localized to Injured Neurons after Diffuse Traumatic Brain Injury in Swine. Exp. Neurol. 2017, 290, 85–94. [Google Scholar] [CrossRef]
- Hernandez, M.L.; Chatlos, T.; Gorse, K.M.; Lafrenaye, A.D. Neuronal Membrane Disruption Occurs Late Following Diffuse Brain Trauma in Rats and Involves a Subpopulation of NeuN Negative Cortical Neurons. Front. Neurol. 2019, 10, 1238. [Google Scholar] [CrossRef]
- Hernandez, M.L.; Marone, M.; Gorse, K.M.; Lafrenaye, A.D. Cathepsin B Relocalization in Late Membrane Disrupted Neurons Following Diffuse Brain Injury in Rats. ASN Neuro 2022, 14, 17590914221099112. [Google Scholar] [CrossRef] [PubMed]
- Chaitanya, G.V.; Babu, P.P. Multiple Apoptogenic Proteins Are Involved in the Nuclear Translocation of Apoptosis Inducing Factor during Transient Focal Cerebral Ischemia in Rat. Brain Res. 2008, 1246, 178–190. [Google Scholar] [CrossRef] [PubMed]
- Chowdhury, K.D.; Sarkar, A.; Chatterjee, S.; Patra, D.; Sengupta, D.; Banerjee, S.; Chakraborty, P.; Sadhukhan, G.C. Cathepsin B Mediated Scramblase Activation Triggers Cytotoxicity and Cell Cycle Arrest by Andrographolide to Overcome Cellular Resistance in Cisplatin Resistant Human Hepatocellular Carcinoma HepG2 Cells. Environ. Toxicol. Pharmacol. 2019, 68, 120–132. [Google Scholar] [CrossRef]
- de Castro, M.; Bunt, G.; Wouters, F. Cathepsin B Launches an Apoptotic Exit Effort upon Cell Death-Associated Disruption of Lysosomes. Cell Death Discov. 2016, 2, 16012. [Google Scholar] [CrossRef] [PubMed]
- Ellis, R.C.; O’Steen, W.A.; Hayes, R.L.; Nick, H.S.; Wang, K.K.W.; Anderson, D.K. Cellular Localization and Enzymatic Activity of Cathepsin B after Spinal Cord Injury in the Rat. Exp. Neurol. 2005, 193, 19–28. [Google Scholar] [CrossRef] [PubMed]
- Foghsgaard, L.; Wissing, D.; Mauch, D.; Lademann, U.; Bastholm, L.; Boes, M.; Elling, F.; Leist, M.; Jäättelä, M. Cathepsin B Acts as a Dominant Execution Protease in Tumor Cell Apoptosis Induced by Tumor Necrosis Factor. J. Cell Biol. 2001, 153, 999–1010. [Google Scholar] [CrossRef] [PubMed]
- Guicciardi, M.E.; Deussing, J.; Miyoshi, H.; Bronk, S.F.; Svingen, P.A.; Peters, C.; Kaufmann, S.H.; Gores, G.J. Cathepsin B Contributes to TNF-α–Mediated Hepatocyte Apoptosis by Promoting Mitochondrial Release of Cytochrome c. J. Clin. Investig. 2000, 106, 1127–1137. [Google Scholar] [CrossRef]
- Mizunoe, Y.; Kobayashi, M.; Hoshino, S.; Tagawa, R.; Itagawa, R.; Hoshino, A.; Okita, N.; Sudo, Y.; Nakagawa, Y.; Shimano, H.; et al. Cathepsin B Overexpression Induces Degradation of Perilipin 1 to Cause Lipid Metabolism Dysfunction in Adipocytes. Sci. Rep. 2020, 10, 634. [Google Scholar] [CrossRef]
- Moles, A.; Tarrats, N.; Fernández-Checa, J.C.; Marí, M. Cathepsin B Overexpression Due to Acid Sphingomyelinase Ablation Promotes Liver Fibrosis in Niemann-Pick Disease. J. Biol. Chem. 2012, 287, 1178–1188. [Google Scholar] [CrossRef]
- Oberle, C.; Huai, J.; Reinheckel, T.; Tacke, M.; Rassner, M.; Ekert, P.G.; Buellesbach, J.; Borner, C. Lysosomal Membrane Permeabilization and Cathepsin Release Is a Bax/Bak-Dependent, Amplifying Event of Apoptosis in Fibroblasts and Monocytes. Cell Death Differ. 2010, 17, 1167–1178. [Google Scholar] [CrossRef]
- Wang, J.; Wang, L.; Zhang, X.; Xu, Y.; Chen, L.; Zhang, W.; Liu, E.; Xiao, C.; Kou, Q. Cathepsin B Aggravates Acute Pancreatitis by Activating the NLRP3 Inflammasome and Promoting the Caspase-1-Induced Pyroptosis. Int. Immunopharmacol. 2021, 94, 107496. [Google Scholar] [CrossRef] [PubMed]
- Wen, Y.D.; Sheng, R.; Zhang, L.S.; Han, R.; Zhang, X.; Zhang, X.D.; Han, F.; Fukunaga, K.; Qin, Z.H. Neuronal Injury in Rat Model of Permanent Focal Cerebral Ischemia Is Associated with Activation of Autophagic and Lysosomal Pathways. Autophagy 2008, 4, 762–769. [Google Scholar] [CrossRef] [PubMed]
- Wu, Q.-Q.; Xu, M.; Yuan, Y.; Li, F.-F.; Yang, Z.; Liu, Y.; Zhou, M.-Q.; Bian, Z.-Y.; Deng, W.; Gao, L.; et al. Cathepsin B Deficiency Attenuates Cardiac Remodeling in Response to Pressure Overload via TNF-α/ASK1/JNK Pathway. Am. J. Physiol.-Heart Circ. Physiol. 2015, 308, H1143–H1154. [Google Scholar] [CrossRef] [PubMed]
- Boutté, A.M.; Hook, V.; Thangavelu, B.; Sarkis, G.A.; Abbatiello, B.N.; Hook, G.; Jacobsen, J.S.; Robertson, C.S.; Gilsdorf, J.; Yang, Z.; et al. Penetrating Traumatic Brain Injury Triggers Dysregulation of Cathepsin B Protein Levels Independent of Cysteine Protease Activity in Brain and Cerebral Spinal Fluid. J. Neurotrauma 2020, 37, 1574–1586. [Google Scholar] [CrossRef]
- Hook, G.R.; Yu, J.; Sipes, N.; Pierschbacher, M.D.; Hook, V.; Kindy, M.S. The Cysteine Protease Cathepsin B Is a Key Drug Target and Cysteine Protease Inhibitors Are Potential Therapeutics for Traumatic Brain Injury. J. Neurotrauma 2013, 31, 515–529. [Google Scholar] [CrossRef]
- Luo, C.-L.; Chen, X.-P.; Yang, R.; Sun, Y.-X.; Li, Q.-Q.; Bao, H.-J.; Cao, Q.-Q.; Ni, H.; Qin, Z.-H.; Tao, L.-Y. Cathepsin B Contributes to Traumatic Brain Injury-Induced Cell Death through a Mitochondria-Mediated Apoptotic Pathway. J. Neurosci. Res. 2010, 88, 2847–2858. [Google Scholar] [CrossRef] [PubMed]
- McNamara, K.C.S.S.; Lisembee, A.M.; Lifshitz, J. The Whisker Nuisance Task Identifies a Late-Onset, Persistent Sensory Sensitivity in Diffuse Brain-Injured Rats. J. Neurotrauma 2010, 27, 695–706. [Google Scholar] [CrossRef]
- Ryu, J.; Jeizan, P.; Ahmed, S.; Ehsan, S.; Jose, J.; Regan, S.; Gorse, K.; Kelliher, C.; Lafrenaye, A. Post-Injury Buprenorphine Administration Is Associated with Long-Term Region-Specific Glial Alterations in Rats. Pharmaceutics 2022, 14, 2068. [Google Scholar] [CrossRef] [PubMed]
- Dixon, C.E.; Lyeth, B.G.; Povlishock, J.T.; Findling, R.L.; Hamm, R.J.; Marmarou, A.; Young, H.F.; Hayes, R.L. A Fluid Percussion Model of Experimental Brain Injury in the Rat. J. Neurosurg. 1987, 67, 110–119. [Google Scholar] [CrossRef]
- Yoon, M.C.; Solania, A.; Jiang, Z.; Christy, M.P.; Podvin, S.; Mosier, C.; Lietz, C.B.; Ito, G.; Gerwick, W.H.; Wolan, D.W.; et al. Selective Neutral pH Inhibitor of Cathepsin B Designed Based on Cleavage Preferences at Cytosolic and Lysosomal pH Conditions. ACS Chem. Biol. 2021, 16, 1628–1643. [Google Scholar] [CrossRef]
- Boya, P.; Andreau, K.; Poncet, D.; Zamzami, N.; Perfettini, J.L.; Metivier, D.; Ojcius, D.M.; Jäättelä, M.; Kroemer, G. Lysosomal Membrane Permeabilization Induces Cell Death in a Mitochondrion-Dependent Fashion. J. Exp. Med. 2003, 197, 1323–1334. [Google Scholar] [CrossRef] [PubMed]
- Marshall, L.F.; Camp, P.E.; Bowers, S. Dimethyl Sulfoxide for the Treatment of Intracranial Hypertension: A Preliminary Trial. Neurosurgery 1984, 14, 659–663. [Google Scholar] [CrossRef] [PubMed]
- Waller, F.T.; Tanabe, C.T.; Paxton, H.D. Treatment of Elevated Intracranial Pressure with Dimethyl Sulfoxide. Ann. N. Y. Acad. Sci. 1983, 411, 286–292. [Google Scholar] [CrossRef] [PubMed]
- Wolf, P.; Simon, M. Dimethyl Sulphoxide (DMSO) Induced Serum Hyperosmolality. Clin. Biochem. 1983, 16, 261–262. [Google Scholar] [CrossRef] [PubMed]
- Di Giorgio, A.M.; Hou, Y.; Zhao, X.; Zhang, B.; Lyeth, B.G.; Russell, M.J. Dimethyl Sulfoxide Provides Neuroprotection in a Traumatic Brain Injury Model. Restor. Neurol. Neurosci. 2008, 26, 501–507. [Google Scholar] [PubMed]
- de la Torre, J.C.; Kawanaga, H.M.; Rowed, D.W.; Johnson, C.M.; Goode, D.J.; Kajihara, K.; Mullan, S. Dimethyl Sulfoxide in Central Nervous System Trauma. Ann. N. Y. Acad. Sci. 1975, 243, 362–389. [Google Scholar] [CrossRef] [PubMed]
- Tung, H.; James, H.E.; Laurin, R.; Marshall, L.F. Modification of the Effect of Dimethyl Sulfoxide on Intracranial Pressure, Brain Water, and Electrolyte Content by Indomethacin. Acta Neurochir. 1983, 68, 101–110. [Google Scholar] [CrossRef]
- Karaca, M.; Bilgin, U.Y.; Akar, M.; de la Torre, J.C. Dimethly Sulphoxide Lowers ICP after Closed Head Trauma. Eur. J. Clin. Pharmacol. 1991, 40, 113–114. [Google Scholar] [CrossRef]
- Gurtovenko, A.A.; Anwar, J. Modulating the Structure and Properties of Cell Membranes: The Molecular Mechanism of Action of Dimethyl Sulfoxide. J. Phys. Chem. B 2007, 111, 10453–10460. [Google Scholar] [CrossRef]
- Notman, R.; Noro, M.; O’Malley, B.; Anwar, J. Molecular Basis for Dimethylsulfoxide (DMSO) Action on Lipid Membranes. J. Am. Chem. Soc. 2006, 128, 13982–13983. [Google Scholar] [CrossRef]
- de Ménorval, M.-A.; Mir, L.M.; Fernández, M.L.; Reigada, R. Effects of Dimethyl Sulfoxide in Cholesterol-Containing Lipid Membranes: A Comparative Study of Experiments In Silico and with Cells. PLoS ONE 2012, 7, e41733. [Google Scholar] [CrossRef] [PubMed]
- Shi, R.; Qiao, X.; Emerson, N.; Malcom, A. Dimethylsulfoxide Enhances CNS Neuronal Plasma Membrane Resealing after Injury in Low Temperature or Low Calcium. J. Neurocytol. 2001, 30, 829–839. [Google Scholar] [CrossRef] [PubMed]
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Hernandez, M.; Regan, S.; Ansari, R.; Logan-Wesley, A.; Lilova, R.; Levi, C.; Gorse, K.; Lafrenaye, A. The Effects of Cathepsin B Inhibition in the Face of Diffuse Traumatic Brain Injury and Secondary Intracranial Pressure Elevation. Biomedicines 2024, 12, 1612. https://doi.org/10.3390/biomedicines12071612
Hernandez M, Regan S, Ansari R, Logan-Wesley A, Lilova R, Levi C, Gorse K, Lafrenaye A. The Effects of Cathepsin B Inhibition in the Face of Diffuse Traumatic Brain Injury and Secondary Intracranial Pressure Elevation. Biomedicines. 2024; 12(7):1612. https://doi.org/10.3390/biomedicines12071612
Chicago/Turabian StyleHernandez, Martina, Sean Regan, Rana Ansari, Amanda Logan-Wesley, Radina Lilova, Chelsea Levi, Karen Gorse, and Audrey Lafrenaye. 2024. "The Effects of Cathepsin B Inhibition in the Face of Diffuse Traumatic Brain Injury and Secondary Intracranial Pressure Elevation" Biomedicines 12, no. 7: 1612. https://doi.org/10.3390/biomedicines12071612