Inhibition of Cathepsin B Alleviates Secondary Degeneration in Ipsilateral Thalamus After Focal Cerebral Infarction in Adult Rats

Secondary degeneration in areas beyond ischemic foci can inhibit poststroke recovery. The cysteine protease Cathepsin B (CathB) regulates cell death and intracellular protein catabolism. To investigate the roles of CathB in the development of secondary degeneration in the ventroposterior nucleus (VPN) of the ipsilateral thalamus after focal cerebral infarction, infarct volumes, immunohistochemistry and immunofluorescence, and Western blotting analyses were conducted in a distal middle cerebral artery occlusion (dMCAO) stroke model in adult rats. We observed marked neuron loss and gliosis in the ipsilateral thalamus after dMCAO, and the expression of CathB and cleaved caspase-3 in the VPN was significantly upregulated; glial cells were the major source of CathB. Although it had no effect on infarct volume, delayed intracerebroventricular treatment with the membrane-permeable CathB inhibitor CA-074Me suppressed the expression of CathB and cleaved caspase-3 in ipsilateral VPN and accordingly alleviated the secondary degeneration. These data indicate that CathB mediates a novel mechanism of secondary degeneration in the VPN of the ipsilateral thalamus after focal cortical infarction and suggest that CathB might be a therapeutic target for the prevention of secondary degeneration in patients after stroke.

[1]  X. Li,et al.  2-(3′,5′-Dimethoxybenzylidene) cyclopentanone, a novel synthetic small-molecule compound, provides neuroprotective effects against ischemic stroke , 2016, Neuroscience.

[2]  M. Kindy,et al.  Cathepsin B is a New Drug Target for Traumatic Brain Injury Therapeutics: Evidence for E64d as a Promising Lead Drug Candidate , 2015, Front. Neurol..

[3]  M. Nilsson,et al.  Chronic stress exacerbates neuronal loss associated with secondary neurodegeneration and suppresses microglial-like cells following focal motor cortex ischemia in the mouse , 2015, Brain, Behavior, and Immunity.

[4]  Christoph Leithner,et al.  MRI Heralds Secondary Nigral Lesion after Brain Ischemia in Mice: A Secondary Time Window for Neuroprotection , 2015, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[5]  M. van Buchem,et al.  MRI Susceptibility Changes Suggestive of Iron Deposition in the Thalamus after Ischemic Stroke , 2015, Cerebrovascular Diseases.

[6]  I. V. van Uden,et al.  Ipsilateral hippocampal atrophy is associated with long‐term memory dysfunction after ischemic stroke in young adults , 2015, Human brain mapping.

[7]  C. Gerloff,et al.  Structural Plasticity of Remote Cortical Brain Regions is Determined by Connectivity to the Primary Lesion in Subcortical Stroke , 2015, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[8]  G. Donnan,et al.  Contralesional Thalamic Surface Atrophy and Functional Disconnection 3 Months after Ischemic Stroke , 2015, Cerebrovascular Diseases.

[9]  M. Nilsson,et al.  Photothrombotic Stroke Induces Persistent Ipsilateral and Contralateral Astrogliosis in Key Cognitive Control Nuclei , 2015, Neurochemical Research.

[10]  Lixuan Zhan,et al.  Hypoxia-Inducible Factor 1&agr; Mediates Neuroprotection of Hypoxic Postconditioning Against Global Cerebral Ischemia , 2014, Journal of neuropathology and experimental neurology.

[11]  B. Tong,et al.  Role of cathepsin B in regulating migration and invasion of fibroblast‐like synoviocytes into inflamed tissue from patients with rheumatoid arthritis , 2014, Clinical and experimental immunology.

[12]  N. Bargalló,et al.  Remote thalamic microstructural abnormalities related to cognitive function in ischemic stroke patients. , 2014, Neuropsychology.

[13]  N. Katunuma,et al.  Inhibition of cysteine cathepsin B and L activation in astrocytes contributes to neuroprotection against cerebral ischemia via blocking the tBid‐mitochondrial apoptotic signaling pathway , 2014, Glia.

[14]  C. Rorden,et al.  Mapping Remote Subcortical Ramifications of Injury after Ischemic Strokes , 2014, Behavioural neurology.

[15]  O. Gröhn,et al.  Progressive Volume Loss and White Matter Degeneration in Cstb-Deficient Mice: A Diffusion Tensor and Longitudinal Volumetry MRI Study , 2014, PloS one.

[16]  Yuhua Fan,et al.  Cerebrolysin reduces amyloid-β deposits, apoptosis and autophagy in the thalamus and improves functional recovery after cortical infarction , 2014, Journal of the Neurological Sciences.

[17]  Seung-Yong Yoon,et al.  CA-074Me, a cathepsin B inhibitor, decreases APP accumulation and protects primary rat cortical neurons treated with okadaic acid , 2013, Neuroscience Letters.

[18]  Ji-zong Zhao,et al.  Cortical electrical stimulation promotes neuronal plasticity in the peri-ischemic cortex and contralesional anterior horn of cervical spinal cord in a rat model of focal cerebral ischemia , 2013, Brain Research.

[19]  M. Klagsbrun,et al.  Netrin-1 Promotes Glioblastoma Cell Invasiveness and Angiogenesis by Multiple Pathways Including Activation of RhoA, Cathepsin B, and cAMP-response Element-binding Protein* , 2012, The Journal of Biological Chemistry.

[20]  Wenzhen Zhu,et al.  Volumetric MRI and 1H MRS study of hippocampus in unilateral MCAO patients: relationship between hippocampal secondary damage and cognitive disorder following stroke. , 2012, European journal of radiology.

[21]  Jian Zhang,et al.  Secondary neurodegeneration in remote regions after focal cerebral infarction: a new target for stroke management? , 2012, Stroke.

[22]  Xianqun Fan,et al.  N-Acetylcysteine Protects Against Hypoxia Mimetic-Induced Autophagy by Targeting the HIF-1α Pathway in Retinal Ganglion Cells , 2012, Cellular and molecular neurobiology.

[23]  Yuhua Fan,et al.  Autophagosomes accumulation is associated with β‐amyloid deposits and secondary damage in the thalamus after focal cortical infarction in hypertensive rats , 2012, Journal of neurochemistry.

[24]  Yuhua Fan,et al.  Beclin 1 knockdown inhibits autophagic activation and prevents the secondary neurodegenerative damage in the ipsilateral thalamus following focal cerebral infarction , 2012, Autophagy.

[25]  Chuo Li,et al.  Reduction of β-Amyloid Deposits by γ-Secretase Inhibitor is Associated with the Attenuation of Secondary Damage in the Ipsilateral Thalamus and Sensory Functional Improvement after Focal Cortical Infarction in Hypertensive Rats , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[26]  T. Dalkara,et al.  Lysosomal rupture, necroapoptotic interactions and potential crosstalk between cysteine proteases in neurons shortly after focal ischemia , 2010, Neurobiology of Disease.

[27]  Lixuan Zhan,et al.  Activation of Akt/FoxO signaling pathway contributes to induction of neuroprotection against transient global cerebral ischemia by hypoxic pre‐conditioning in adult rats , 2010, Journal of neurochemistry.

[28]  T. Lah,et al.  Glioblastoma and endothelial cells cross-talk, mediated by SDF-1, enhances tumour invasion and endothelial proliferation by increasing expression of cathepsins B, S, and MMP-9. , 2010, Cancer Letters.

[29]  Q. Hou,et al.  Endostatin expression in neurons during the early stage of cerebral ischemia is associated with neuronal apoptotic cell death in adult hypertensive rat model of stroke , 2010, Brain Research.

[30]  B. Yoo,et al.  Induction of glioma apoptosis by microglia-secreted molecules: The role of nitric oxide and cathepsin B. , 2009, Biochimica et biophysica acta.

[31]  Q. Hou,et al.  Neurogenesis and Angiogenesis within the Ipsilateral Thalamus with Secondary Damage after Focal Cortical Infarction in Hypertensive Rats , 2009, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[32]  H. Nakanishi,et al.  Possible involvement of cathepsin B released by microglia in methylmercury-induced cerebellar pathological changes in the adult rat , 2008, Neuroscience Letters.

[33]  Zhijian Liang,et al.  Ebselen attenuates oxidative DNA damage and enhances its repair activity in the thalamus after focal cortical infarction in hypertensive rats , 2007, Brain Research.

[34]  U. Felbor,et al.  Proteomic analysis of cathepsin B and L-deficient mouse brain lysosomes , 2007, Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics.

[35]  Fang Wang,et al.  Nogo-A is involved in secondary axonal degeneration of thalamus in hypertensive rats with focal cortical infarction , 2007, Neuroscience Letters.

[36]  John H. Zhang,et al.  Cathepsin and Calpain Inhibitor E64d Attenuates Matrix Metalloproteinase-9 Activity After Focal Cerebral Ischemia in Rats , 2006, Stroke.

[37]  F. Block,et al.  Inflammation in areas of remote changes following focal brain lesion , 2005, Progress in Neurobiology.

[38]  J. Braudeau,et al.  Activation of Proinflammatory Caspases by Cathepsin B in Focal Cerebral Ischemia , 2004, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[39]  S. Halpain,et al.  Cathepsin B-like proteolysis and MARCKS degradation in sub-lethal NMDA-induced collapse of dendritic spines , 2004, Neuropharmacology.

[40]  M. Chopp,et al.  A selective cysteine protease inhibitor is non-toxic and cerebroprotective in rats undergoing transient middle cerebral artery ischemia , 2001, Brain Research.

[41]  J. Pocock,et al.  Microglial secreted cathepsin B induces neuronal apoptosis , 2001, Journal of neurochemistry.

[42]  R. Busto,et al.  Transient Middle Cerebral Artery Occlusion by Intraluminal Suture: I. Three-Dimensional Autoradiographic Image-Analysis of Local Cerebral Glucose Metabolism—Blood Flow Interrelationships during Ischemia and Early Recirculation , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[43]  T. Ogawa,et al.  Secondary thalamic degeneration after cerebral infarction in the middle cerebral artery distribution: evaluation with MR imaging. , 1997, Radiology.

[44]  H. Matsuda,et al.  Discrepancy between blood flow and muscarinic receptor distribution in rat brain after middle cerebral artery occlusion , 1997, European Journal of Nuclear Medicine.

[45]  N. Katunuma,et al.  Novel epoxysuccinyl peptides A selective inhibitor of cathepsin B, in vivo , 1991, FEBS letters.

[46]  A. Tamura,et al.  Progressive shrinkage of the thalamus following middle cerebral artery occlusion in rats. , 1990, Stroke.

[47]  L. Swanson.  The Rat Brain in Stereotaxic Coordinates, George Paxinos, Charles Watson (Eds.). Academic Press, San Diego, CA (1982), vii + 153, $35.00, ISBN: 0 125 47620 5 , 1984 .

[48]  J. Zeng,et al.  An ischemic stroke model of nonhuman primates for remote lesion studies: a behavioral and neuroimaging investigation. , 2015, Restorative neurology and neuroscience.

[49]  B. Zhivotovsky,et al.  Proteases in autophagy. , 2012, Biochimica et biophysica acta.

[50]  H. Nakanishi,et al.  Involvement of cathepsin B in the processing and secretion of interleukin‐1β in chromogranin A‐stimulated microglia , 2010, Glia.

[51]  A. Foundas,et al.  The Cerebral Vascular System , 2008 .

[52]  P. Weinstein,et al.  Reversible middle cerebral artery occlusion without craniectomy in rats. , 1989, Stroke.

[53]  G. Paxinos.  The Rat nervous system , 1985 .