دورية أكاديمية
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Extending the Calpain-Cathepsin Hypothesis to the Neurovasculature: Protection of Brain Endothelial Cells and Mice from Neurotrauma.

التفاصيل البيبلوغرافية
العنوان: Extending the Calpain-Cathepsin Hypothesis to the Neurovasculature: Protection of Brain Endothelial Cells and Mice from Neurotrauma.
المؤلفون: Knopp RC; Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago (UIC), Chicago, Illinois 60612, United States., Jastaniah A; Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago (UIC), Chicago, Illinois 60612, United States., Dubrovskyi O; Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago (UIC), Chicago, Illinois 60612, United States., Gaisina I; Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago (UIC), Chicago, Illinois 60612, United States.; UICentre (Drug Discovery @ UIC), University of Illinois at Chicago (UIC), Chicago, Illinois 60612, United States., Tai L; Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago (UIC), Chicago, Illinois 60612, United States., Thatcher GRJ; Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States.
المصدر: ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2021 Feb 02; Vol. 4 (1), pp. 372-385. Date of Electronic Publication: 2021 Feb 02 (Print Publication: 2021).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101721411 Publication Model: eCollection Cited Medium: Internet ISSN: 2575-9108 (Electronic) Linking ISSN: 25759108 NLM ISO Abbreviation: ACS Pharmacol Transl Sci Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : American Chemical Society, [2018]-
مستخلص: The calpain-cathepsin hypothesis posits a key role for elevated calpain-1 and cathepsin-B activity in the neurodegeneration underlying neurotrauma and multiple disorders including Alzheimer's disease (AD). AD clinical trials were recently halted on alicapistat, a selective calpain-1 inhibitor, because of insufficient exposure of neurons to the drug. In contrast to neuroprotection, the ability of calpain-1 and cathepsin-B inhibitors to protect the blood-brain barrier (BBB), is understudied. Since cerebrovascular dysfunction underlies vascular dementia, is caused by ischemic stroke, and is emerging as an early feature in the progression of AD, we studied protection of brain endothelial cells (BECs) by selective and nonselective calpain-1 and cathepsin-B inhibitors. We show these inhibitors protect both neurons and murine BECs from ischemia-reperfusion injury. Cultures of primary BECs from ALDH2 - / - mice that manifest enhanced oxidative stress were sensitive to ischemia, leading to reduced cell viability and loss of tight junction proteins; this damage was rescued by calpain-1 and cathepsin-B inhibitors. In ALDH2 - / - mice 24 h after mild traumatic brain injury (mTBI), BBB damage was reflected by significantly increased fluorescein extravasation and perturbation of tight junction proteins, eNOS, MMP-9, and GFAP. Both calpain and cathepsin-B inhibitors alleviated BBB dysfunction caused by mTBI. No clear advantage was shown by selective versus nonselective calpain inhibitors in these studies. The lack of recognition of the ability of calpain inhibitors to protect the BBB may have led to the premature abandonment of this therapeutic approach in AD clinical trials and requires further mechanistic studies of cerebrovascular protection by calpain-1 inhibitors.
Competing Interests: The authors declare the following competing financial interest(s): G.R.J.T. is an inventor on patents assigned to UIC.
(© 2021 American Chemical Society.)
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معلومات مُعتمدة: R01 AG061114 United States AG NIA NIH HHS; T32 AG057468 United States AG NIA NIH HHS
تواريخ الأحداث: Date Created: 20210222 Latest Revision: 20220520
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC7887848
DOI: 10.1021/acsptsci.0c00217
PMID: 33615187
قاعدة البيانات: MEDLINE
الوصف
تدمد:2575-9108
DOI:10.1021/acsptsci.0c00217