Calpastatin Overexpression Protects against Excitotoxic Hippocampal Injury and Traumatic Spinal Cord Injury

Chen Guang Yu, Vimala Bondada, Aashish Joshi, Dexter V. Reneer, Glenn C. Telling, Kathryn E. Saatman, James W. Geddes

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Small molecule inhibitors of calcium-dependent proteases, calpains (CAPNs), protect against neurodegeneration induced by a variety of insults including excitotoxicity and spinal cord injury (SCI). Many of these compounds, however, also inhibit other proteases, which has made it difficult to evaluate the contribution of calpains to neurodegeneration. Calpastatin is a highly specific endogenous inhibitor of classical calpains, including CAPN1 and CAPN2. In the present study, we utilized transgenic mice that overexpress human calpastatin under the prion promoter (PrP-hCAST) to evaluate the hypothesis that calpastatin overexpression protects against excitotoxic hippocampal injury and contusive SCI. The PrP-hCAST organotypic hippocampal slice cultures showed reduced neuronal death and reduced calpain-dependent proteolysis (α-spectrin breakdown production, 145 kDa) at 24 h after N-methyl-D-aspartate (NMDA) injury compared with the wild-type (WT) cultures (n = 5, p < 0.05). The PrP-hCAST mice (n = 13) displayed a significant improvement in locomotor function at one and three weeks after contusive SCI compared with the WT controls (n = 9, p < 0.05). Histological assessment of lesion volume and tissue sparing, performed on the same animals used for behavioral analysis, revealed that calpastatin overexpression resulted in a 30% decrease in lesion volume (p < 0.05) and significant increases in tissue sparing, white matter sparing, and gray matter sparing at four weeks post-injury compared with WT animals. Calpastatin overexpression reduced α-spectrin breakdown by 51% at 24 h post-injury, compared with WT controls (p < 0.05, n = 3/group). These results provide support for the hypothesis that sustained calpain-dependent proteolysis contributes to pathological deficits after excitotoxic injury and traumatic SCI.

Original languageEnglish
Pages (from-to)2268-2276
Number of pages9
JournalJournal of Neurotrauma
Volume37
Issue number21
DOIs
StatePublished - Nov 1 2020

Bibliographical note

Publisher Copyright:
© Copyright 2020, Mary Ann Liebert, Inc., publishers 2020.

Keywords

  • calpastatin overexpression
  • hippocampal injury
  • spinal cord injury

ASJC Scopus subject areas

  • Clinical Neurology

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