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New calpain inhibitor preserves brain architecture in 3‐nitropropionic acid (3‐NP) model of Huntington disease
Author(s) -
Kesner Leo,
Yang Lichuan,
Beal M. Flint,
Stracher Alfred,
Hassen Getaw Worku,
Shulman Abraham
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.675.7
Subject(s) - calpain , huntington's disease , leupeptin , spectrin , saline , necrosis , pharmacology , apoptosis , protease , western blot , chemistry , medicine , endocrinology , biochemistry , disease , cell , enzyme , cytoskeleton , gene
The 3‐nitropropionic acid model Of Huntington's disease produces a variety of biochemical anomalies. One of these, is the activation of the protease calpain. Excess calpain activity is probably responsible for major cell death expressed as striatial degeneration. Protease inhibitors designed to reduce damage from calpain should have qualities such as the ability to cross the blood‐brain barrier, have some selective targeting ability to nervous tissue and be non‐toxic in the concentrations used. We have designed a new inhibitor (Gabadur) with many of these qualities. The targeting end is an analog of the anti‐epileptic compound "pregabalin" and the calpain inhibitor end is argininal, similar to leupeptin. Twelve week old Lewis rats were treated with 3‐nitropropionic acid (3NP) 50mg/kg/day for 5 days. In addition some of these rats were treated with either saline or Gabadur (10mg/rat/day IP). Brain slices taken from these rats, and treated only with saline, showed focal degeneration and necrosis with complete loss of architecture. Brains from Gabadur treated rats showed about 50% preservation of the architecture. Calpain activity was similarly depressed, as measured by Western blot techniques. Alpha‐2 Spectrin degradation products were almost normal in Gabadur treated rats, but increased three fold in the saline treated rats.