A new mechanism of methylprednisolone and other corticosteroids action demonstrated in vitro: inhibition of a proteinase (calpain) prevents myelin and cytoskeletal protein degradation.
The affect of methylprednisolone (MP), an anti-inflammatory drug upon purified calpain and the Ca2+-mediated degradation of endogenous proteins of spinal cord homogenate in vitro has been examined. Activity of calpain purified from rabbit muscle was greatly inhibited in a dose-dependent fashion by MP. A 50% inhibition was obtained with 3.2 mM MP concentration and the activity was inhibited further (80%) at 8.1 mM. More potent inhibition of the purified enzyme (70-80%) was produced by dexamethasone (3.9 mM) and prednisolone (4.1 mM). Calpain-mediated degradation of myelin basic protein (MBP) was also inhibited by MP as was cathepsin B-mediated MBP breakdown. The effect of MP and other steroids upon calcium-mediated degradation of spinal cord homogenate was also evaluated. SDS-PAGE analysis revealed significant inhibition of neurofilament protein breakdown by MP and other corticosteroids. This inhibitory effect was much less than that exerted by the calpain inhibitors calpeptin and/or E64-d. These results indicate that MP acts as a proteinase (calpain) inhibitor and define a new mechanism for its actions.
Banik
N L
NL
Department of Neurology, Medical University of South Carolina, Charleston 29425, USA.
Matzelle
D
D
Terry
E
E
Hogan
E L
EL
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002401:Cathepsin B / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D066298:In Vitro Techniques; D008775:Methylprednisolone / Q000494:pharmacology*; D004676:Myelin Basic Protein / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D003598:Cytoskeletal Proteins; D004676:Myelin Basic Protein; D002154:Calpain; D002401:Cathepsin B; D008775:Methylprednisolone