Prevention of axonal injury using calpain inhibitor in chronic progressive experimental autoimmune encephalomyelitis.
Axonal injury is the major correlate of permanent disability in neurodegenerative diseases such as multiple sclerosis (MS), especially in secondary-progressive MS which follows relapsing-remitting disease course. Proteolytic enzyme, calpain, is a potential candidate for causing axonal injury. Most current treatment options only target the inflammatory component of MS. Previous work using calpain inhibitor CYLA in our laboratory showed significant reduction in clinical sign, demyelination and tissue calpain content in acute experimental autoimmune encephalomyelitis (EAE). Here we evaluated markers of axonal injury (amyloid precursor protein, Na(v)1.6 channels), neuronal calpain content and the effect of CYLA on axonal protection using histological methods in chronic EAE [myelin oligodendrocyte glycoprotein (MOG)-induced disease model of MS]. Intraperitoneal application of CYLA (2 mg/mouse/day) significantly reduced the clinical signs, tissue calpain content, demyelination and inflammatory infiltration of EAE. Similarly, markers for axonal injury were barely detectable in the treated mice. Thus, this novel drug, which markedly suppresses the disease course, axonal injury and its progression, is a candidate for the treatment of a neurodegenerative disease such as multiple sclerosis.
Hassen
Getaw Worku
GW
SUNY Downstate Medical Center, Brooklyn, New York, USA.
Feliberti
Jason
J
Kesner
Leo
L
Stracher
Alfred
A
Mokhtarian
Foroozan
F
D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D006023:Glycoproteins / Q000627:therapeutic use*; D007976:Leupeptins / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D012720:Severity of Illness Index; D016622:Silver Staining; D015222:Sodium Channels / Q000378:metabolism
C539819:CYLA (leupeptin); D006023:Glycoproteins; D007976:Leupeptins; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C491046:Scn8a protein, mouse; D015222:Sodium Channels; C039304:calpain inhibitors; D002154:Calpain; D010751:Phosphopyruvate Hydratase