The calpain inhibitor MDL 28170 prevents inflammation-induced neurofilament light chain breakdown in the spinal cord and reduces thermal hyperalgesia.
Since long-term hyperexcitability of nociceptive neurons in the spinal cord has been suggested to be caused and maintained by changes of protein expression we assessed protein patterns in lumbar spinal cord during a zymosan induced paw inflammation employing two-dimensional (2D) gel electrophoresis. 2D PAGE revealed a time-dependent breakdown of scaffolding proteins one of which was neurofilament light chain (NFL) protein, which has been previously found to be important for axonal architecture and transport. Nociception induced breakdown of NFL in the spinal cord and dorsal root ganglias was prevented by pretreatment of the animals with a single dose of the specific inhibitor of the protease calpain (MDL-28170) which has been shown to be the primary protease involved in neurofilament degradation in neurodegenerative diseases. Treatment with the calpain inhibitor also provided anti-inflammatory and anti-hyperalgesic effects in the zymosan-induced paw inflammation model irrespective of whether the drug was administered systemically (i.p.) or delivered onto the lumbar spinal cord. This suggests that the activation of calpain is involved in the sensitization of nociceptive neurons what is partly due to neurofilament breakdown but cleavage of other calpain substrates may also be involved. Our results indicate that inhibition of pathological calpain activity may present an interesting novel drug target in the treatment of pain and inflammation.
pharmazentrum frankfurt, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
Susanne
S
Kunz
Ellen
E
Niederberger
Corina
C
Ehnert
Ovidiu
O
Coste
Anja
A
Pfenninger
Jochen
J
Kruip
Thomas M
TM
Wendrich
Achim
A
Schmidtko
Irmgard
I
Tegeder
Gerd
G
Geisslinger
D000818:Animals; D002154:Calpain / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D004151:Dipeptides / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D005455:Fluorescent Antibody Technique / Q000379:methods; D006930:Hyperalgesia / Q000188:drug therapy*; D015151:Immunoblotting / Q000379:methods; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D016900:Neurofilament Proteins / Q000378:metabolism*; D010147:Pain Measurement; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013116:Spinal Cord / Q000187:drug effects*; D013997:Time Factors; D015054:Zymosan
D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D016900:Neurofilament Proteins; D012333:RNA, Messenger; C044882:neurofilament protein L; D015054:Zymosan; D002154:Calpain; C058076:calpain inhibitor III