1. Voluntary wheel running prevents formation of membrane attack complexes and myelin degradation after peripheral nerve injury.
- Author
-
Green-Fulgham, Suzanne M., Lacagnina, Michael J., Willcox, Kendal F., Li, Jiahe, Harland, Michael E., Ciena, Adriano Polican, Rocha, Igor R. Correia, Ball, Jayson B., Dreher, Renee A., Zuberi, Younus A., Dragavon, Joseph M., Chacur, Marucia, Maier, Steven F., Watkins, Linda R., and Grace, Peter M.
- Subjects
- *
PERIPHERAL nerve injuries , *SCIATIC nerve injuries , *MYELIN , *ECULIZUMAB , *COMPLEMENT (Immunology) , *MYELIN proteins , *PERFORINS - Abstract
CCI increases C3b deposition as a response to nerve injury. C3 convertase (C3bBb) is regulated by the inhibitors CR1, CD55 or CFH. In the absence of inhibitors, C3b cleaves C5 into C5a and C5b. C5b along with C6, C7, C8 and poly-C9 combine to form the terminal component, the membrane attack complex (MAC). MAC targeting myelin leads to myelin degradation, which is cleared by phagocytes. MAC can be regulated by the binding of inhibitors Clusterin and CD59. Voluntary wheel running appears to reduce MAC deposition by increasing the inhibitor CD59, thereby preserving myelin. Running did not alter Clusterin or C3b inhibitors in a manner that would result in decreased MAC. [Display omitted] • Six weeks of wheel running prior to nerve injury reduced MAC at the injury site. • Loss of myelin in the injury site after CCI was decreased with prior running. • Complement C3, CD55, CR1, CFH, Clusterin and CD59 were altered by CCI. • CD59, an inhibitor of MAC was increased with prior running. • Treatment with exogenous CD59 reduced mechanical allodynia and MAC deposition. Regular aerobic activity is associated with a reduced risk of chronic pain in humans and rodents. Our previous studies in rodents have shown that prior voluntary wheel running can normalize redox signaling at the site of peripheral nerve injury, attenuating subsequent neuropathic pain. However, the full extent of neuroprotection offered by voluntary wheel running after peripheral nerve injury is unknown. Here, we show that six weeks of voluntary wheel running prior to chronic constriction injury (CCI) reduced the terminal complement membrane attack complex (MAC) at the sciatic nerve injury site. This was associated with increased expression of the MAC inhibitor CD59. The levels of upstream complement components (C3) and their inhibitors (CD55, CR1 and CFH) were altered by CCI, but not increased by voluntary wheel running. Since MAC can degrade myelin, which in turn contributes to neuropathic pain, we evaluated myelin integrity at the sciatic nerve injury site. We found that the loss of myelinated fibers and decreased myelin protein which occurs in sedentary rats following CCI was not observed in rats with prior running. Substitution of prior voluntary wheel running with exogenous CD59 also attenuated mechanical allodynia and reduced MAC deposition at the nerve injury site, pointing to CD59 as a critical effector of the neuroprotective and antinociceptive actions of prior voluntary wheel running. This study links attenuation of neuropathic pain by prior voluntary wheel running with inhibition of MAC and preservation of myelin integrity at the sciatic nerve injury site. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF