A retinoic acid receptor beta agonist (CD2019) overcomes inhibition of axonal outgrowth via phosphoinositide 3-kinase signalling in the injured adult spinal cord.
After spinal cord injury in the adult mammal, axons do not normally regrow and this commonly leads to paralysis. Retinoic acid (RA) can stimulate neurite outgrowth in vitro of both the embryonic central and peripheral nervous system, via activation of the retinoic acid receptor (RAR) beta2. We show here that regions of the adult CNS, including the cerebellum and cerebral cortex, express RARbeta2. We show that when cerebellar neurons are grown in the presence of myelin-associated glycoprotein (MAG) which inhibits neurite outgrowth, RARbeta can be activated in a dose dependent manner by a RARbeta agonist (CD2019) and neurite outgrowth can occur via phosphoinositide 3-kinase (PI3K) signalling. In a model of spinal cord injury CD2019 also acts through PI3K signalling to induce axonal outgrowth of descending corticospinal fibres and promote functional recovery. Our data suggest that RARbeta agonists may be of therapeutic potential for human spinal cord injuries.
The Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK.
Marta
M
Agudo
Ping
P
Yip
Meirion
M
Davies
Elizabeth
E
Bradbury
Patrick
P
Doherty
Stephen
S
McMahon
Malcolm
M
Maden
Jonathan P T
JP
Corcoran
D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D009281:Naphthalenes / Q000008:administration & dosage / Q000819:agonists / Q000378:metabolism / Q000494:pharmacology*; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011712:Pyramidal Tracts / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000503:physiopathology
C101407:CD 2019; D018992:Myelin-Associated Glycoprotein; D009281:Naphthalenes; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases