TY - JOUR
T1 - Intraocular injection of dibutyryl cyclic AMP promotes axon regeneration in rat optic nerve
AU - Monsul, Nicholas T.
AU - Geisendorfer, Abram R.
AU - Han, Paul J.
AU - Banik, Rudrani
AU - Pease, Mary Ellen
AU - Skolasky, Richard L.
AU - Hoffman, Paul N.
N1 - Funding Information:
This work was supported by grants from the Spinal Cord Research Foundation of the Paralyzed Veterans of America and the Jackson Family Fund. The authors thank John Griffin for his continued encouragement and support. We also thank Neil Miller, Harry Quigley, Thomas Brushart, David Ginty, Prem Subramanian, Salil Shukla, and Pamela Talalay for their helpful editorial comments.
PY - 2004/4
Y1 - 2004/4
N2 - The optic nerve is a CNS pathway containing molecules capable of inhibiting axon elongation. The growth program in embryonic retinal ganglion cell (RGC) neurons enables axons to regenerate in the optic nerve through at least two mechanisms. Namely, high cyclic AMP (cAMP) levels abrogate the ability of CNS molecules to inhibit elongation, and the pattern of gene expression enables axons to undergo rapid, sustained, and lengthy elongation. In adult mammals, recovery of visual function after optic nerve injury is limited by both the death of most RGC neurons and the inability of surviving axons to regenerate. We now report that a single intraocular injection of the membrane-permeable cAMP analogue dibutyryl cAMP (db cAMP) promotes the regeneration of RGC axons in the optic nerves of adult rats, but does not prevent the death of RGC neurons. This regeneration in optic nerves crushed within the orbit (2 mm from the eye) was equally effective either 1 day before or 1 day after db cAMP injection. The number of regenerating axons, which was maximal 14 days after crush, declined with increasing time after injury (i.e., 28, 56, and 112 days) and distance beyond the crush site (i.e., 0.25, 0.5, and 1.0 mm). Thus, db cAMP promotes optic nerve regeneration without increasing the survival of axotomized RGC neurons. Furthermore, since db cAMP does not enable axons to undergo rapid, sustained, and lengthy elongation, strategies that increase survival and promote these changes in elongation may critically complement the ability of db cAMP to promote regeneration.
AB - The optic nerve is a CNS pathway containing molecules capable of inhibiting axon elongation. The growth program in embryonic retinal ganglion cell (RGC) neurons enables axons to regenerate in the optic nerve through at least two mechanisms. Namely, high cyclic AMP (cAMP) levels abrogate the ability of CNS molecules to inhibit elongation, and the pattern of gene expression enables axons to undergo rapid, sustained, and lengthy elongation. In adult mammals, recovery of visual function after optic nerve injury is limited by both the death of most RGC neurons and the inability of surviving axons to regenerate. We now report that a single intraocular injection of the membrane-permeable cAMP analogue dibutyryl cAMP (db cAMP) promotes the regeneration of RGC axons in the optic nerves of adult rats, but does not prevent the death of RGC neurons. This regeneration in optic nerves crushed within the orbit (2 mm from the eye) was equally effective either 1 day before or 1 day after db cAMP injection. The number of regenerating axons, which was maximal 14 days after crush, declined with increasing time after injury (i.e., 28, 56, and 112 days) and distance beyond the crush site (i.e., 0.25, 0.5, and 1.0 mm). Thus, db cAMP promotes optic nerve regeneration without increasing the survival of axotomized RGC neurons. Furthermore, since db cAMP does not enable axons to undergo rapid, sustained, and lengthy elongation, strategies that increase survival and promote these changes in elongation may critically complement the ability of db cAMP to promote regeneration.
KW - Axon elongation
KW - Axon regeneration
KW - Axotomy
KW - CNS regeneration
KW - Dibutyryl cyclic AMP
KW - Optic nerve injury
KW - Rat optic nerve
KW - Retinal ganglion cell
UR - http://www.scopus.com/inward/record.url?scp=1542408477&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1542408477&partnerID=8YFLogxK
U2 - 10.1016/S0014-4886(03)00311-X
DO - 10.1016/S0014-4886(03)00311-X
M3 - Article
C2 - 15026251
AN - SCOPUS:1542408477
SN - 0014-4886
VL - 186
SP - 124
EP - 133
JO - Experimental Neurology
JF - Experimental Neurology
IS - 2
ER -