Nature Medicine Online
Damien D Pearse1, Francisco C Pereira2, Alexander E Marcillo1, Margaret L Bates1, Yerko A Berrocal1, Marie T Filbin3 & Mary Bartlett Bunge1, 4, 5
Published online: 23 May 2004 | doi:10.1038/nm1056
cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury
1Â The Miami Project to Cure Paralysis, University of Miami School of Medicine, 1095 NW 14th Terrace, Miami, Florida 33136, USA.
2Â Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415, Sao Paulo, CEP 05508-900, Brazil.
3Â Biology Department, Hunter College, 695 Park Ave., New York, New York, USA, 10021.
4Â Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, Florida 33136, USA.
5Â Department of Neurological Surgery, University of Miami School of Medicine, Miami, Florida 33136, USA.
Correspondence should be addressed to Damien D Pearse dpearse@miamiproject.med.miami.edu
Abstract: Central neurons regenerate axons if a permissive environment is provided; after spinal cord injury, however, inhibitory molecules are present that make the local environment nonpermissive. A promising new strategy for inducing neurons to overcome inhibitory signals is to activate cAMP signaling. Here we show thatcAMP levels fall in the rostral spinal cord, sensorimotor cortex and brainstem after spinal cord contusion. Inhibition of cAMP hydrolysis by the phosphodiesterase IV inhibitor rolipram prevents this decrease and when combined with Schwann cell grafts promotes significant supraspinal and proprioceptive axon sparing and myelination. Furthermore, combining rolipram with an injection of db-cAMP near the graft not only prevents the drop in cAMP levels but increases them above those in uninjured controls. This further enhances axonal sparing and myelination, promotes growth of serotonergic fibers into and beyond grafts, and significantly improves locomotion. These findings show that cAMP levels are key for protection, growth and myelination of injured CNS axons in vivo and recovery of function.
Damien D Pearse1, Francisco C Pereira2, Alexander E Marcillo1, Margaret L Bates1, Yerko A Berrocal1, Marie T Filbin3 & Mary Bartlett Bunge1, 4, 5
Published online: 23 May 2004 | doi:10.1038/nm1056
cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury
1Â The Miami Project to Cure Paralysis, University of Miami School of Medicine, 1095 NW 14th Terrace, Miami, Florida 33136, USA.
2Â Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415, Sao Paulo, CEP 05508-900, Brazil.
3Â Biology Department, Hunter College, 695 Park Ave., New York, New York, USA, 10021.
4Â Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, Florida 33136, USA.
5Â Department of Neurological Surgery, University of Miami School of Medicine, Miami, Florida 33136, USA.
Correspondence should be addressed to Damien D Pearse dpearse@miamiproject.med.miami.edu
Abstract: Central neurons regenerate axons if a permissive environment is provided; after spinal cord injury, however, inhibitory molecules are present that make the local environment nonpermissive. A promising new strategy for inducing neurons to overcome inhibitory signals is to activate cAMP signaling. Here we show thatcAMP levels fall in the rostral spinal cord, sensorimotor cortex and brainstem after spinal cord contusion. Inhibition of cAMP hydrolysis by the phosphodiesterase IV inhibitor rolipram prevents this decrease and when combined with Schwann cell grafts promotes significant supraspinal and proprioceptive axon sparing and myelination. Furthermore, combining rolipram with an injection of db-cAMP near the graft not only prevents the drop in cAMP levels but increases them above those in uninjured controls. This further enhances axonal sparing and myelination, promotes growth of serotonergic fibers into and beyond grafts, and significantly improves locomotion. These findings show that cAMP levels are key for protection, growth and myelination of injured CNS axons in vivo and recovery of function.
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