Delayed Nogo receptor therapy improves recovery from spinal cord contusion

When the adult mammalian central nervous system is injured, severed axons from surviving neurons do not extend and reconnect to their synaptic targets.1–4 The resulting axonal disconnection constitutes a significant cause of persistent neurological deficits in many neurological conditions. Traumatic spinal cord injury (SCI) is perhaps the purest example of a disconnection-based syndrome secondary to failed axonal growth. Although focal neuronal loss contributes to segmental dysfunction at the level of injury after SCI, chronic neurological deficits below the level of injury are principally due to the failure of axonal regrowth. Recent laboratory studies have identified three myelin-associated proteins, Nogo-A, Myelin-Associated Protein (MAG), and Oligodendrocyte Myelin Glycoprotein (OMgp), which bind to an axonal Nogo-66 receptor (NgR) protein to collapse axonal growth cones and stop axonal extension.1,5–13 The importance of this pathway has been documented in a range of genetic and pharmacological studies in rodent SCI. Pharmacological studies have used peptides that competitively inhibit Nogo-66 interaction with NgR,14,15 anti–Nogo-A antibodies,16,17 and a soluble ectodomain fragment of the NgR.2,18–20 The NgR fragment fused to the constant region of IgG in the NgR(310)ecto-Fc reagent contains the entire ligand-binding site of NgR. Thus, this fragment can sequester all three myelin-associated inhibitors from active endogenous axonal NgR. When infused intrathecally into rats with midthoracic dorsal spinal hemisection injuries, the NgR(310)ecto-Fc protein stimulates corticospinal tract (CST) and raphespinal axonal growth.19 Critically, the recovery of locomotor performance was stimulated by NgR(310)ecto-Fc. A group of recent studies have generated interest in the notion that intracellular cyclic adenosine mono-phosphate (cAMP) levels play a role in determining the propensity of neurons to extend axons. In particular, elevated cAMP levels reduce inhibition by myelin-associated proteins in vitro.21–25 Several combinatorial therapies to promote axonal growth and functional recovery after for including a method for increasing cAMP.21,22 Ro- lipram is a type VI cyclic nucleotide phosphodiesterase inhibitor most commonly used in axonal regeneration experiments. An extrapolation of the benefits of blocking myelin-associated inhibitors to human SCI is limited by two factors. First, the experimental studies have focused on simplified transection models of SCI that do not include the complex inflammatory and hemorrhagic tissue reaction that occurs in typical clinical injuries caused by abrupt contusion from displaced vertebral bodies. Second, most previous experiments using simple transection studies have initiated therapy at the time of injury. As is clear from numerous studies of stroke, the benefits of immediate therapy are not always translatable to the clinic. Here, we determined whether blocking myelin-associated inhibitors with NgR(310)ecto-Fc is effective under conditions thought to be most similar to those encountered clinically. The recovery of rats from spinal contusion injury was assessed.26 Treatment was initiated by intrathecal spinal catheter at the time of injury or was provided by an intracerebroventricular catheter beginning at 3 days after injury. Furthermore, a combination of rolipram and NgR(310)ecto-Fc was compared with monotherapy. We report that NgR(310)ecto-Fc substantially improves locomotor recovery. This recovery is associated with CST and raphespinal axonal growth. Rolipram is less effective and is not synergistic with NgR(310)ecto-Fc. These findings provide a rationale for investigating the benefit of NgR(310)ecto-Fc therapy in human SCI.