ABSTRACT
OBJECTIVE: The myelin protein Nogo inhibits axon regeneration by binding to its receptor (NgR) on axons. Intrathecal delivery of an NgR antagonist (NEP1-40) promotes growth of injured corticospinal axons and recovery of motor function following a dorsal hemisection. The authors used a similar design to examine recovery and repair after a lesion that interrupts the rubrospinal tract (RST). METHODS: Rats received a lateral funiculotomy at C4 and NEP1-40 or vehicle was delivered to the cervical spinal cord for 4 weeks. Outcome measures included motor and sensory tests and immunohistochemistry. RESULTS: Gait analysis showed recovery in the NEP1-40-treated group compared to operated controls, and a test of forelimb usage also showed a beneficial effect. The density of labeled RST axons increased ipsilaterally in the NEP1-40 group in the lateral funiculus rostral to the lesion and contralaterally in both gray and white matter. Thus, rubrospinal axons exhibited diminished dieback and/or growth up to the lesion site. This was accompanied by greater density of 5HT and calcitonin gene-related peptide axons adjacent to and into the lesion/matrix site in the NEP1-40 group. CONCLUSIONS: NgR blockade after RST injury is associated with axonal growth and/or diminished dieback of severed RST axons up to but not into or beyond the lesion/matrix site, and growth of serotonergic and dorsal root axons adjacent to and into the lesion/matrix site. NgR blockade also supported partial recovery of function. The authors' results indicate that severed rubrospinal axons respond to NEP1-40 treatment but less robustly than corticospinal, raphe-spinal, or dorsal root axons.
Subject(s)
Growth Cones/drug effects , Myelin Proteins/antagonists & inhibitors , Myelin Proteins/pharmacology , Nerve Regeneration/drug effects , Peptide Fragments/pharmacology , Receptors, Cell Surface/antagonists & inhibitors , Spinal Cord Injuries/drug therapy , Animals , Behavior, Animal/drug effects , Denervation , Efferent Pathways/drug effects , Efferent Pathways/metabolism , Efferent Pathways/physiopathology , Female , GPI-Linked Proteins , Growth Cones/metabolism , Myelin Proteins/metabolism , Myelin Proteins/therapeutic use , Nerve Regeneration/physiology , Neuronal Plasticity/drug effects , Neuronal Plasticity/physiology , Nogo Receptor 1 , Peptide Fragments/therapeutic use , Pyramidal Tracts/drug effects , Pyramidal Tracts/metabolism , Pyramidal Tracts/physiopathology , Raphe Nuclei/drug effects , Raphe Nuclei/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Cell Surface/metabolism , Recovery of Function/drug effects , Recovery of Function/physiology , Red Nucleus/drug effects , Red Nucleus/metabolism , Spinal Cord Injuries/metabolism , Spinal Cord Injuries/physiopathology , Spinal Nerve Roots/drug effects , Spinal Nerve Roots/metabolism , Treatment Outcome , Wallerian Degeneration/drug therapy , Wallerian Degeneration/metabolism , Wallerian Degeneration/physiopathologyABSTRACT
We compared the intact alpha7 nicotinic acetylcholine receptor (alpha7nAChR) protein levels in the peripheral blood leukocytes in 15 Alzheimer's disease (AD) patients and 13 normal elderly control subjects. Demographic data and Mini-Mental State Examination (MMSE) scores were obtained. Western blot analysis for alpha7nAChR protein levels in peripheral blood leukocytes was performed. There were no significant differences in sex and age between the AD and control groups. The mean MMSE score of the AD subjects was significantly lower than that of the normal control subjects (15.4 +/- 5.5 vs. 28.5 +/- 1.9 respectively; p < 0.001). The median value of normalized alpha7nAChR protein levels (optical density, arbitrary unit) of the AD group was significantly higher than that of the normal control group (0.6923 vs. 0.4803 respectively; p = 0.045, Mann-Whitney U test). The normalized alpha7nAChR protein levels showed a significant inverse correlation with the MMSE scores (Spearman rho = -0.45; p = 0.016; n = 28). Receiver Operating Characteristic curve analyses showed that the area under curve was 0.72 (95% CI 0.52- 0.87). If the cut-off of the alpha7nAChR protein level was >0.312, the sensitivity, specificity, positive predictive value and negative predictive value would be 80, 39, 60 and 63%, respectively. These findings showed that the alpha7nAChR protein levels would be a potentially useful diagnostic marker for AD.
