Blockade of Nociceptin Signaling Reduces Biochemical, Structural and Cognitive Deficits after Traumatic Brain Injury

Abstract : Protecting military personnel from blast-induced traumatic brain injury (TBI) has been a tremendous challenge. TBI results in hypoxia and ischemia reperfusion injury to the brain. Nociceptin (Noc), an endogenous peptide, is upregulated within one hour of TBI, impairs cerebral reactivity and exacerbates TBI by activating proapoptotic cascades. Long term neuroprotection involves inhibition of NF-appaB (NFkB). We hypothesized that activation of NFkB by the elevated Noc following blast-induced TBI contributes to metabolic and cellular changes underlying the appearance of neuronal and cognitive defects. Our objective was to determine if ORL1 antagonists will be neuroprotective against NFkB activation in a blast-induced TBI rat model and in cultured neuronal cells. TBI was simulated by shock tube to the head or chest; both reduced cerebral glucose uptake, especially to the thalamus, hippocampus and cerebellum as determined by 18-F-FDG uptake and PET imaging. Brain blast (80 psi) significantly reduced vestibulomotor function as determined with rotarod. Brain tissue histology revealed that markers for apoptosis and reactive gliosis were significantly elevated in the cerebellum and Noc levels trended towards significance. Apoptotic and neuronal injury markers were also elevated in sensory and motor cortex, consistent with the blast and the behavioral deficits measured. Cognitive defects were assessed using Morris water maze (MWM). NFkB activation by Noc was demonstrated by an NFkB reporter gene assay in SH-SY5Y and NG108-15 neuroblastoma cells. Noc also stimulated NFkB binding to DNA that was specifically blocked by ORL1 antagonism, and Noc also activated RSK signaling cascades in both cell lines.