Failure of Opioids to Modify Noradrenergic Neuronal Recovery From a Dorsal Bundle Lesion in Neonatal Rats

Morphine and exogenous opioid peptides alter the development of central noradrenergic neurons damaged by neonatal treatment with the neurotoxin 6-hydroxydopa. Transection of the dorsal noradrenergic bundle (DNB) in neonatal rats produces nearly the same alteration in the developmental pattern. It was of interest to determine whether morphine or an exogenous opioid peptide (metenkephalin) was able to modify the recovery of noradrenergic neurons after neonatal surgical transection of the DNB. Neonatal rats were divided into two groups. Both groups received saline (0.85%) or naloxone (2.0 mg/kg) by the intraperitoneal (i.p.) route. In the first group the animals received an additional i.p. injection of either saline or morphine sulfate (3.33 mg/kg). The second group received an intraventricular injection of either saline, morphine (10 (mu)g/5 (mu)l), or methionine-enkephalin (25 (mu)g/5 (mu)l) ten minutes after the i.p. injection. Half the animals in these groups then received a DNB lesion, made with a blade 3mm (depth) by 5mm (width) at the level of the colliculi. At 6 weeks brains were removed for assay of norepinephrine (NE) content by a fluorometric method, and for determination of the rate of (\u273)H-NE uptake, in order to assess noradrenergic fiber number. It was found that in the cerebellum both the (\u273)H-NE uptake rate and NE content were significantly elevated by approximately 75% in the animals that received the lesion. The recovery in the anterior cortex (39%) was significantly greater than in the posterior cortex (27%), while recovery in the hippocampus (21%) was the least. This indicates a regional difference in recovery in the more distal projections of the DNB. Within the lesion group, however, there was no alteration in (\u273)H-NE uptake rate nor NE content in any of the above regions with any of the drug treatments. Therefore, none of the drug treatments effectively altered the recovery from surgical transection of the DNB. It is suggested that opioids are capable of modifying neurotoxin damage per se, but not capable of modifying regeneration of noradrenergic neurons

Combined delivery of Nogo-A antibody, neurotrophin-3 and the NMDA-NR2d subunit establishes a functional ‘detour’ in the hemisected spinal cord

To encourage re-establishment of functional innervation of ipsilateral lumbar motoneurons by descending fibers after an intervening lateral thoracic (T10) hemisection (Hx), we treated adult rats with the following agents: (i) anti-Nogo-A antibodies to neutralize the growth-inhibitor Nogo-A; (ii) neurotrophin-3 (NT-3) via engineered fibroblasts to promote neuron survival and plasticity; and (iii) the NMDA-receptor 2d (NR2d) subunit via an HSV-1 amplicon vector to elevate NMDA receptor function by reversing the Mg2+ block, thereby enhancing synaptic plasticity and promoting the effects of NT-3. Synaptic responses evoked by stimulation of the ventrolateral funiculus ipsilateral and rostral to the Hx were recorded intracellularly from ipsilateral lumbar motoneurons. In uninjured adult rats short-latency (1.7-ms) monosynaptic responses were observed. After Hx these monosynaptic responses were abolished. In the Nogo-Ab + NT-3 + NR2d group, long-latency (approximately 10 ms), probably polysynaptic, responses were recorded and these were not abolished by re-transection of the spinal cord through the Hx area. This suggests that these novel responses resulted from new connections established around the Hx. Anterograde anatomical tracing from the cervical grey matter ipsilateral to the Hx revealed increased numbers of axons re-crossing the midline below the lesion in the Nogo-Ab + NT-3 + NR2d group. The combined treatment resulted in slightly better motor function in the absence of adverse effects (e.g. pain). Together, these results suggest that the combination treatment with Nogo-Ab + NT-3 + NR2d can produce a functional ‘detour’ around the lesion in a laterally hemisected spinal cord. This novel combination treatment may help to improve function of the damaged spinal cord

Human Stiff-Person Syndrome IgG Induces Anxious Behavior in Rats

Background: Anxiety is a heterogeneous behavioral domain playing a role in a variety of neuropsychiatric diseases. While anxiety is the cardinal symptom in disorders such as panic disorder, co-morbid anxious behavior can occur in a variety of diseases. Stiff person syndrome (SPS) is a CNS disorder characterized by increased muscle tone and prominent agoraphobia and anxiety. Most patients have high-titer antibodies against glutamate decarboxylase (GAD) 65. The pathogenic role of these autoantibodies is unclear. Methodology/Principal Findings: We re-investigated a 53 year old woman with SPS and profound anxiety for GABA-A receptor binding in the amygdala with (11)C-flumazenil PET scan and studied the potential pathogenic role of purified IgG from her plasma filtrates containing high-titer antibodies against GAD 65. We passively transferred the IgG fraction intrathecally into rats and analyzed the effects using behavioral and in vivo electrophysiological methods. In cell culture, we measured the effect of patient IgG on GABA release from hippocampal neurons. Repetitive intrathecal application of purified patient IgG in rats resulted in an anxious phenotype resembling the core symptoms of the patient. Patient IgG selectively bound to rat amygdala, hippocampus, and frontal cortical areas. In cultured rat hippocampal neurons, patient IgG inhibited GABA release. In line with these experimental results, the GABA-A receptor binding potential was reduced in the patient’s amygdala/hippocampus complex. No motor abnormalities were found in recipient rats. Conclusion/Significance: The observations in rats after passive transfer lead us to propose that anxiety-like behavior can be induced in rats by passive transfer of IgG from a SPS patient positive for anti-GAD 65 antibodies. Anxiety, in this case, thus may be an antibody-mediated phenomenon with consecutive disturbance of GABAergic signaling in the amygdala region

Syndromics: A Bioinformatics Approach for Neurotrauma Research

Substantial scientific progress has been made in the past 50 years in delineating many of the biological mechanisms involved in the primary and secondary injuries following trauma to the spinal cord and brain. These advances have highlighted numerous potential therapeutic approaches that may help restore function after injury. Despite these advances, bench-to-bedside translation has remained elusive. Translational testing of novel therapies requires standardized measures of function for comparison across different laboratories, paradigms, and species. Although numerous functional assessments have been developed in animal models, it remains unclear how to best integrate this information to describe the complete translational “syndrome” produced by neurotrauma. The present paper describes a multivariate statistical framework for integrating diverse neurotrauma data and reviews the few papers to date that have taken an information-intensive approach for basic neurotrauma research. We argue that these papers can be described as the seminal works of a new field that we call “syndromics”, which aim to apply informatics tools to disease models to characterize the full set of mechanistic inter-relationships from multi-scale data. In the future, centralized databases of raw neurotrauma data will enable better syndromic approaches and aid future translational research, leading to more efficient testing regimens and more clinically relevant findings