Trans-synaptic spreading of alpha-synuclein pathology through sensory afferents leads to sensory nerve degeneration and neuropathic pain.

Pain is a common non-motor symptom of Parkinson's disease (PD), with current limited knowledge of its pathophysiology. Here, we show that peripheral inoculation of mouse alpha-synuclein (α-Syn) pre-formed fibrils, in a transgenic mouse model of PD, elicited retrograde trans-synaptic spreading of α-Syn pathology (pSer129) across sensory neurons and dorsal nerve roots, reaching central pain processing regions, including the spinal dorsal horn and the projections of the anterolateral system in the central nervous system (CNS). Pathological peripheral to CNS propagation of α-Syn aggregates along interconnected neuronal populations within sensory afferents, was concomitant with impaired nociceptive response, reflected by mechanical allodynia, reduced nerve conduction velocities (sensory and motor) and degeneration of small- and medium-sized myelinated fibers. Our findings show a link between the transneuronal propagation of α-Syn pathology with sensory neuron dysfunction and neuropathic impairment, suggesting promising avenues of investigation into the mechanisms underlying pain in PD.

An Analysis of Retinal Nerve Fiber Layer Thickness before and after Pituitary Adenoma Surgery and its Correlation with Visual Acuity.

INTRODUCTION: Pituitary adenomas comprise approximately 10% of all intracranial tumors. Initially, subtle changes occur in the field of vision, which are difficult to assess clinically. It has been seen that following surgery of pituitary macroadenoma, total recovery of normal vision occurs in 35% of the patients, improvement of vision occurs in 60%, and in the rest there is no change in vision. Retinal nerve fiber layer thickness (RNFLT) undergoes retrograde degeneration following compression of optic apparatus by pituitary tumor. We planned a study to evaluate RNFLT before and after pituitary adenoma surgery and its correlation with visual acuity. MATERIAL AND METHODS: Twenty patients (40 eyes) with diagnosed pituitary adenoma were included in the study. Preoperative visual acuity, fundus and RNFL thickness were calculated using spectral-domain OCT Optovue, Heidelberg Engineering, Heidelberg, Germany (RT 100 version 5.1), and postoperative measurement was done after 1 and 3 months. Four-quadrant mean of RNFLT was calculated. Results were tabulated and analyzed. STATISTICAL ANALYSIS: Results of the study were analyzed using IBM SPSS Statistics version 19.0. RESULTS: There was no significant change in RNFLT after pituitary adenoma surgery, and it was found that patients with RNFLT within normal range preoperatively showed improvement in visual acuity after pituitary surgery. On the other hand, patients who had thinned-out RNFLT preoperatively showed no improvement in visual acuity. It was also found that once optic disc pallor sets due to chronic compression, then chances of its reversion to normal depend on its grading: only mild pallor disc has some chance to revert to normal, whereas moderate and severe pallor do not revert to normal. CONCLUSION: RNFLT and optic disc can be used as prognostic factors for evaluation of visual outcome in pituitary adenoma surgery.

Survival of retinal ganglion cells after damage to the occipital lobe in humans is activity dependent.

Damage to the optic radiations or primary visual cortex leads to blindness in all or part of the contralesional visual field. Such damage disconnects the retina from its downstream targets and, over time, leads to trans-synaptic retrograde degeneration of retinal ganglion cells. To date, visual ability is the only predictor of retinal ganglion cell degeneration that has been investigated after geniculostriate damage. Given prior findings that some patients have preserved visual cortex activity for stimuli presented in their blind field, we tested whether that activity explains variability in retinal ganglion cell degeneration over and above visual ability. We prospectively studied 15 patients (four females, mean age = 63.7 years) with homonymous visual field defects secondary to stroke, 10 of whom were tested within the first two months after stroke. Each patient completed automated Humphrey visual field testing, retinotopic mapping with functional magnetic resonance imaging, and spectral-domain optical coherence tomography of the macula. There was a positive relation between ganglion cell complex (GCC) thickness in the blind field and early visual cortex activity for stimuli presented in the blind field. Furthermore, residual visual cortex activity for stimuli presented in the blind field soon after the stroke predicted the degree of retinal GCC thinning six months later. These findings indicate that retinal ganglion cell survival after ischaemic damage to the geniculostriate pathway is activity dependent.

Robust Visual Responses and Normal Retinotopy in Primate Lateral Geniculate Nucleus following Long-term Lesions of Striate Cortex.

Lesions of striate cortex (V1) trigger massive retrograde degeneration of neurons in the LGN. In primates, these lesions also lead to scotomas, within which conscious vision is abolished. Mediation of residual visual capacity within these regions (blindsight) has been traditionally attributed to an indirect visual pathway to the extrastriate cortex, which involves the superior colliculus and pulvinar complex. However, recent studies have suggested that preservation of the LGN is critical for behavioral evidence of blindsight, raising the question of what type of visual information is channeled by remaining neurons in this structure. A possible contribution of LGN neurons to blindsight is predicated on two conditions: that the neurons that survive degeneration remain visually responsive, and that their receptive fields continue to represent the region of the visual field inside the scotoma. We tested these conditions in male and female marmoset monkeys (Callithrix jacchus) with partial V1 lesions at three developmental stages (early postnatal life, young adulthood, old age), followed by long recovery periods. In all cases, recordings from the degenerated LGN revealed neurons with well-formed receptive fields throughout the scotoma. The responses were consistent and robust, and followed the expected eye dominance and retinotopy observed in the normal LGN. The responses had short latencies and preceded those of neurons recorded in the extrastriate middle temporal area. These findings suggest that the pathway that links LGN neurons to the extrastriate cortex is physiologically viable and can support residual vision in animals with V1 lesions incurred at various ages.SIGNIFICANCE STATEMENT Patients with a lesion of the primary visual cortex (V1) can retain certain visually mediated behaviors, particularly if the lesion occurs early in life. This phenomenon ("blindsight") not only sheds light on the nature of consciousness, but also has implications for studies of brain circuitry, development, and plasticity. However, the pathways that mediate blindsight have been the subject of debate. Recent studies suggest that projections from the LGN might be critical, but this finding is puzzling given that the lesions causes severe cell death in the LGN. Here we demonstrate in monkeys that the surviving LGN neurons retain a remarkable level of visual function and could therefore be the source of the visual information that supports blindsight.

Sonography of Carpal Tunnel Syndrome According to Pathophysiologic Type: Conduction Block Versus Axonal Degeneration.

OBJECTIVES: The purpose of this study was to investigate sonographic findings according to the pathophysiologic type in patients with carpal tunnel syndrome. METHODS: We retrospectively reviewed the records of 80 patients (148 hands) with carpal tunnel syndrome. Patients were classified into 3 groups according to electrophysiologic findings: (1) conduction block and conduction delay; (2) axonal degeneration; and (3) mixed. We used sonographic evaluations to assess the cross-sectional area at the distal wrist crease and the distal forearm and the wrist-to-forearm ratio of the median nerve. RESULTS: Patients with axonal degeneration had significantly larger cross-sectional areas and wrist-to-forearm ratios than those with a conduction block (P < .05). The increased wrist-to-forearm ratio correlated with a reduced amplitude of the sensory nerve action potential, which reflects the degree of axonal degeneration. CONCLUSIONS: The cross-sectional area and wrist-to-forearm ratio were associated with the pathophysiologic type of carpal tunnel syndrome, with larger nerve swellings seen in patients with axonal degeneration compared with those with demyelinating lesions. In addition to helping in the localization of the nerve lesion, sonography may indicate the type of nerve lesion.

Trans-synaptic degeneration of motoneurons distal to chronic cervical spinal cord compression in cervical spondylotic myelopathy.

OBJECTIVE: To assess the effect of chronic cervical spinal cord compression upon remote motor unit function in patients with cervical spondylotic myelopathy (CSM). METHODS: Fifty-three CSM patients and 47 healthy subjects were included. Bilateral motor unit number estimations (MUNEs) were recorded from both abductor digiti minimi and abductor pollicis brevis, and bilateral flexor carpi radialis (FCR) H-reflexes were examined in all subjects along with the nine-hole peg test (NHPT). The main outcome measures included the number of motor units, the average single motor unit potential (SMUP) area, the FCR Hmax/Mmax ratios and the NHPT time. RESULTS: Statistically significant results compared to healthy controls included increased average SMUP area, increased FCR Hmax/Mmax ratio and increased NHPT time (p < 0.05). Abnormal SMUP was observed in 10/53 (18.9%) CSM patients along with reduced motor units in 3 of these 10 patients, while the FCR Hmax/Mmax ratios in the CSM patients with abnormal MUNE were higher than those in others (p < 0.05). There was a positive correlation between the NHPT time and the average SMUP area, and a negative correlation was noted between the NHPT time and the number of motor units (p < 0.05). CONCLUSION: In CSM patients, the motor units below the level of compression may exhibit dysfunction, which is likely a result of trans-synaptic degeneration. Both cervical spinal cord compressive injury and this trans-synaptic degeneration contribute to the impairment of fine motor ability in CSM patients. Therefore, treatment and rehabilitation efforts should account for these two dysfunctions.

Evaluation of retinal nerve fiber layer thickness measured by optical coherence tomography in Moroccan patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by focal inflammatory infiltrates, demyelinating lesions and axonal injury. The purpose of the study was to evaluate the retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) in Moroccan patients with MS and to assess the relationship between RNFL thickness and disease duration, Expanded Disability Status Scale (EDSS) score, visual acuity and automated visual field indices. MATERIALS AND METHODS: Thirty-one patients with definite MS and thirty-one disease-free controls were enrolled in the study. After neurologic consultation, ophthalmologic examination including visual acuity, automated visual field testing and OCT were performed. RESULTS: Significant differences between both groups were observed in OCT parameters (total, temporal and macular ganglion cell layer) with lower thickness in the MS group. In patients without a history of optic neuritis, there were statistically significant inverse correlations between total RNFL thickness and disease duration, neurologic disability evaluated by the EDSS, logMAR visual acuity and automated visual field indices. CONCLUSIONS: OCT seems to be a reproducible test to detect axonal loss of ganglion cells in MS. Further and larger longitudinal prospective studies would be valuable to assess the evolution over time of the RNFL measurements in Moroccan MS patients.

Axonal Terminals Exposed to Amyloid-ß May Not Lead to Pre-Synaptic Axonal Damage.

BACKGROUND: Synaptic deficits and neuronal loss are the major pathological manifestations of Alzheimer's disease. However, the link between the early synaptic loss and subsequent neurodegeneration is not entirely clear. Cell culture studies have shown that amyloid-ß (Aß) applied to axonal terminals can cause retrograde degeneration leading to the neuronal loss, but this process has not been demonstrated in live animals. OBJECTIVE: To test if Aß applied to retinal ganglion cell axonal terminals can induce axonal damage in the optic nerve and optic tract in mice. METHODS: Aß was injected into the terminal field of the optic tract, in the left lateral geniculate nucleus of wildtype C57BL/6 mice. Following the injection, monthly diffusion tensor imaging was performed. Three months after the injection, mice underwent visual evoked potential recordings, and then sacrificed for immunohistochemical examination. RESULTS: There were no significant changes seen with diffusion tensor imaging in the optic nerve and optic tract 3 months after the Aß injection. The myelin and axons in these regions remained intact according to immunohistochemistry. The only significant changes observed in this study were delayed transduction and reduced amplitude of visual evoked potentials, although both Aß and its reversed form caused similar changes. CONCLUSION: Despite the published in vitro studies, there was no significant axonal damage in the optic nerve and optic tract after injecting Aß onto retinal ganglion cell axonal terminals of wildtype C57BL/6 mice.

Lesions in the posterior visual pathway promote trans-synaptic degeneration of retinal ganglion cells.

OBJECTIVE: Retrograde trans-synaptic degeneration of retinal ganglion cell layer (GCL) has been proposed as one of the mechanisms contributing to permanent disability after visual pathway damage. We set out to test this mechanism taking advantage of the new methods for imaging the macula with high resolution by optical coherence tomography (OCT) in patients with lesions in the posterior visual pathway. Additionally, we explored the association between thinning of GCL as an imaging marker of visual impairment such as visual field defects. METHODS: Retrospective case note review of patients with retrogeniculate lesions studied by spectral domain OCT of the macula and quadrant pattern deviation (PD) of the visual fields. RESULTS: We analysed 8 patients with either hemianopia or quadrantanopia due to brain lesions (stroke  = 5; surgery  = 2; infection  = 1). We found significant thinning of the GCL in the projecting sector of the retina mapping to the brain lesion. Second, we found strong correlation between the PD of the visual field quadrant and the corresponding macular GCL sector for the right (R = 0.792, p<0.001) and left eyes (R = 0.674, p<0.001). CONCLUSIONS: The mapping between lesions in the posterior visual pathway and their projection in the macula GCL sector corroborates retrograde trans-synaptic neuronal degeneration after brain injury as a mechanism of damage with functional consequences. This finding supports the use of GCL thickness as an imaging marker of trans-synaptic degeneration in the visual pathway after brain lesions.

[Pathogenesis of spinal cord injuries and mechanisms of repair induced by olfactory ensheathing cells]. / Patogenia de la lesion medular y mecanismos de reparacion inducidos por las celulas de la glia envolvente olfatoria.

INTRODUCTION: Spinal cord injury is a catastrophic event with permanent consequences during the all life. Treatment research has been based in the development of therapies that reduce the discapacity, but since the nineties there has been an important advance and several cellular transplants have been tested in spinal cord animal models, like Schwann cells, astrocytes and olfactory and olfactory ensheathing cells (OEC). AIM: Detailed account of spinal cord injury pathogeny, primary and secondary, and the OEC mechanisms for the regeneration effects that have been described in the literature. DEVELOPMENT: After the trauma, spinal cord injury develops in two phases, the primary injury with characteristics compression lesions, and the secondary produce for several factors that occur in parallel and include: vascular, cellular and molecular factors, and glial scar formation. The most of spinal cord models and OEC transplants have been reported functional recovery, remielinization and axonal regeneration. These cells exert their action in a direct way by producing grow factors and in an indirect way inducing directly neuronal an axonal regeneration and remielinization. CONCLUSIONS: OEC are a therapeutic option in patients with spinal cord injury, because they induce in a direct or indirect way, neuronal and axonal regeneration, remielinization, decrease the glial scar and produce other effects that conduce a functional recovery.

TITLE: Patogenia de la lesion medular y mecanismos de reparacion inducidos por las celulas de la glia envolvente olfatoria.Introduccion. La lesion medular es un evento catastrofico, cuyas consecuencias persisten durante toda la vida del paciente. La investigacion en tratamiento se ha basado principalmente en el desarrollo de terapias que reduzcan la discapacidad, pero desde los anos noventa hay un avance significativo y se han probado varios trasplantes celulares en modelos animales de lesion medular, celulas de Schwann, astrocitos y celulas de la glia envolvente olfatoria (CGEO). Objetivo. Hacer un recuento detallado de la patogenia de la lesion medular primaria y secundaria y de los mecanismos por los cuales las CGEO inducirian sus posibles efectos regenerativos descritos en la bibliografia. Desarrollo. Despues del traumatismo, la lesion se desarrolla en dos fases, la primaria se caracteriza por las lesiones de compresion y la secundaria se produce por una serie de factores que se dan en paralelo y que incluyen factores vasculares, celulares, moleculares y formacion de cicatriz glial. La mayoria de los modelos de lesion medular y trasplante con CGEO han comunicado recuperacion funcional, remielinizacion y regeneracion axonal. Estas celulas ejercen su accion de manera indirecta a traves de la produccion de factores de crecimiento y de manera directa induciendo regeneracion neuronal, axonal y remielinizacion. Conclusiones. Las CGEO son una opcion terapeutica en pacientes con lesion medular debido a que inducen de modo directo o indirecto regeneracion neuronal, axonal, remielinizacion de axones, disminucion de cicatriz glial y otros efectos que conducen a la recuperacion funcional.

Retrograde and Wallerian axonal degeneration occur synchronously after retinal ganglion cell axotomy.

Axonal injury and degeneration are pivotal pathological events in diseases of the nervous system. In the past decade, it has been recognized that the process of axonal degeneration is distinct from somal degeneration and that axoprotective strategies may be distinct from those that protect the soma. Preserving the cell body via neuroprotection cannot improve function if the axon is damaged, because the soma is still disconnected from its target. Therefore, understanding the mechanisms of axonal degeneration is critical for developing new therapeutic interventions for axonal disease treatment. We combined in vivo imaging with a multilaser confocal scanning laser ophthalmoscope and in vivo axotomy with a diode-pumped solid-state laser to assess the time course of Wallerian and retrograde degeneration of unmyelinated retinal ganglion cell axons in living rats for 4 weeks after intraretinal axotomy. Laser injury resulted in reproducible axon loss both distal and proximal to the site of injury. Longitudinal polarization-sensitive imaging of axons demonstrated that Wallerian and retrograde degeneration occurred synchronously. Neurofilament immunostaining of retinal whole-mounts confirmed axonal loss and demonstrated sparing of adjacent axons to the axotomy site. In vivo fluorescent imaging of axonal transport and photobleaching of labeled axons demonstrated that the laser axotomy model did not affect adjacent axon function. These results are consistent with a shared mechanism for Wallerian and retrograde degeneration.

Failure of lower motor neuron radial outgrowth precedes retrograde degeneration in a feline model of spinal muscular atrophy.

Feline spinal muscular atrophy (SMA) is a fully penetrant, autosomal recessive lower motor neuron disease in domestic cats that clinically resembles human SMA Type III. A whole genome linkage scan identified a ∼140-kb deletion that abrogates expression of LIX1, a novel SMA candidate gene of unknown function. To characterize the progression of feline SMA, we assessed pathological changes in muscle and spinal cord from 3 days of age to beyond onset of clinical signs. Electromyographic (EMG) analysis indicating denervation occurred between 10 and 12 weeks, with the first neurological signs occurring at the same time. Compound motor action potential (CMAP) amplitudes were significantly reduced in the soleus and extensor carpi radialis muscles at 8-11 weeks. Quadriceps femoris muscle fibers from affected cats appeared smaller at 10 weeks; by 12 weeks atrophic fibers were more prevalent than in age-matched controls. In affected cats, significant loss of L5 ventral root axons was observed at 12 weeks. By 21 weeks of age, affected cats had 40% fewer L5 motor axons than normal. There was no significant difference in total L5 soma number, even at 21 weeks; thus degeneration begins distal to the cell body and proceeds retrogradely. Morphometric analysis of L5 ventral roots and horns revealed that 4 weeks prior to axon loss, motor axons in affected cats failed to undergo radial enlargement, suggesting a role for the putative disease gene LIX1 in radial growth of axons.

Differential involvement of perineuronal astrocytes and microglia in synaptic stripping after hypoglossal axotomy.

Following peripheral axotomy, the presynaptic terminals are removed from lesioned neurons, that is synaptic stripping. To elucidate involvement of astrocytes and microglia in synaptic stripping, we herein examined the motoneuron perineuronal circumference after hypoglossal nerve transection. As reported previously, axotomy-induced slow cell death occurred in C57BL/6 mice but not in Wistar rats. Synaptophysin labeling in the hypoglossal nucleus exhibited a minor reduction in both species after axotomy. Slice patch recording showed that the mean frequency of miniature postsynaptic currents in axotomized motoneurons was significantly lower in rats than in mice. We then estimated the relative coverage of motoneuron perineuronal circumference by line profile analysis. In the synaptic environment, axotomy-induced intrusion of astrocytic processes was significantly more extensive in rats than in mice, whereas microglial intrusion into the synaptic space was significantly more severe in mice than in rats. Interestingly, in the extrasynaptic environment, the prevalence of contact between astrocytic processes and lesioned motoneurons was significantly increased in rats, while no significant axotomy-induced alterations in astrocytic contact were observed in mice. These findings indicate that astrocytic, but not microglial, reaction may primarily mediate some anti-apoptotic effects through synaptic stripping after hypoglossal nerve axotomy. In addition, enlargement of astrocytic processes in the extrasynaptic environment may also be involved in neuronal protection via the increased uptake of excessive glutamate.

Primary retinal pathology in multiple sclerosis as detected by optical coherence tomography.

Optical coherence tomography studies in multiple sclerosis have primarily focused on evaluation of the retinal nerve fibre layer. The aetiology of retinal changes in multiple sclerosis is thought to be secondary to optic nerve demyelination. The objective of this study was to use optical coherence tomography to determine if a subset of patients with multiple sclerosis exhibit primary retinal neuronopathy, in the absence of retrograde degeneration of the retinal nerve fibre layer and to ascertain if such patients may have any distinguishing clinical characteristics. We identified 50 patients with multiple sclerosis with predominantly macular thinning (normal retinal nerve fibre-layer thickness with average macular thickness < 5th percentile), a previously undescribed optical coherence tomography defined phenotype in multiple sclerosis, and compared them with 48 patients with multiple sclerosis with normal optical coherence tomography findings, 48 patients with multiple sclerosis with abnormal optical coherence tomography findings (typical for multiple sclerosis) and 86 healthy controls. Utilizing a novel retinal segmentation protocol, we found that those with predominant macular thinning had significant thinning of both the inner and outer nuclear layers, when compared with other patients with multiple sclerosis (P < 0.001 for both), with relative sparing of the ganglion cell layer. Inner and outer nuclear layer thicknesses in patients with non-macular thinning predominant multiple sclerosis were not different from healthy controls. Segmentation analyses thereby demonstrated extensive deeper disruption of retinal architecture in this subtype than may be expected due to retrograde degeneration from either typical clinical or sub-clinical optic neuropathy. Functional corroboration of retinal dysfunction was provided through multi-focal electroretinography in a subset of such patients. These findings support the possibility of primary retinal pathology in a subset of patients with multiple sclerosis. Multiple sclerosis-severity scores were also significantly increased in patients with the macular thinning predominant phenotype, compared with those without this phenotype (n = 96, P=0.006). We have identified a unique subset of patients with multiple sclerosis in whom there appears to be disproportionate thinning of the inner and outer nuclear layers, which may be occurring as a primary process independent of optic nerve pathology. In vivo analyses of retinal layers in multiple sclerosis have not been previously performed, and structural demonstration of pathology in the deeper retinal layers, such as the outer nuclear layer, has not been previously described in multiple sclerosis. Patients with inner and outer nuclear layer pathology have more rapid disability progression and thus retinal neuronal pathology may be a harbinger of a more aggressive form of multiple sclerosis.

Use of laser microdissection in the investigation of facial motoneuron and neuropil molecular phenotypes after peripheral axotomy.

The mechanism underlying axotomy-induced motoneuron loss is not fully understood, but appears to involve molecular changes within the injured motoneuron and the surrounding local microenvironment (neuropil). The mouse facial nucleus consists of six subnuclei which respond differentially to facial nerve transection at the stylomastoid foramen. The ventromedial (VM) subnucleus maintains virtually full facial motoneuron (FMN) survival following axotomy, whereas the ventrolateral (VL) subnucleus results in significant FMN loss with the same nerve injury. We hypothesized that distinct molecular phenotypes of FMN existed within the two subregions, one responsible for maintaining cell survival and the other promoting cell death. In this study, we used laser microdissection to isolate VM and VL facial subnuclear regions for molecular characterization. We discovered that, regardless of neuronal fate after injury, FMN in either subnuclear region respond vigorously to injury with a characteristic "regenerative" profile and additionally, the surviving VL FMN appear to compensate for the significant FMN loss. In contrast, significant differences in the expression of pro-inflammatory cytokine mRNA in the surrounding neuropil response were found between the two subnuclear regions of the facial nucleus that support a causative role for glial and/or immune-derived molecules in directing the contrasting responses of the FMN to axonal transection.

Proteasome inhibition promotes functional recovery after peripheral nerve reperfusion injury.

BACKGROUND: The proteasome degrades NF-kappaB blocking protein (I-kappaB) and activates NF-kappaB that plays as a key transcriptional factor to regulate inflammatory factors that are involved in the tissue reperfusion injury. This study was designed to assess whether the proteasome inhibitor can attenuate peripheral nerve ischemia/reperfusion (I/R) injury and consequently promote motor functional recovery after ischemic insult. METHODS: Rat sciatic nerves were exposed to 2 hour of ischemia followed by various periods of reperfusion. Rats were administered either proteasome inhibitor (bortezomib) or phosphate-buffered saline 30 minutes before reperfusion start. Results were evaluated using a walking track test, and an isolated muscle contraction test, and by muscle weight, and histology. RESULTS: Bortezomib treatment induced an earlier improvement in sciatic functional index and a more rapid restoration of contractile force and wet weight of extensor digitorum longus muscle. Bortezomib reduced early axonal degeneration and promoted regeneration. CONCLUSION: This study indicates that bortezomib; a proteasome inhibitor, is effective at promoting the functional recovery of reperfused peripheral nerve. The proteasome inhibition may play a role as one of the clinical strategy in the peripheral nervous system I/R injury with further understanding its mechanism of action.

Contribution of white matter lesions to gray matter atrophy in multiple sclerosis: evidence from voxel-based analysis of T1 lesions in the visual pathway.

BACKGROUND: The biological basis of gray matter (GM) atrophy in multiple sclerosis is not well understood, but GM damage seems to be the most critical factor leading to permanent disability. OBJECTIVE: To assess to what extent white matter (WM) lesions contribute to regional GM atrophy in multiple sclerosis. DESIGN: Because optic pathway GM atrophy and optic radiation lesions, rather than being related to each other, could be independent results of the disease, we applied a nonaprioristic WM method to analyze the interrelationships of both phenomena. On a voxel-by-voxel basis, we correlated T1 magnetic resonance imaging-derived lesion probability maps of the entire brain with atrophy of the lateral geniculate nuclei and calcarine/pericalcarine cortices. SETTING: Multiple sclerosis center, University of Navarra, Pamplona, Spain. PATIENTS: Sixty-one patients with multiple sclerosis. MAIN OUTCOME MEASURE: Mapping of WM regions contributing to GM atrophy in the optic pathway. RESULTS: Patients with multiple sclerosis had lateral geniculate nucleus atrophy, which correlated with the presence of lesions specifically in the optic radiations but not in the rest of the brain. Optic pathway lesions explained up to 28% of the change of variance in lateral geniculate nucleus atrophy. Patients also had occipital cortex atrophy, which did not correlate with lesions in the optic radiations or any other WM region. CONCLUSIONS: Focal WM damage is associated with upstream GM atrophy, suggesting that retrograde damage of the perikarya from axonal injury in multiple sclerosis plaques is one of the significant factors in the genesis of GM atrophy, although other neurodegenerative processes are probably at work as well.

G-protein-coupled receptor screen reveals a role for chemokine receptor CCR5 in suppressing microglial neurotoxicity.

G-protein-coupled receptors (GPCRs) form the largest superfamily of membrane proteins, and several GPCRs have been implicated in signaling between neurons and glia to protect neurons from pathological stresses. Here, we have used a screening strategy to investigate GPCRs that are involved in neuronal protection. The real-time PCR was performed using 274 primers targeting nonsensory GPCR mRNAs, which were listed on the database. The cDNAs from control and nerve-injured hypoglossal nuclei of mouse brain were used, and the alterations of PCR products were compared. This screen and the subsequent in situ hybridization screen exhibited six GPCR mRNAs which were prominently and convincingly induced in nerve-injured hypoglossal nuclei. Among these candidates, the chemokine receptor CCR5 was selected, based on the marked induction in CCR5 mRNA in microglia after nerve injury. The mRNA expression of ligands for CCR5, such as regulated on activation normal T-cell expressed and secreted (RANTES/CCL5), MIP-1alpha, and MIP-1beta, were induced in injured motor neurons, indicating that CCR5 and its ligands were expressed in microglia and neurons, respectively, in response to nerve injury. In vitro, lipopolysaccharide (LPS)-induced expression of mRNAs for inflammatory cytokines (IL-1beta, IL-6, and tumor necrosis factor-alpha) and inducible nitric oxide synthase (iNOS) in microglia were all suppressed by RANTES. Those suppressions were not observed in microglia from CCR5 null mice. In addition, nerve injury-induced motor neuron death seen in wild type C56BL/6J mice was accelerated in CCR5 knock-out C57BL/6J. These results may suggest that CCR5-mediated neuron-glia signaling functions to protect neurons by suppressing microglia toxicity.

Undesired effects of a combinatorial treatment for spinal cord injury--transplantation of olfactory ensheathing cells and BDNF infusion to the red nucleus.

Transplantations of olfactory ensheathing cells (OECs) have been reported to promote axonal regeneration and functional recovery after spinal cord injury, but have demonstrated limited growth promotion of rat rubrospinal axons after a cervical dorsolateral funiculus crush. Rubrospinal neurons undergo massive atrophy after cervical axotomy and show only transient expression of regeneration-associated genes. Cell body treatment with brain-derived neurotrophic factor (BDNF) prevents this atrophy, stimulates regeneration-associated gene expression and promotes regeneration of rubrospinal axons into peripheral nerve transplants. Here, we hypothesized that the failure of rubrospinal axons to regenerate through a bridge of OEC transplants was due to this weak intrinsic cell body response. Hence, we combined BDNF treatment of rubrospinal neurons with transplantation of highly enriched OECs derived from the nasal mucosa and assessed axonal regeneration as well as behavioral changes after a cervical dorsolateral funiculus crush. Each treatment alone as well as their combination prevented the dieback of the rubrospinal axons, but none of them promoted rubrospinal regeneration beyond the lesion/transplantation site. Motor performance in a food-pellet reaching test and forelimb usage during vertical exploration (cylinder test) were more impaired after combining transplantation of OECs with BDNF treatment. This impaired motor performance correlated with lowered sensory thresholds in animals receiving the combinatorial therapy - which were not seen with each treatment alone. Only this combinatorial treatment group showed enhanced sprouting of calcitonin gene-related peptide-positive axons rostral to the lesion site. Hence, some combinatorial treatments, such as OECs with BDNF, may have undesired effects in the injured spinal cord.