Persistent reduction of conduction velocity and myelinated axon damage in vibrated rat tail nerves

Prolonged hand‐transmitted vibration exposure in the workplace has been recognized for almost a century to cause neurodegenerative and vasospastic disease. Persistence of the diseased state for years after cessation of tool use is of grave concern. To understand persistence of vibration injury, the present study examined recovery of nerve conduction velocity and structural damage of myelinated axons in a rat tail vibration model. Both 7 and 14 days of vibration (4 h/day) decreased conduction velocity. The decrease correlated directly with the increased percentage of disrupted myelinated axons. The total number of myelinated axons was unchanged. During 2 months of recovery, conduction velocity returned to control level after 7‐day vibration but remained decreased after 14‐day vibration. The rat tail model provides insight into understanding the persistence of neural deficits in hand–arm vibration syndrome. Muscle Nerve, 2009     

Substantial archaeocortical atrophy and neuronal loss in multiple sclerosis

Recent studies have revealed extensive neocortical pathology in multiple sclerosis (MS). The hippocampus is a unique archaeocortical structure understudied in MS. It plays a central role in episodic and anterograde memory—the most frequently impaired cognitive modalities in MS. This histopathological study aimed to investigate inflammatory demyelination and neurodegenerative changes in the MS archaeocortex. A detailed quantitative analysis was performed on hippocampal autopsy tissue from 45 progressive MS cases and seven controls. Forty-one lesions were identified in 28 of the 45 hippocampal MS-blocks examined, with percentage area of demyelination averaging 30.4%. The majority of lesions were chronic and subpially or subependymally located. Compared to controls, neuronal numbers were decreased by 27% in CA1 and 29.7% in CA3-2. Furthermore, the size of neurones was decreased by 17.4% in CA1. There was evidence of gross hippocampal atrophy with a 22.3% reduction in the average cross-sectional area, which correlated with neuronal loss. Our study provides evidence of substantial archaeocortical pathology largely resembling patterns seen in the neocortex and suggests that hippocampal involvement could contribute to memory impairments often seen in MS.     

Connexin 43 gap junction proteins are up-regulated in remyelinating spinal cord

Alterations in the expression of gap junction proteins have previously been observed in several diseases affecting the central nervous system; however, the status of connexin 43 (Cx43) has not yet been reported in spinal cord remyelination. We studied Cx43 expression in demyelination and remyelination by using a chronic guinea pig model of experimental allergic encephalomyelitis (EAE). Hartley guinea pigs were immunized with homogenized whole CNS and complete Freund's adjuvant. Animals became chronically ill by day 40 postimmunization, and animals with paralysis were entered into the study. Animals were treated on days 40-60 postimmunization with either saline or drugs that promote remyelination: an adenosine amine congener (100 mug/kg), an anti-alpha4-integrin blocker (CT301; ELN 69299; 30 mg/kg), or a combination of both drugs. Remyelination was induced in all drug-treated groups. Cx43 expression was virtually absent in demyelinated lesions of saline-treated controls compared with healthy tissue and normal appearing white matter (P < 0.001), whereas Cx43 was considerably increased (300-500%) in remyelinating lesions of all treatment groups (P < 0.001), most notably in CT301-treated animals. These changes in Cx43 expression indicate that Cx43 may beimportant for recovery from neuroinflammation.     

Double-stranded RNA induces iNOS gene expression in Schwann cells, sensory neuronal death, and peripheral nerve demyelination

Inflammation in the peripheral nervous system (PNS) is one of the characteristics of virus-induced peripheral neuropathy. In this inflammatory response, Schwann cells are actively involved. Previously, toll-like receptor 3 (TLR3) was reported as a receptor for double-stranded RNA (dsRNA) that induces antiviral and inflammatory responses in cells of the innate immune system. In this study, we investigated the expression and putative role of TLR3 in Schwann cells. TLR3 was constitutively expressed in Schwann cells. Stimulation with polyinosinic-polycytidylic acid, a synthetic dsRNA analogue, induced the expression of inducible nitric oxide synthase (iNOS) gene in Schwann cells. Studies on the intracellular signal transduction pathways using iSC, an immortalized Schwann cell line, revealed that dsRNA induces the activation of NF-kappaB, p38, and c-Jun N-terminal kinase (JNK). The activation of NF-kappaB, p38, JNK, and dsRNA-dependent protein kinase is required for dsRNA-mediated iNOS gene expression. However, the activation of PI3 kinase and GSK-3beta inhibited iNOS gene induction, a process mediated by their inhibitory effects on NF-kappaB and p38 activation. dsRNA-induced NO production caused neuronal cell death in cultured dorsal root ganglion. Finally, the introduction of dsRNA into the rat sciatic nerve induced iNOS gene expression and peripheral nerve demyelination in vivo. Taken together, these data suggest that viral RNA may induce inflammatory Schwann cell activation via TLR3 and peripheral nerve damage in the PNS.     

Reduced raft-association of NF155 in active MS-lesions is accompanied by the disruption of the paranodal junction

Neurofascin155 (NF155) is required for the establishment of the paranodal axo-glial junction, the predominant interaction site between myelin and axon. It has been shown that the distribution of NF155 is altered in demyelinating diseases such as multiple sclerosis (MS). However, little is known about the biochemical mechanisms underlying these changes. We therefore compared NF155 in postmortem tissue of active and chronic inactive MS lesions with white matter from healthy controls. Although NF155 showed a very similar expression in all control white matter samples, a strong individual variation was observed in MS-lesions with NF155-levels reduced in most samples. At the same time an NF155-fragment was increased in MS-lesions, suggesting that NF155 is subject to protein degradation in lesion sites. Interestingly, the association of NF155 to membrane microdomains (rafts) was reduced in all lesions, irrespective of the amount of NF155, indicating that membrane association of NF155 was generally affected. Therefore, myelin fractionation experiments were performed to analyze the fate of paranodal proteins during demyelination. Although NF155 was enriched in heavy myelin from both control white matter and active MS-lesions, association of Caspr1/paranodin with heavy myelin was abolished in MS-lesions, demonstrating that paranodal junctions are disrupted. In conclusion, the data support the hypothesis that efficient raft-association of NF155 is essential for the assembly of the paranodal junction and demonstrate that reduced association of NF155 to lipid rafts is accompanied by the disassembly of the paranodal junction and thus contributes to the demyelination process in MS.     

Physiological effects of auditory nerve myelinopathy in chinchillas

The goals were to study the physiological effects of auditory nerve myelinopathy in chinchillas and to test the hypothesis that myelin abnormalities could account for auditory neuropathy, a hearing disorder characterized by absent auditory brainstem responses (ABRs) with preserved outer hair cell function. Doxorubicin, a cytotoxic drug used as an experimental demyelinating agent, was injected into the auditory nerve bundle of 18 chinchillas; six other chinchillas were injected with vehicle alone. Cochlear microphonics, compound action potentials (CAPs), inferior colliculus evoked potentials (IC-EVPs), cubic distortion product otoacoustic emissions and ABRs were recorded before and up to 2 months after injection. Cochleograms showed no hair cell loss in any of the animals and measures of outer hair cell function were normal (cubic distortion product otoacoustic emissions) or enhanced (cochlear microphonics) after injection. ABR was present in animals with mild myelin damage (n = 10) and absent in animals with severe myelin damage that included the myelin surrounding spiral ganglion cell bodies and fibers in Rosenthal's canal (n = 8). Animals with mild damage had reduced response amplitudes at 1 day, followed by recovery of CAP and enhancement of the IC-EVP. In animals with severe damage, CAP and IC-EVP thresholds were elevated, amplitudes were reduced, and latencies were prolonged at 1 day and thereafter. CAPs deteriorated over time, whereas IC-EVPs partially recovered; latencies remained consistently prolonged despite changes in amplitudes. The results support auditory nerve myelinopathy as a possible pathomechanism of auditory neuropathy but indicate that myelinopathy must be severe before physiological measures are affected.     

The chemokine receptor CXCR2 is differentially regulated on glial cells in vivo but is not required for successful remyelination after cuprizone-induced demyelination

Unravelling the factors that can positively influence remyelination is one of the major challenges in multiple sclerosis research. Expression of the chemokine receptor CXCR2 on oligodendrocytes both in vitro and in MS lesions has suggested a possible role for CXCR2 in the recruitment of oligodendrocyte precursor cells (OPC). To investigate the function of CXCR2 during remyelination in vivo, we studied this receptor in cuprizone-induced demyelination and subsequent remyelination. We found that CXCR2 is constitutively expressed on OPC, whereas on macrophages/microglia CXCR2 is upregulated upon activation during demyelination. Hence, the expression of CXCR2 is differentially regulated in oligodendrocytes and macrophages/microglia. Furthermore, we subjected CXCR2-/- mice to the cuprizone model demonstrating that remyelination was not altered in comparison to wildtype controls. In addition, the number of OPC and the amount of microglial accumulation were similar in both CXCR2-/- and wildtype animals during the whole demyelination and remyelination process. These results suggest that despite expression on OPC and microglia CXCR2 plays only a minor role during remyelination.     

Novel expression of PINCH in the central nervous system and its potential as a biomarker for human immunodeficiency virus-associated neurodegeneration

Particularly interesting cysteine histidine-rich (PINCH) protein functions as a shuttling protein in Schwann cells after peripheral nerve damage, during repair and remodeling, and in maintaining neuronal polarity. However, the presence of PINCH in the human CNS during disease has not been addressed. Because HIV-associated damage to cells of the CNS involves dysregulation of neuronal signaling and white matter damage, we hypothesized that PINCH may play a role in neuropathological processes during the course of HIV infection. To determine the expression of PINCH in the CNS, brain, and cerebrospinal fluid (CSF) obtained at autopsy from HIV patients with no CNS alterations, HIV encephalitic (HIVE) patients, and HIV-negative individuals with no CNS alterations were examined for PINCH immunoreactivity. Our results show that PINCH is expressed robustly in the brains and CSF of HIV patients, but is nearly undetectable in HIV-negative individuals. However, HIVE patients' CSF contained significantly less PINCH than HIV patients with no CNS alterations. PINCH immunolabeling was significantly more intense in the white matter than in the grey matter and was associated exclusively with neuronal cell bodies or processes, or with the extracellular matrix. Given the recently discovered importance of PINCH in maintaining neuronal fitness, our observations that PINCH is robustly expressed in the CNS of HIV patients suggests an important role for PINCH in HIV-associated neurodegenerative processes. Understanding mechanisms by which PINCH functions during HIV-associated CNS alterations will provide new insight into potential treatments to limit neurological alterations in HIV.     

Brain magnetic resonance imaging abnormalities in neuromyelitis optica

Objective – Brain abnormalities in neuromyelitis optica (NMO) attracted much attention. Our study was to identify the brain magnetic resonance imaging (MRI) abnormalities in Chinese NMO patients. Methods – Patients who fulfilled the latest diagnostic criteria of NMO proposed by Wingerchuk et al. [Neurology 66 (2006) 1485] and whose brain MRI did not meet the multiple sclerosis (MS) criteria of McDonald et al. [Ann Neurol 50 (2001) 121] were selected to perform MRI scanning of the brain, spinal cord and optic nerves. Results – Twenty‐eight of 33 patients (84.8%) had abnormal MRI findings. Twenty‐two patients (66.7%) presented with well‐defined brain parenchymal lesions and the other six patients (18.2%) with macroscopic symmetrical diffuse hyperintensities in deep white matter. Fifteen of 22 patients had more than one lesion (≥2 lesions) and the other seven patients had single lesion. In the supratentorium, most lesions were punctate or small round dot and non‐specific in juxtacortical, subcortical and deep white matter regions, a few were patchy atypical confluent lesions. Brainstem was easily involved (14/33, 42.4%) especially in medulla (7/33, 21.2%). Conclusions – This study demonstrates the characteristics of brain MRI abnormalities in Chinese NMO patients, which are helpful to the revision of diagnostic criteria for NMO.