Journal of neuropathology and experimental neurology
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J. Neuropathol. Exp. Neurol. · Feb 2008
Enhancement of cutaneous nerve regeneration by 4-methylcatechol in resiniferatoxin-induced neuropathy.
To generate an experimental neuropathy model in which small-diameter sensory nerves are specifically affected and to test a potential treatment, adult mice were given a single injection (50 microg/kg, i.p.) of the capsaicin analog resiniferatoxin (RTX). On Day 7 after RTX treatment, there was a 53% reduction in unmyelinated nerve density in the medial plantar nerve (p = 0.0067) and a 66% reduction in epidermal nerve density of hind paw skin (p = 0.0004) compared with vehicle-treated controls. Substance P-immunoreactive dorsal root ganglion neurons were also markedly depleted (p = 0.0001). ⋯ The potential therapeutic effects of 4-methylcatechol (4MC) on this neuropathy were then tested by daily injections of 4MC (10 microg/kg, i.p.) from Days 7 to 35 after neuropathy induction. On Day 35, 4MC-treated mice had an increase in unmyelinated (p = 0.014) and epidermal nerve (p = 0.0013) densities and a reduction in thermal withdrawal latency (p = 0.0091) compared with RTX-only controls. These results indicate that 4MC promoted regeneration of unmyelinated nerves in experimental RTX-induced neuropathy and enhanced function.
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J. Neuropathol. Exp. Neurol. · Aug 2007
Granulocyte colony-stimulating factor attenuates neuronal death and promotes functional recovery after spinal cord injury in mice.
Granulocyte colony-stimulating factor (G-CSF) is a protein that stimulates differentiation, proliferation, and survival of granulocytic lineage cells. Recently, a neuroprotective effect of G-CSF was reported in a model of cerebral infarction. The aim of the present study was to elucidate the potential therapeutic effect of G-CSF for spinal cord injury (SCI) in mice. ⋯ Moreover, administration of G-CSF promoted hindlimb functional recovery. Examination of signaling pathways downstream of the G-CSF receptor suggests that G-CSF might promote functional recovery by inhibiting neuronal apoptosis after SCI. G-CSF is currently used in the clinic for hematopoietic stimulation, and its ongoing clinical trial for brain infarction makes it an appealing molecule that could be rapidly placed into trials for patients with acute SCI.
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J. Neuropathol. Exp. Neurol. · Mar 2007
Perisomatic thalamic axotomy after diffuse traumatic brain injury is associated with atrophy rather than cell death.
Morbidity and mortality associated with traumatic brain injury (TBI) stem from diffuse axonal injury (DAI) throughout subcortical and brainstem white matter and subcortical nuclei. After midline fluid percussion brain injury, DAI in the thalamus includes perisomatic axotomy and resembles human post-traumatic pathology where the degree of morbidity correlates with thalamic damage. After axotomy, acute somatic perturbations resolve and appear compatible with cell survival; however, the long-term fate of neurons in an area with perisomatic axotomy is unknown. ⋯ Furthermore, by 1 day and persisting through 1 week after injury, the mean neuronal nuclear volume was atrophied significantly compared with sham. Therefore, diffuse TBI results in early perisomatic axonal injury followed by neuronal atrophy in the ventral basal complex, without gross degeneration. Enduring atrophy in thalamic relays could underlie circuit disruption responsible for post-traumatic morbidity.
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J. Neuropathol. Exp. Neurol. · Dec 2006
Fractalkine expression in the rhesus monkey brain during lentivirus infection and its control by 6-chloro-2',3'-dideoxyguanosine.
Existing data concerning the role of the delta-chemokine fractalkine (CX3CL1) and its receptor (CX3CR1) in lentivirus-induced encephalitis are limited and controversial. We explored, by quantitative in situ hybridization and immunohistochemistry, the cell-specific changes of CX3CL1 and CX3CR1 in rhesus macaque brain during simian immunodeficiency virus (SIV) infection and antiretroviral treatment. Neuronal expression of CX3CL1 was significantly reduced in cortex and striatum of AIDS-diseased monkeys as compared with uninfected and asymptomatic SIV-infected monkeys. ⋯ Treatment of AIDS monkeys with the central nervous system-permeant 6-chloro-2',3'-dideoxyguanosine fully reversed SIV burden, productive inflammation, nuclear NF-kappaB translocation as well as focal induction of CX3CL1 in astrocytes and macrophages and downregulation in neurons. In contrast, diffuse CX3CR1-positive microgliosis and GFAP-positive astrogliosis were partially reversed by 6-chloro-2',3'-dideoxyguanosine. Thus, focally induced CX3CL1 may be a target for therapeutic intervention to limit ongoing inflammatory infiltration into brain in lentivirus infection.
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J. Neuropathol. Exp. Neurol. · Aug 2006
Intrathecal upregulation of granulocyte colony stimulating factor and its neuroprotective actions on motor neurons in amyotrophic lateral sclerosis.
To investigate cytokine/chemokine changes in amyotrophic lateral sclerosis (ALS), we simultaneously measured 16 cytokine/chemokines (interleukin [IL]-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 [p70], IL-13, IL-17, interferon-gamma, tumor necrosis factor-alpha, granulocyte colony stimulating factor [G-CSF], macrophage chemoattractant protein-1 [MCP-1], and macrophage inflammatory protein-1beta) in cerebrospinal fluid (CSF) and sera from 37 patients with sporadic ALS and 33 controls using a multiplexed fluorescent bead-based immunoassay. We also conducted immunohistochemical analyses from 8 autopsied ALS cases and 6 nonneurologic disease controls as well as cell culture analyses of relevant cytokines and their receptors. We found that concentrations of G-CSF and MCP-1 were significantly increased in ALS CSF compared with controls. ⋯ Biologically, G-CSF had a protective effect on the NSC34 cell line under conditions of both oxidative and nutritional stress. We suggested that G-CSF has potentially neuroprotective effects on motor neurons in ALS and that downregulation of its receptor might contribute to ALS pathogenesis. On the other hand, MCP-1 correlated with disease severity, which may aggravate motor neuron damage.