Journal of neuroscience research
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Spinal cord injury (SCI) is a devastating and complex clinical condition involving proinflammatory cytokines and nitric oxide toxicity that produces a predictable pattern of progressive injury entailing neuronal loss, axonal destruction, and demyelination at the site of impact. The involvement of proinflammatory cytokines and inducible nitric oxide synthase (iNOS) in exacerbation of SCI pathology is well documented. We have reported previously the antiinflammatory properties and immunomodulatory activities of statins (3-hydroxy-3-methylglutaryl [HMG]-CoA reductase inhibitors) in the animal model of multiple sclerosis, experimental allergic encephalitis (EAE). ⋯ LP also provided protection against SCI-induced tissue necrosis, neuronal and oligodendrocyte apoptosis, demyelination, and reactive gliosis. Furthermore, rats treated with LP scored much higher on the locomotor rating scale after SCI (19.13 +/- 0.53) than did untreated rats (9.04 +/- 1.22). This study therefore reports the beneficial effect of atorvastatin for the treatment of SCI-related pathology and disability.
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Experimental traumatic brain injury (TBI) and spinal cord injury (SCI) result in a rapid and significant necrosis of neuronal tissue at the site of injury. In the ensuing hours and days, secondary injury exacerbates the primary damage, resulting in significant neurologic dysfunction. It is believed that alterations in excitatory amino acids (EAA), increased reactive oxygen species (ROS), and the disruption of Ca(2+) homeostasis are major factors contributing to the ensuing neuropathology. ⋯ The underlying mechanism of neuroprotection afforded by CsA is most likely via interaction with the mPTP because the immunosuppressant FK506, which has no effect on the mPT, was not neuroprotective. When CsA was administrated after experimental SCI at the same dosage and regimen used TBI paradigms, however, it had no beneficial neuroprotective effects. This review takes a comprehensive and critical look at the evidence supporting the role for mPT in central nervous system (CNS) trauma and highlights the differential responses of CNS mitochondria to mPT induction and the implications this has for therapeutically targeting the mPT in TBI and SCI.
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Comparative Study
High-resolution magic angle spinning and 1H magnetic resonance spectroscopy reveal significantly altered neuronal metabolite profiles in CLN1 but not in CLN3.
The neuronal ceroid lipofuscinoses (NCLs) are among the most severe inherited progressive neurodegenerative disorders of children. The purpose of this study was to compare the in vivo 1.5-T 1H magnetic resonance (MR) and ex vivo 14.3-T high-resolution (HR) magic angle spinning (MAS) 1H MR brain spectra of patients with infantile (CLN1) and juvenile (CLN3) types of NCL, to obtain detailed information about the alterations in the neuronal metabolite profiles in these diseases and to test the suitability of the ex vivo HR MAS (1)H MRS technique in analysis of autopsy brain tissue. Ex vivo spectra from CLN1 autopsy brain tissue (n = 9) significantly differed from those of the control (n = 9) and CLN3 (n = 5) groups, although no differences were found between the CLN3 and the control groups. ⋯ Again, the spectra of patients with CLN3 (n = 13) did not differ from those of controls (n = 15). In conclusion, the ex vivo and in vivo spectroscopic findings were in good agreement within all analyzed groups and revealed significant alterations in metabolite profiles in CLN1 brain tissue but not in CLN3 compared with controls. Furthermore, HR MAS 1H MR spectra facilitated refined detection of neuronal metabolites, including GABA, and composition of lipids in the autopsy brain tissue of NCL patients.
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Previous studies have established that reciprocal interactions between the low-affinity p75 nerve growth factor (NGF) receptor (p75(NTR)) and the high-affinity TrkA NGF receptor can dictate the cellular response to NGF. As the most important interaction, TrkA signaling was found to inhibit p75(NTR)-mediated sphingomyelinase (SMase) stimulation, ceramide production, and apoptosis. However, the mechanism by which TrkA counteracts p75(NTR)-coupled sphingolipid signaling is still unclear. ⋯ In SH-SY5Y, another neuroblastoma cell line, which coexpresses TrkA and p75(NTR), NGF induced PKC stimulation through a TrkA/PI3K signaling pathway, whereas there was no ceramide production. However, in these cells, the inhibition of TrkA, PI3K, and PKC resulted in the restoration of NGF-induced ceramide production. Thus, our study demonstrates for the first time that TrkA interferes with p75(NTR) signaling through a PI3K/PKC-dependent mechanism.
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The present study was performed to explore the involvement of opioid receptors in the calcitonin gene-related peptide 8-37 (CGRP8-37, an antagonist of CGRP receptor)-induced inhibition of the activity of wide-dynamic-range (WDR) neurons in the spinal dorsal horn of rats. Extracellular recording was performed with a multibarrelled glass micropipette, and the chemicals were delivered by micro-iontophoresis. The discharge frequency of WDR neurons was evoked by subcutaneous electrical stimulation applied to the ipsilateral hindpaw. ⋯ The inhibitory effect of CGRP8-37 on the activity of WDR neurons was attenuated by later iontophoretic application of the opioid antagonist naloxone. Furthermore, the effect of CGRP8-37 was attenuated by either iontophoretic application of the kappa-receptor antagonist nor-binaltorphimine (nor-BNI) or the mu-receptor antagonist beta-funaltrexamine (beta-FNA) but not by the delta-receptor antagonist naltrindole. The results indicate that kappa- and mu-opioid receptors on the membrane of WDR neurons are involved in the modulation of CGRP8-37-induced antinociception in dorsal horn of the spinal cord in rats.