Axonal degeneration is now recognized as an important pathological feature of multiple sclerosis (MS). Acute axonal damage happens early in the disease course, and therefore early changes might occur ...in markers in body fluids, such as cerebrospinal fluid (CSF) and blood. In our study we investigated the relevance of serum and CSF markers for axonal damage in patients with clinically isolated syndrome indicative for MS. We measured the concentration of tau, phospho-tau, S100B, Amyloid beta and neuron specific enolase (NSE) in CSF and serum. Interestingly, the NSE concentration in CSF and serum was decreased in clinically isolated syndrome (CIS)-patients in comparison to the control group indicating reduced neuronal metabolic activity in the early stage of the disease. Concerning other biomarkers, we did not observe any changes in the concentrations between groups. Moreover, we did not detect any correlation between Expanded Disability Status Scale (EDSS) and the concentration of investigated proteins.
Ciguatoxins (CTXs) are marine toxins that cause ciguatera fish poisoning, a debilitating disease dominated by sensory and neurological disturbances that include cold allodynia and various painful ...symptoms as well as long-lasting pruritus. Although CTXs are known as the most potent mammalian sodium channel activator toxins, the etiology of many of its neurosensory symptoms remains unresolved. We recently described that local application of 1 nM Pacific Ciguatoxin-1 (P-CTX-1) into the skin of human subjects induces a long-lasting, painful axon reflex flare and that CTXs are particularly effective in releasing calcitonin-gene related peptide (CGRP) from nerve terminals. In this study, we used mouse and rat skin preparations and enzyme-linked immunosorbent assays (ELISA) to study the molecular mechanism by which P-CTX-1 induces CGRP release. We show that P-CTX-1 induces CGRP release more effectively in mouse as compared to rat skin, exhibiting EC
concentrations in the low nanomolar range. P-CTX-1-induced CGRP release from skin is dependent on extracellular calcium and sodium, but independent from the activation of various thermosensory transient receptor potential (TRP) ion channels. In contrast, lidocaine and tetrodotoxin (TTX) reduce CGRP release by 53-75%, with the remaining fraction involving L-type and T-type voltage-gated calcium channels (VGCC). Using transgenic mice, we revealed that the TTX-resistant voltage-gated sodium channel (VGSC) Na
1.9, but not Na
1.8 or Na
1.7 alone and the combined activation of the TTX-sensitive VGSC subtypes Na
1.7 and Na
1.1 carry the largest part of the P-CTX-1-caused CGRP release of 42% and 34%, respectively. Given the contribution of CGRP to nociceptive and itch sensing pathways, our findings contribute to a better understanding of sensory symptoms of acute and chronic ciguatera that may help in the identification of potential therapeutics.
Axonal destruction and neuronal loss occur early during multiple sclerosis (MS), an autoimmune inflammatory central nervous system disease that frequently manifests with acute optic neuritis. ...Glatiramer acetate (GA) and interferon-beta-1b (IFN-beta-1b) are two immunomodulatory agents that have been shown to decrease the frequency of MS relapses. However, the question of whether these substances can slow neurodegeneration in MS patients is the subject of controversy. In a rat model of experimental autoimmune encephalomyelitis, we investigated the effects of GA and IFN-beta-1b on the survival of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. For each substance, therapy was started 14 days before immunization, on the day of immunization, or on the day of clinical disease onset. After myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis became clinically manifest, optic neuritis was monitored by recording visual evoked potentials. The function of RGCs was measured by electroretinograms. Although early GA or IFN-beta-1b treatment showed benefit on disease activity, only treatment with GA exerted protective effects on RGCs, as revealed by measuring neurodegeneration and neuronal function. Furthermore, we demonstrate that this GA-induced neuroprotection does not exclusively depend on the reduction of inflammatory infiltrates within the optic nerve.
Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS which leads to demyelination, axonal destruction and neuronal loss in the early stages. Available therapies mainly target the ...inflammatory component of the disease but fail to prevent neurodegeneration. To investigate the effect of ciliary neurotrophic factor (CNTF) on the survival of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve, we used a rat model of myelin oligodendrocyte glycoprotein‐induced experimental autoimmune encephalomyelitis. Optic neuritis in this model was diagnosed by recording visual evoked potentials, and RGC function was monitored by measuring electroretinograms. This study demonstrates that CNTF has a neuroprotective effect on affected RGCs during acute optic neuritis. Furthermore, we demonstrate that CNTF exerts its neuroprotective effect through activation of the Janus kinase/signal transducer and activator of transcription pathway, mitogen activated protein kinases and a shift in the Bcl‐2 family of proteins towards the anti‐apoptotic side. In summary, our results demonstrate that CNTF can serve as an effective neuroprotective treatment in a rat model of MS that especially reflects the neurodegenerative aspects of this disease.
Berberine bridge enzyme (BBE) from the California poppy enantioselectively converts benzylisoquinolines into berbines by oxidative CC coupling that consumes O2 as a stoichiometric oxidant. In their ...Communication on page 1068 ff., W. Kroutil and co‐workers describe the first biocatalytic application of BBE on a preparative scale. Novel optically pure benzylisoquinolines and berbines were prepared by BBE‐catalyzed oxidative kinetic resolution of racemic substrates. Cover picture by V. Resch.
Voltage gated sodium channels (Nav), are proposed mediators of neuronal damage in ischemic and excitotoxicity disease models. We evaluated the neuroprotective effects of lamotrigine, a Nav blocker, ...in the acute and chronic rat ocular hypertension models. Additionally, expression of the main Nav subtypes in the optic nerve (ON) was assessed to test whether their upregulation plays a role in the pathogenesis of ocular hypertension induced optic neuropathy. Unilateral intraocular pressure (IOP) elevation was induced for 60 min (80 mmHg) and 14–21 days (670–859 mmHg*day) in the acute and chronic models, respectively. Lamotrigine was administered at dosages of 10 mg/kg twice daily and 12.5 mg/kg once daily in the acute (n = 9) and chronic (n = 11) trials, respectively. Treatment began 2 days prior to IOP elevation until sacrifice. Outer and inner retinal function was evaluated with dark- and light-adapted flash electroretinography and pattern electroretinography, respectively, 6 and 14 days post acute IOP elevation and 13, 28 and 48 days post chronic IOP elevation. Retinal ganglion cell and axon densities and inflammatory reaction were evaluated through Fluorogold, Bielschowsky's silver impregnation and ED1 labeling respectively. Immunohistochemistry for Nav1.1, 1.2 and 1.6 was performed in ONs of untreated rats 7 and 15 days post IOP elevation in the acute model and after 7, 28 and 50 days in the chronic model. In the acute model, no differences were found in the a-wave amplitudes between lamotrigine-treated and vehicle-treated rats. B-wave amplitudes decreased by 40–66% in both treatment groups 6 days post IOP elevation, with no significant difference between groups (p = 0.38). However, a partial recovery of b-wave amplitudes was found in lamotrigine-treated rats between day 6 and day 14 post procedure (p < 0.05). No differences were found in any other parameter tested in this model. Similarly, lamotrigine treatment did not result in any beneficial effect in structural parameters of the chronic model. Functional evaluation of this model was inconclusive due to super-normal values in the hypertensive eyes. Up-regulation of Nav1.1 and 1.2 expression was found in both models, beginning by day 7; an increase of the former continued in a time-dependent manner in the chronic model. Nav1.6 labeling was inconclusive. In conclusion we found lamotrigine treatment to be mostly ineffective in both acute and chronic ocular hypertension models.
•Neuroprotection with lamotrigine was tested in 2 rat ocular hypertension models.•Minor functional protection was observed in the acute hypertension model.•No structural protection was found in either model.•Changes in Nav channel expression were observed in hypertensive optic nerves.•Lamotrigine was ineffective in an ischemic, as well as degenerative, environment.
In multiple sclerosis, long-term disability is caused by axonal and neuronal damage. Established therapies target primarily the inflammatory component of the disease, but fail to prevent ...neurodegeneration. Fingolimod (codenamed FTY720) is an oral sphingosine 1-phosphate (S1P) receptor modulator with promising results in phase II trials in multiple sclerosis patients and is under further development as a novel treatment for multiple sclerosis. To evaluate whether FTY720 has neuroprotective properties, we tested this drug in a rat model of myelin oligodendrocyte glycoprotein-induced optic neuritis. FTY720 exerted significant anti-inflammatory effects during optic neuritis and reduced inflammation, demyelination, and axonal damage; however, FTY720 treatment did not prevent apoptosis of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. Consistent with this lack of effect on RGC survival, FTY720 treatment did not improve visual function, nor did it prevent apoptosis of RGCs in vitro . We observed a persistent activation of apoptotic signaling pathways in RGCs under FTY720 treatment, a possible underlying mechanism for the lack of neuroprotection in the presence of strong anti-inflammatory effects, Furthermore, FTY720 shifted the remaining inflammation in the optic nerve toward neurotoxicity by modest up-regulation of potential neurotoxic cytokines. We conclude that FTY720-induced anti-inflammation and axon protection did not of itself protect neurons from apoptotic cell death.
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