Myelin structure is unaltered in chemotherapy-induced peripheral neuropathy

Purpose

Alterations in mRNA for myelin proteins are reported in animal models of chemotherapy-induced peripheral neuropathies (CIPN); however, ultrastructural changes in aldehyde-fixed and plastic-embedded myelin are not evident by electron microscopy. Therefore, we used X-ray diffraction (XRD) to investigate more subtle changes in myelin sheath structure from unfixed nerves.

Experimental design

We used in vivo chronic animal models of CIPN in female Wistar rats, administering cisplatin (CDDP 2 mg/kg, i.p. twice/week), paclitaxel (PT 10 mg/kg, i.v. once/week) or bortezomib (0.20 mg/kg, i.v. three times/week) over a total period of 4 weeks. Animal weights were monitored, and tail nerve conduction velocity (NCV) was determined at the end of the treatments to assess the occurrence of peripheral neuropathy. Sciatic nerves were collected and the myelin structure was analyzed using electron microscopy (EM) and XRD.

Results

All the rats treated with the chemotherapy agents developed peripheral neuropathy, as indicated by a decrease in NCV values; however, light and electron microscopy indicated no severe pathological alterations of the myelin morphology. XRD also did not demonstrate significant differences between sciatic nerves in treated vs. control rats with respect to myelin period, relative amount of myelin, membrane structure, and regularity of membrane packing.

Conclusions

These results indicate that experimental peripheral neuropathy caused by CDDP, PT, and bortezomib—which are among the most widely used chemotherapy agents—does not significantly affect the structure of internodal myelin in peripheral nerve.     

Linguistic abilities in major vascular cognitive impairment: a comparative study with Alzheimer’s disease

We assessed the linguistic abilities of multi-infarct (cortical) dementia and subcortical ischemic vascular dementia (VaD) patients and compared the linguistic performance of VaD and Alzheimer’s Disease (AD) patients. A total of 23 VaD patients, 20 mild AD patients, and 31 controls participated in the study. All were evaluated using the Arizona Battery for Communication Disorders of Dementia (ABCD). Neuropsychological testing was performed to ascertain that VaD and AD patients had comparable cognitive performance. Both dementia groups performed more poorly than controls in the ABCD measures, except for the comparative question subtest. Comparison between VaD and AD patients showed statistically significant differences only in the confrontation naming subtest (p?<?0.05), where paraphasias and visual errors were the most prevalent. AD patients showed a trend towards more circumlocution errors than VaD patients (p?=?0.0483). When compared to controls, linguistic abilities of VaD patients were impaired in all measures of linguistic expression and linguistic comprehension, except for the comparative question subtest. Linguistic differences between VaD and AD patients were observed only in the confrontation naming subtest.     

Valeriana officinalis does not alter the orofacial dyskinesia induced by haloperidol in rats: role of dopamine transporter

Chronic treatment with classical neuroleptics in humans can produce a serious side effect, known as tardive dyskinesia (TD). Here, we examined the effects of V. officinalis, a medicinal herb widely used as calming and sleep-promoting, in an animal model of orofacial dyskinesia (OD) induced by long-term treatment with haloperidol. Adult male rats were treated during 12 weeks with haloperidol decanoate (38 mg/kg, i.m., each 28 days) and with V. officinalis (in the drinking water). Vacuous chewing movements (VCMs), locomotor activity and plus maze performance were evaluated. Haloperidol treatment produced VCM in 40% of the treated rats and the concomitant treatment with V. officinalis did not alter either prevalence or intensity of VCMs. The treatment with V. officinalis increased the percentage of the time spent on open arm and the number of entries into open arm in the plus maze test. Furthermore, the treatment with haloperidol and/or V. officinalis decreased the locomotor activity in the open field test. We did not find any difference among the groups when oxidative stress parameters were evaluated. Haloperidol treatment significantly decreased [(3)H]-dopamine uptake in striatal slices and V. officinalis was not able to prevent this effect. Taken together, our data suggest a mechanism involving the reduction of dopamine transport in the maintenance of chronic VCMs in rats. Furthermore, chronic treatment with V. officinalis seems not produce any oxidative damage to central nervous system (CNS), but it also seems to be devoid of action to prevent VCM, at least in the dose used in this study.     

A placebo-controlled double-blind randomized study of venlafaxine in the treatment of depression in dementia

BACKGROUND/AIMS: To evaluate the efficacy and safety of venlafaxine in the treatment of major depression in dementia. METHODS: Thirty-one outpatients who had dementia and major depression participated in this randomized, double-blind, placebo-controlled, 6-week, flexible dose clinical trial. The screening measures were Cornell Scale for depression in dementia, DSM-IV for depression and dementia and Mini-Mental State Examination. The outcome measures were response rate, Montgomery-Asberg Depression Rating scale and Clinical Global Impressions. RESULTS: The percentage of patients defined as Montgomery-Asberg Depression Rating scale responders was approximately the same in the placebo and in the venlafaxine groups. Clinical Global Impressions showed no significant difference between the groups. The reasons for dropouts show borderline significance between the two groups. There was no statistically significant difference in the incidence of adverse events between the venlafaxine and placebo-treated groups. CONCLUSIONS: Our data do not support the hypothesis that venlafaxine improves mood in elderly demented patients.     

Cholinergic direct inhibition of N‐methyl‐D aspartate receptor‐mediated currents in the rat neocortex

Acetylcholine (ACh) and N‐methyl‐D aspartate receptors (NMDARs) interact in the regulation of multiple important brain functions. NMDAR activation is indirectly modulated by ACh through the activation of muscarinic or nicotinic receptors. Scant information is available on whether ACh directly interacts with the NMDAR. By using a cortical brain slice preparation we found that the application of ACh and of other drugs acting on muscarinic or nicotinic receptors induces an acute and reversible reduction of NMDAR‐mediated currents (I_NMDA), ranging from 20 to 90% of the control amplitude. The reduction displayed similar features in synaptic I_NMDA in brain slices, as well as in currents evoked by NMDA application in brain slices or from acutely dissociated cortical cells, demonstrating its postsynaptic nature. The cholinergic inhibition of I_NMDA displayed an onset–offset rate in the order of a second, and was resistant to the presence of the muscarinic antagonist atropine (10 μM) in the extracellular solution, and of G‐protein blocker GDP_βS (500 μM) and activator GTP_γS (400 μM) in the intracellular solution, indicating that it was not G‐protein dependent. Recording at depolarized or hyperpolarized holding voltages reduced NMDAR‐mediated currents to similar extents, suggesting that the inhibition was voltage‐independent, whereas the reduction was markedly more pronounced in the presence of glycine (20 μM). A detailed analysis of the effects of tubocurarine suggested that at least this drug interfered with glycine‐dependent NMDAR‐activity. We conclude that NMDAR‐mediated current scan be inhibited directly by cholinergic drugs, possibly by direct interaction within one or more subunits of the NMDAR. Our results could supply a new interpretation to previous studies on the role of ACh at the glutamatergic synapse. Synapse 63:308–318, 2009. © 2009 Wiley‐Liss, Inc.     

FTDP-17 mutations in tau transgenic mice provoke lysosomal abnormalities and Tau filaments in forebrain.

The tauopathies, which include Alzheimer's disease (AD) and frontotemporal dementias, are a group of neurodegenerative disorders characterized by filamentous Tau aggregates. That Tau dysfunction can cause neurodegeneration is indicated by pathogenic tau mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). To investigate how Tau alterations provoke neurodegeneration we generated transgenic mice expressing human Tau with four tubulin-binding repeats (increased by FTDP-17 splice donor mutations) and three FTDP-17 missense mutations: G272V, P301L, and R406W. Ultrastructural analysis of mutant Tau-positive neurons revealed a pretangle appearance, with filaments of Tau and increased numbers of lysosomes displaying aberrant morphology similar to those found in AD. Lysosomal alterations were confirmed by activity analysis of the marker acid phosphatase, which was increased in both transgenic mice and transfected neuroblastoma cells. Our results show that Tau modifications can provoke lysosomal aberrations and suggest that this may be a cause of neurodegeneration in tauopathies.     

Chromosome 7 long arm deletion in myeloid disorders: a narrow breakpoint region in 7q22 defined by molecular mapping

The involvement of the erythropoietin (EPO), plasminogen activator inhibitor type I (PAI1), and multi-drug resistance (MDR2) genes located in chromosomal region 7q21-22 was studied in patients with myeloid disorders and with or without a chromosome 7 abnormality. Separated blood mononuclear cells and granulocytes from 21 patients were used in restriction fragment length polymorphism (RFLP) studies with gene- specific DNA probes. A marked weakness of one of the allelic bands was observed in granulocyte-derived DNA from heterozygous patients with monosomy 7. In four patients with a partial deletion of chromosome 7 long arm (7q-), marked weakness of an allelic band was observed in granulocyte-derived DNA with PAI1 probe (four heterozygous patients) and MDR2 probe (one heterozygous patient), implying deletion of these genes. In contrast, the EPO gene was not deleted in these patients, as demonstrated by the presence of two allelic bands of equal strength in granulocyte-derived DNA (two patients) or by gene dosage estimation (two patients). Two allelic bands of equal strength were also observed in three heterozygous patients with an arbitrary probe (pKV13) located in 7cen-q21.3. Unexpected hemizygosity or hybridization bands were not observed in any patient. We conclude that PAI1 and MDR2 are located distally of EPO in 7q22, and that none of these genes is commonly rearranged in myeloid disorders. The chromosome 7 long arm deletion breakpoint is located in a relatively narrow segment between the PAI1 and EPO genes in different patients. The deletion may involve a specific site in DNA, since the genetic distance between the PAI1 and EPO genes is only 3 cM.