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G Cavaletti

Publications and source records attributed to G Cavaletti.

At least 37 records · Page 2Linked to original sources
PubMed2000

Distribution of paclitaxel within the nervous system of the rat after repeated intravenous administration.

The distribution of paclitaxel (Taxol) within the central and peripheral nervous system after repeated administration of this antineoplastic agent is still largely unknown. In this study we determined for the first time paclitaxel tissue concentration in the brain, spinal cord, dorsal root ganglia (DRG) and sciatic nerve using an experimental paradigm in the rat which reproduces the features of paclitaxel peripheral neurotoxicity in humans. Pathological confirmation of the onset of paclitaxel-induced peripheral neurotoxicity was performed. In order to achieve reliable results even with low concentrations of paclitaxel, a newly reported analytical method (high-performance liquid chromatography with tandem mass spectrometry) was used. We demonstrated that paclitaxel has easy access to the DRG, where it accumulates, while the lowest concentrations of the drug were measured in the brain. The intermediate concentrations of paclitaxel observed in the sciatic nerve and spinal cord may be due to paclitaxel transport along the centrifugal and centripetal branches of the DRG neuron axons.

Animals↗
PubMed1999

Clinical presentation and outcome of Guillain-Barré and related syndromes in relation to anti-ganglioside antibodies.

We correlated the clinical features of 78 patients with Guillain-Barré syndrome (GBS) or related variants, with the presence of serum antibodies to the gangliosides GM1, GM2, GD1a, GD1b and GQ1b in order to determine whether these antibodies may influence the clinical presentation or outcome of GBS. Sixty-three patients had typical GBS (81%), nine a pure motor form (11%), three a paraparetic form (4%), and three had Miller Fisher syndrome (MFS). IgG or IgM (or both) anti-ganglioside antibodies were found by ELISA in 37% of patients, including 36% with typical, 33% with pure motor and 100% with MFS. Beside the constant occurrence of anti-GQ1b antibodies in patients with MFS (P<0.00001), the other clinical forms were not associated with a specific anti-ganglioside reactivity. Anti-GM1 and anti-GD1a antibodies tended to be associated with a worse disability at 6 month than other or no reactivity and, similarly to anti-GM2 antibodies, with a more frequent respiratory impairment. Anti-GM2 and anti-GD1b antibodies were always associated with typical GBS and, in all but one patient, with a complete recovery; still they were found in only 13 and 3%, respectively, of the patients with this presentation. Anti-GQ1b antibodies, though always associated with ophthalmoplegia and ataxia in both MFS and GBS, were found in only 36 and 26%, respectively, of patients with these symptoms. Even if different anti-ganglioside antibodies tend to be associated with some clinical features possibly suggesting that they may influence the clinical presentation or outcome, with the exception of anti-GQ1b antibodies for ophthalmoplegia and ataxia, they do not permit to predict the clinical presentation or outcome in individual patients.

Adolescent↗
PubMed1999

Effect of recombinant human nerve growth factor on cisplatin neurotoxicity in rats.

In this study we evaluated the effect of recombinant human nerve growth factor (rhNGF) on cisplatin (CDDP)-induced sensory neuronopathy in an experimental paradigm in the rat. Young adult female Wistar rats were treated with CDDP (2 mg/kg ip twice weekly for nine times) alone or in combination with rhNGF (1 mg/kg sc on alternate days). The effect of CDDP +/- NGF treatment was evaluated with behavioral (tail-flick test) and neurophysiological (nerve conduction velocity in the tail) methods immediately after treatment and after a follow-up period of 6 weeks. Pathological and morphometrical examinations of the dorsal root ganglia (DRG) and sciatic and saphenous nerves were also performed. rhNGF treatment induced a significant reduction in the CDDP-induced decrease in nerve conduction velocity (P < 0.05), and this was associated with a significant protection against the decrease in somatic (P < 0.05), nuclear (P < 0.05), and nucleolar size (P < 0.01) caused by CDDP treatment. However, for each of the parameters examined the neuroprotection obtained with rhNGF treatment was not complete. At the follow-up examination no differences between the three groups were observed in tail-flick test and nerve conduction velocity. We conclude that rhNGF, administered according to the schedule used in this experiment, exerts a biologically significant neuroprotective effect against CDDP peripheral neurotoxicity.

Animals↗
PubMed1999

Chronic axonal sensory and autonomic polyneuropathy without motor involvement: a new 'chronic inflammatory neuropathy?'.

We report the case of a woman with axonal sensory and autonomic neuropathy lasting several months who improved in association with steroid administration. During the course of her disease and in the follow-up, the patient underwent repeated cerebrospinal fluid (CSF) examinations, neurophysiological somatic, autonomic nervous system studies and sural nerve biopsy. Clinical and laboratory assessments demonstrated the occurrence of a monophasic, chronic sensory and autonomic neuropathy. A sural nerve biopsy suggested an axonopathy. After a progressive worsening of symptoms lasting about 6 months, steroid treatment was started and within 6 months a complete recovery, with normalization of the CSF findings, was observed. Although the 'chronic inflammatory neuropathies' are still debated entities, the features of this chronic, exclusively sensory and autonomic neuropathy are new, and the occurrence of a high protein level in the CSF, together with the favorable outcome associated with steroid treatment, suggests that our case might be another variant in this debated area.

Autonomic Nervous System Diseases↗
PubMed1999

Resveratrol, map kinases and neuronal cells: might wine be a neuroprotectant?

Alcohol is noxious to the brain and peripheral nervous system. However, wine contains substances that may have positive biological and pharmacological effects. Resveratrol is the most studied and probably the most active of these substances. This naturally occurring compound, which is present in wine and grapes, reduces oxidative stress in neuronal-like cell cultures. We have shown that resveratrol induces phosphorylation of the mitogen-activated protein (MAP) kinase family members, extracellular regulated kinase 1 (ERK1) and ERK2, in the human neuroblastoma SH-SY5Y cells in vitro at much lower concentrations than those found in the plasma of rats after oral wine administration. MAP kinases are involved in numerous different aspects of signal transduction in the cells. In particular, phosphorylation of ERK2 has been related to the synaptic changes at the basis of memory and learning processes. These findings, together with our own, on resveratrol-induced activation of MAP kinases in human neuronal-like cells, and previously published epidemiological studies which have demonstrated an inverse relationship between moderate wine intake and dementia, suggest that wine (not alcohol) may have a positive effect on nervous cells.

Animals↗
PubMed1999

Cisplatin-induced DNA-platination in experimental dorsal root ganglia neuronopathy.

The mechanism(s) and site(s) of the neurotoxic effect of cisplatin (CDDP) are still not entirely elucidated. A more detailed knowledge of these aspects of CDDP treatment might be useful to obtain a better understanding of the pathogenesis of its peripheral neurotoxicity, which is the dose-limiting side effect of CDDP. In the present study, the occurrence of CDDP-induced DNA-platination in dorsal root ganglia (DRG) of rats was evaluated in relation to DRG neuron pathological changes and CDDP-induced neuronopathy. Eight adult Wistar rats were treated with 2 mg/kg i.p. CDDP twice weekly for 9 times to induce sensory peripheral neuropathy. DNA-platination in specimens of DRG and kidney was measured immunohistochemically, with a polyclonal antibody (GPt) detecting CDDP-induced Pt-DNA adducts. Results were compared with those of untreated rats. Chronic CDDP-induced neurotoxicity, in a well described experimental model of chronic CDDP neurotoxicity in the Wistar rat, was confirmed by sensory DRG neuronopathy with secondary neuropathy, and demonstrated by reduced pain detection, decreased nerve conduction velocity in the tail nerve as well as morphological and morphometric changes in DRG neurons. Nuclear immunostaining for Pt-DNA adducts was observed in tubular cells of the kidney in 75% of the evaluated CDDP-treated rats, while in DRG cells CDDP-induced Pt-DNA adducts formation was found in 43% of the evaluated CDDP-treated rats. CDDP-induced DNA-platination was demonstrated in rat DRG neurons using a schedule of chronic CDDP administration which induced the onset of a sensory neuronopathy with secondary peripheral neuropathy. This finding further supports the hypothesis that CDDP is neurotoxic because it directly damages the DRG neurons.

Animals↗
PubMed1998

Polyneuropathy due to cobalamin deficiency in the rat.

In the present study, we investigated the peripheral nervous system (PNS) (both in terms of its ultrastructure and in terms of its function) of rats made cobalamin (Cbl)-deficient either through total gastrectomy or through prolonged feeding on a Cbl-deficient diet. In both these types of Cbl-deficient neuropathies we found: (a) ultrastructurally, intramyelin and endoneural edema, with no or minimal axonal damage in the PNS, in dorsal root ganglia, and the ventral and dorsal rootlets of the spinal cord; (b) electrophysiologically, a significant reduction in the nerve conduction velocity, consistent with that reported in (a); (c) morphometrically, a significant reduction in the density of myelinated fibers both in the sciatic nerve and in the peroneal nerve. All these pathological changes were reversed by chronic postoperative administration of Cbl into totally gastrectomized (TGX)-rats, hinting at the specificity of the damage itself in relation to the permanent Cbl-deficient status of the TGX-rats. No signs of segmental demyelination or remyelination were found. We also observed a turning of type I fibers into type II fibers in the soleus muscle of all our Cbl-deficient rats, however the Cbl deficiency had been induced. This muscular change was still present in TGX- and Cbl-treated rats, and it cannot be related to a malnutrition status, since it has been observed also in rats fed a Cbl-deficient diet. All these results demonstrate that Cbl deficiency strongly affects rat PNS within different parameters.

Animals↗
PubMed1998

Experimental cisplatin neuronopathy in rats and the effect of retinoic acid administration.

Peripheral nervous system alterations were induced in adult rats by administration of cisplatin (CDDP) 2 mg/kg twice weekly for 4.5 weeks. Dorsal root ganglion neurons showed pathological changes. Morphometric determinations demonstrated a reduction in size of the somatic, nuclear and nucleolar area. The nucleoli were the most involved subcellular structures. Nerve conduction velocity and the tail-flick test for pain were both significantly altered in CDDP treated rats, whereas the rota-rod test for coordination revealed no changes in either treated or control rats. Analytical determinations demonstrated platinum accumulation in the DRG of CDDP treated rats. Spontaneous recovery, demonstrated by morphometric, electrophysiological, functional and analytical determinations, occurred after treatment discontinuation within about 7 weeks. A pilot study of the possible neuroprotective action of retinoic acid (RA) was also performed with this model of cisplatin neuronopathy. The rationale for using RA was based on its assumed antioxidant and neurotrophic effect. However, RA failed to prevent morphometric, electrophysiological, functional and analytical alterations induced by CDDP on DRG neurons. RA induced only a mild generalized protective effect.

Animals↗
PubMed1998

Carboplatin toxic effects on the peripheral nervous system of the rat.

BACKGROUND: The most striking of carboplatin's advantages (CBDCA) over cisplatin (CDDP) is its markedly reduced rate of neurotoxic effects. However, the use of CBDCA higher-intensity schedules and the association with other neurotoxic drugs in polychemotherapy may cause some concern about its safety with respect to peripheral nervous system damage. MATERIALS AND METHODS: Two different schedules of CBDCA administration (10 mg/kg and 15 mg/kg i.p. twice a week for nine times) were evaluated in Wistar rats. Neurotoxicity was assessed for behavioral (tail-flick test), neurophysiological (nerve conduction velocity in the tail nerve), morphological, morphometrical and analytical effects. RESULTS: CBDCA administration induced dose-dependent peripheral neurotoxicity. Pain perception and nerve conduction velocity in the tail were significantly impaired, particularly after the high-dose treatment. The dorsal root ganglia sensory neurons and, to a lesser extent, satellite cells showed the same changes as those induced by CDDP, mainly affecting the nucleus and nucleolus of ganglionic sensory neurons. Moreover, significant amounts of platinum were detected in the dorsal root ganglia and kidney after CBDCA treatment. CONCLUSIONS: CBDCA is neurotoxic in our model, and the type of pathological changes it induces are so closely similar to those caused by CDDP that it is probable that neurotoxicity is induced in the two drugs by the same mechanism. This model can be used alone or in combination with other drugs to explore the effect of CBDCA on the peripheral nervous system.

Animals↗
PubMed1998

Subacute combined degeneration in totally gastrectomized rats: an ultrastructural study.

Severe permanent cobalamin (Cbl) deficiency was induced in rats either by total gastrectomy (TG) or through prolonged dietary Cbl deprivation. This paper deals with an ultrastructural investigation of different parts of the central nervous system (CNS) of rats made Cbl-deficient through one of these of two procedures. In both totally gastrectomized (TGX) rats and in rats chronically fed a Cbl-deficient diet, we observed intramyelin edema, with splitting of the lamellae, and interstitial edema affecting the white matter, mainly in the spinal cord (SC). These lesions were also present in the subcortical white matter, although to a lesser degree. In both TGX-rats and in rats chronically fed a Cbl-deficient diet the pyramidal tract and the optic nerve were completely spared. Vascular lesions were never observed. Intramyelin edema and interstitial edema of the white matter account for the patchy myelopathic spongy vacuolation, which is the histological hallmark of human subacute combined degeneration and has been previously seen in SC white matter of TGX-rats. Macro- and micro-glial cells in the white matter were activated, at least as seen ultrastructurally. Interestingly enough, there were activated glial cells even in the gray matter, in which neurons showed absolutely no alterations. Chronic subcutaneous Cbl administration of TGX-rats partially repaired the CNS damage. However, the amelioration produced by this treatment was greater when Cbl was given shortly after TG than when given three and four months after TG, i.e. when the lesions have already been formed.

Animals↗
PubMed1997

Antibodies of the anti-Yo and anti-Ri type in the absence of paraneoplastic neurological syndromes: a long-term survey of ovarian cancer patients.

In recent years several authors have described a close correlation between circulating antineuronal antibodies of different types and the occurrence of paraneoplastic neurological syndromes. Because this has not been widely accepted, we screened 300 serum samples from 181 ovarian cancer patients for the presence of circulating antineuronal antibodies by immunofluorescence. The findings were confirmed by immunoblotting. In 11 patients circulating antineuronal antibodies were detected. In 4 patients they were classified as anti-Yo and in 7 as anti-Ri, titres ranging from 1:400 to 1: 204,800. All the patients underwent thorough neurological and neurophysiological investigations, with special regard to paraneoplastic syndrome. None of them had symptoms pointing to a paraneoplastic neurological syndrome, although patients were followed up to 2 years after the first examination. Thus the frequency of circulating antineuronal antibodies in ovarian cancer patients is higher than the frequency of paraneoplastic syndromes, and antibody positivity does not necessarily lead to the appearance of a neurological paraneoplastic syndrome.

Autoantibodies↗
PubMed1997

Neurotoxicity and ototoxicity of cisplatin plus paclitaxel in comparison to cisplatin plus cyclophosphamide in patients with epithelial ovarian cancer.

PURPOSE: To compare the neurotoxicity and ototoxicity of combination cisplatin plus paclitaxel versus cisplatin plus cyclophosphamide using extensive clinical and instrumental evaluation. PATIENTS AND METHODS: Forty-six of 51 consecutive patients affected by-epithelial ovarian cancer seen in our institution between October 1994 and August 1995 entered the study. After randomization, they were assigned to receive cisplatin 75 mg/m2 every 3 weeks associated with cyclophosphamide 750 mg/m2 (CC group, n = 22) or paclitaxel 175 mg/m2 over a 3-hour infusion (CP group, n = 24). Treatment was repeated six times in 43 patients and nine times in 25. Before treatment and after three, six, and nine courses of chemotherapy, patients underwent clinical and instrumental neurologic and otologic examinations. RESULTS: Mild sensory impairment was evident even after only three courses of both treatments and signs and symptoms were more severe at the end of treatment. On clinical grounds only, it was possible to demonstrate after six and nine courses a difference between CC and CP treatment, due to the involvement in some CP patients of pain and thermal sensory modalities. However, the overall severity of the neuropathy was similar. Audiometric parameters demonstrated a more negative outcome after treatment in CC compared with CP patients. However, the different severity of the involvement was closely correlated to this initial difference in audiologic performance. CONCLUSION: Up to nine courses of chemotherapy, the CC and CP schedules are similar in terms of severity of neurotoxicity and ototoxicity when patients are evaluated during and immediately after treatment. With the doses used in our study, these toxicities are not dose-limiting. Our results suggest that most of the toxic effects observed during the treatment were due to cisplatin.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Effect on the peripheral nervous system of the short-term intravenous administration of paclitaxel in the rat.

The effectiveness of paclitaxel (Taxol) in the treatment of different tumors is well-known but, on the other hand, there is little information regarding its neurotoxicity and the mechanism(s) underlying this potentially severe side effect. In this study, using behavioral, neurophysiological, morphological and morphometric methods, we evaluated the effect of intravenous administration of paclitaxel on the rat nervous system. After 2 pilot studies, 40 female Wistar rats were treated with intravenous paclitaxel via a catheter placed in the jugular vein, while 20 animals were used as controls. Paclitaxel dissolved in ethanol/Tween 80/saline (5/5/90%) was administered 5 times over a period of 10 days. At the end of the experiment half the surviving animals in each group were evaluated and sacrificed (day 11), while the rest of the rats were evaluated and sacrificed on day 25. On day 11 the treated animals had significant impairment in pain perception (tail-flick test), coordination (rota-rod test) and nerve conduction velocity in the tail nerve. At the light microscope minimal axonal damage and Schwann cell activation were observed in the sciatic nerve. At the electron microscope microtubular accumulation was present within the axon in dorsal and ventral spinal roots and in the sciatic nerve. On day 25 the behavioral tests were normal in treated rats, while the nerve conduction velocity was still moderately reduced in comparison with the controls. At the electron microscope a morphological examination evidenced that microtubular accumulation was less severe, but still evident, especially in the sciatic nerve. Morphometric determinations performed on days 11 and 25 did not evidence differences between paclitaxel-treated rats and controls. The results of this study, the first in which an extended examination of the nervous system of animals treated intravenously with paclitaxel has been carried out, suggest that short-term administration of the drug induces mainly reversible changes in the peripheral nerves and spinal roots. Microtubules seem to be the main target of paclitaxel neurotoxicity, in much the same way as has been described for its antineoplastic activity. Finally, no pathological changes were seen in the neuronal bodies of the spinal cord and dorsal root ganglia. This model may be used for further studies with combination treatments with other antineoplastic or neuroprotective agents.

Animals↗
PubMed1996

Neuropeptides and morphological changes in cisplatin-induced dorsal root ganglion neuronopathy.

Dorsal root ganglia (DRG) neuronopathy was induced in rats by chronic treatment (2 mg/kg twice a week for nine injections) with the antineoplastic drug cisplatin. Morphological alterations and changes in peptide [calcitonin gene-related peptide (CGRP), substance P, galanin (Gal), and somatostatin] concentration were studied in the DRG, the spinal cord, and the sciatic nerve. Peptide concentration was increased in DRG neurons, with CGRP and Gal showing the highest increase. Conversely, in the sciatic nerve there was a general decrease in peptide content. In DRG a reduction in the nuclear, cytoplasmic, and nucleolar areas of primary sensory neurons was evident and was accompanied by clear-cut aspects of nucleolar structural damage. In peripheral nerves only extensive morphometric determinations could evidence a reduction in nerve conduction velocities and impairment in pain detection and coordination. Some of the nerve fibers presented axonal and adaxonal accumulations, suggesting the presence of an axonopathy. These results confirm that DRG cells are the primary target of cisplatin-induced neurotoxicity. Milder alterations can be detected in peripheral nerves. The increase in peptide concentration in DRG is probably due to cisplatin-related damage to the axonal transport system rather than to an increased synthesis.

Animals↗
PubMed1996

Anatomical organization of the spinal paths to the soleus and gastrocnemius muscles of the rat hind limb.

The anatomical organization of the motoneuronal columns of the soleus and lateral gastrocnemius muscle and of the related premotor interneurons was studied in rats, using the retrograde transneuronal transport of WGA-HRP. Motoneurons of the gastrocnemius muscle have a well-developed dendritic arborization which spreads into the transverse plane of the spinal cord extending to the intermediate region of the grey matter, while dendrites of the soleus muscle motoneurons spread mainly in the rosto-caudal plane, where they remain inside the border of the motoneuronal column and form small dendritic bundles, suggesting a coupling of neuronal activity as is to be expected in the motoneurons of a tonically active postural muscle such as the soleus. Gastrocnemial premotor interneurons are located close to the motoneuronal column, while the soleus premotor interneurons are scattered all over the ventral horn and intermediate grey. The number of labelled premotor interneurons is greater when the WGA-HRP is injected into the soleus muscle. In both cases, the premotor interneurons could be classified as four different types on the basis of the shape and size of the neuronal somata. The differences in the anatomical organization of the spinal paths to the gastrocnemius and soleus muscles reflect the different tasks performed by these two synergic muscles in normal motor behaviour: fast phasic activity by the gastrocnemius muscle, slow tonic anti-gravity activity by the soleus muscle.

Animals↗
PubMed1995

Peripheral neurotoxicity of taxol in patients previously treated with cisplatin.

BACKGROUND: Taxol is a new anticancer drug that acts as a tubulin polymeration enhancer. Its major toxicities are myelosuppression, hypersensitivity, and mucositis, but it also induces peripheral nerve damage. The use of taxol has recently been proposed for platinum-resistant cancers, but in these cases there is a possibility of cumulative toxicity in the peripheral nervous system. METHODS: Twenty-two patients affected by a relapse of cisplatin-treated ovarian cancer were examined clinically and neurophysiologically to determine the evolution of taxol-induced peripheral somatic and autonomic neurotoxicity and the possible cumulative effect of a combination of taxol and cisplatin. Each patient was examined before, during, and after taxol treatment (using a dose of 135 or 175 mg/m2 in 3 hours every 3 weeks). RESULTS: No patients were excluded from the study because of unacceptable toxicities of any kind. The serial examinations demonstrated that taxol induced onset of (or worsening of preexisting) neuropathic symptoms and signs in almost all the patients. The features were those of a distal, symmetrical, sensory polyneuropathy due to an axonopathy. Motor nerves and the autonomic nervous system were unaffected. Taxol neurotoxicity appeared early in the course of the treatment (i.e., after three courses) and was not severely disabling. In most cases after the early onset of peripheral neuropathy, stabilization of this side effect occurred. CONCLUSIONS: Considering the low doses of taxol used in this study, the sensory nerve damage was unexpectedly severe. It appears that a cumulative, but not dose-limiting, neurotoxic effect occurs using taxol in patients previously treated with cisplatin.

Adult↗