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Guido Cavaletti

Publications and source records attributed to Guido Cavaletti.

16 recordsLinked to original sources
PubMed2007

Bortezomib-induced peripheral neurotoxicity: a neurophysiological and pathological study in the rat.

Bortezomib is a new proteasome inhibitor with a high antitumor activity, but also with a potentially severe peripheral neurotoxicity. To establish a preclinical model and to characterize the changes induced on the peripheral nerves, dorsal root ganglia (DRG) and spinal cord, bortezomib was administered to Wistar rats (0.08, 0.15, 0.20, 0.30 mg/kg/day twice [2q7d] or three times [3q7d] weekly for a total of 4 weeks). At baseline, on days 14, 21 and 28 after the beginning the treatment period and during a 4-week follow-up period sensory nerve conduction velocity (SNCV) was determined in the tail of each animal. Sciatic nerve, DRG and spinal cord specimens were processed for light and electron microscope observations and morphometry. At the maximum tolerated dose bortezomib induced a significant reduction in SNCV, with a complete recovery at the end of the follow-up period. Sciatic nerve examination and morphometric determinations demonstrated mild to moderate pathological changes, involving predominantly the Schwann cells and myelin, although axonal degeneration was also observed. Bortezomib-induced changes were also observed in DRG and they were represented by satellite cell intracytoplasmatic vacuolization due to mitochondrial and endoplasmic reticulum damage, closely resembling the changes observed in sciatic nerve Schwann cells. Only rarely did the cytoplasm of DRG neurons has a dark appearance and clear vacuoles occurring in the cytoplasm. Spinal cord was morphologically normal. This model is relevant to the neuropathy induced by bortezomib in the treatment of human malignancies and it could be useful in increasing our knowledge regarding the mechanisms underlying bortezomib neurotoxicity.

Animals↗
PubMed2006

Protective effect of erythropoietin and its carbamylated derivative in experimental Cisplatin peripheral neurotoxicity.

PURPOSE: Antineoplastic drugs, such as cisplatin (CDDP), are severely neurotoxic, causing disabling peripheral neuropathies with clinical signs known as chemotherapy-induced peripheral neurotoxicity. Cotreatment with neuroprotective agents and CDDP has been proposed for preventing or reversing the neuropathy. Erythropoietin given systemically has a wide range of neuroprotective actions in animal models of central and peripheral nervous system damage. However, the erythropoietic action is a potential cause of side effects if erythropoietin is used for neuroprotection. We have successfully identified derivatives of erythropoietin, including carbamylated erythropoietin, which do not raise the hematocrit but retain the neuroprotective action exerted by erythropoietin. EXPERIMENTAL DESIGN: We have developed previously an experimental chemotherapy-induced peripheral neurotoxicity that closely resembles CDDP neurotoxicity in humans. The present study compared the effects of erythropoietin and carbamylated erythropoietin (50 microg/kg/d thrice weekly) on CDDP (2 mg/kg/d i.p. twice weekly for 4 weeks) neurotoxicity in vivo. RESULTS: CDDP given to Wistar rats significantly lowered their growth rate (P < 0.05), with slower sensory nerve conduction velocity (P < 0.001) and reduced intraepidermal nerve fibers density (P < 0.001 versus controls). Coadministration of CDDP and erythropoietin or carbamylated erythropoietin partially but significantly prevented the sensory nerve conduction velocity reduction. Both molecules preserved intraepidermal nerve fiber density, thus confirming their neuroprotective effect at the pathologic level. The protective effects were not associated with any difference in platinum concentration in dorsal root ganglia, sciatic nerve, or kidney specimens. CONCLUSIONS: These results widen the spectrum of possible use of erythropoietin and carbamylated erythropoietin as neuroprotectant drugs, strongly supporting their effectiveness.

Animals↗
PubMed2006

Multi-center assessment of the Total Neuropathy Score for chemotherapy-induced peripheral neurotoxicity.

The aim of this multi-center study was to assess with reduced versions of the Total Neuropathy Score (TNS), the severity of chemotherapy-induced peripheral neurotoxicity (CIPN), and to compare the results with those obtained with common toxicity scales. An unselected population of 428 cancer patients was evaluated at 11 different centers using a composite (clinical + neurophysiological, TNSr) or clinical (TNSc) examination and with the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) 2.0 and Eastern Cooperative Oncology Group (ECOG) scores. A highly significant correlation was demonstrated between the TNSr and the NCI-CTC 2.0 and ECOG scores; but the TNSr evaluation was more accurate in view of the more extended score range. Also, the simpler and faster TNSc (based only on the clinical neurological examination) allowed to grade accurately CIPN and correlated with the common toxicity scores. The correlation tended to be closer when the sensory items were considered, but also the TNSr motor items, which were not specifically investigated in any other previous study, significantly correlated with the results of the common toxicity scales. In conclusion, this study suggests that the TNSr is a reliable tool for accurately grading and reporting CIPN, with the additional and so far unique support of a formal comparison with known and widely used common toxicity scales. The TNSc is a valid alternative if neurophysiological examination is not feasible. The longer time needed to calculate the TNSr and TNSc in comparison to the ECOG or the NCI-CTC 2.0 scales is offset by the more detailed knowledge of the CIPN characteristics.

Adolescent↗
PubMed2006

Current status and future prospective of immunointervention in multiple sclerosis.

Multiple sclerosis (MS) is a complex neurological disorder characterized by inflammation and degeneration of the central nervous system, primarily involving the white matter. On the basis of a wide body of evidence in experimental models and in affected patients, several attempts to treat MS using drugs which modulate immune reactions have been performed or are currently ongoing. However, it should be stressed that inflammation does not have only a detrimental effect in MS. In fact, parts of the inflammatory events are crucial for the control and conclusion of the acute phase of damage and it is probable that they actually favor regeneration and recovery. Due to the above, several trials with immunosuppressant drugs failed or were suspended because of unexpected worsening of the course of MS. The knowledge of MS immunopathogenesis is so rapidly evolving that any attempt to review it is in some way frustrating. On the other hand, this evolution is at the basis of the several new treatment options which can be hypothesized for this disease. The current status of immunosuppression in MS and the possible future development of MS treatment will be reviewed, with particular reference to those treatments which have already been tested in clinical trials and which are based on sound evidence of a putative interference with specific events occurring in MS, with the sparing of general immunity.

Azathioprine↗
PubMed2005

Effects of pixantrone on immune-cell function in the course of acute rat experimental allergic encephalomyelitis.

Pixantrone is an immunesuppressor similar to mitoxantrone but with lower cardiotoxicity. We evaluated the effect of pixantrone on B cells and lymphomononuclear cells in the course of acute EAE. Pixantrone reduced the number of B cells and suppressed myelin basic protein (MBP) specific IgG production. In vitro, pixantrone induced apoptosis of rat B lymphocytes in a way similar to mitoxantrone. In addition, pixantrone inhibited antigen specific and mitogen induced lymphomononuclear cell proliferation, as well as IFN-gamma production, during EAE. These findings suggest a similar mechanism of action for pixantrone and mitoxantrone on the effector function of lymphomonocyte B and T cells.

Analysis of Variance↗
PubMed2005

Morphological and morphometric analysis of paclitaxel and docetaxel-induced peripheral neuropathy in rats.

The experimentally induced neurotoxic effects of paclitaxel and docetaxel have never been compared, since no animal models of docetaxel peripheral neurotoxicity have yet been reported. In this experiment, we examined the effect of the chronic administration of these two taxanes in the Wistar rat using neurophysiological, neuropathological and morphometrical methods. Our results showed that both paclitaxel and docetaxel induced a significant, equally severe and dose-dependent reduction in nerve conduction velocity. On the contrary, the morphometric examination demonstrated that the effect on the nerve fibres was more severe after paclitaxel administration when the same schedule was used. However, the overall severity of the pathological changes was milder than expected on the basis of the neurophysiological results. Our results support the hypothesis that taxanes (and particularly docetaxel) may exert their neurotoxic effect not only on the microtubular system of the peripheral nerves, but also on other less obvious targets.

Analysis of Variance↗
PubMed2005

Intraepidermal nerve fiber density in rat foot pad: neuropathologic-neurophysiologic correlation.

Quantification of cutaneous innervation in rat footpad is a useful tool to investigate sensory small-diameter nerve fibers, which are affected early in peripheral neuropathies. The aim of this work was to provide normative reference data on the density of intraepidermal nerve fibers (IENFs) and Langerhans cells in the hindpaw footpad of Sprague-Dawley and Wistar rats. We also evaluated the sensibility of IENF density by comparing neuropathologic findings with neurophysiologic examination and the presence of peripheral neuropathy in two well-characterized animal models of neuropathy. IENF density was quantified in 22 Sprague-Dawley rats and 13 Wistar rats and compared with 19 age-matched Sprague-Dawley rats with streptozotocin-induced diabetic neuropathy and 30 age-matched Wistar rats with cisplatin- or paclitaxel-induced neuropathy. Antidromic tail sensory nerve conduction velocity (SNCV) was assessed in all animals. IENF and Langerhans cell densities were constant in healthy Sprague-Dawley rats at any age, and they were similar to those observed in healthy Wistar rats. In neuropathic rats, both SNCV and IENF density were significantly reduced with respect to controls. Quantification of IENF density was significantly correlated with changes in conduction velocity. Diabetic neuropathy rats alone showed a significantly higher density of Langerhans cells compared with controls. Our study demonstrated that IENF density quantification correlates with SNCV changes and suggests that this might represent a useful outcome measurement in experimental neuropathies.

Animals↗
PubMed2005

Low-dose cisplatin protects human neuroblastoma SH-SY5Y cells from paclitaxel-induced apoptosis.

Combined anticancer therapy using platinum compounds and antitubulins has increased the risk of neurotoxicity. However, the combination of low-dose cisplatin (CDDP) with toxic doses of paclitaxel significantly reduces cellular death in a human neuroblastoma SH-SY5Y cell line. To analyze the mechanisms of this protection, we evaluated various signaling molecules possibly involved in apoptosis and some relevant cell cycle regulatory proteins. CDDP does not interfere with the tubulin-stabilizing action of paclitaxel. The evaluation of molecular pathways involved in apoptosis indicates that the Bcl-2 but not the caspases may be involved in the CDDP protection of paclitaxel-induced apoptosis. The increase in p53 protein and its nuclear accumulation suggests a possible involvement of p53 in CDDP protection. The use of the chemical inhibitor of p53, pifithrin alpha, excluded this possibility. The study of cyclins and the flow cytometric analysis (fluorescence-activated cell sorting) suggest that CDDP exerts a protective action by blocking cells early in the cell cycle. The determination of the mitotic index indicates that CDDP prevents cells from reaching the mitosis. We concluded that low doses of CDDP are protective against toxic doses of paclitaxel and that the possible mechanism of this protection is that the CDDP prevents human neuroblastoma SH-SY5Y cells from achieving mitosis.

Antineoplastic Agents↗
PubMed2004

Erythropoietin both protects from and reverses experimental diabetic neuropathy.

Erythropoietin (EPO) possesses generalized neuroprotective and neurotrophic actions. We tested the efficacy of recombinant human EPO (rhEPO) in preventing and reversing nerve dysfunction in streptozotocin (STZ)-induced diabetes in rats. Two days after STZ [60 mg/kg of body weight (b.w.), i.p.], diabetic animals were administered rhEPO (40 microg/kg of b.w.) three times weekly for 5 weeks either immediately (preventive) before or after a 5-week delay (therapeutic) after induction of hyperglycemia or at a lower dose (8 microg/kg of b.w. once per week) for 8 weeks (prolonged). Tail-nerve conduction velocities (NCV) was assessed at 5 and 11 weeks for the preventive and therapeutic schedule, respectively. Compared to nondiabetic rats, NCV was 20% lower after 5 weeks in the STZ group, and this decrease was attenuated 50% by rhEPO. Furthermore, the reduction of Na(+),K(+)-ATPase activity of diabetic nerves (by 55%) was limited to 24% in the rhEPO-treated group. In the therapeutic schedule, NCV was reduced by 50% after 11 weeks but by only 23% in the rhEPO-treated group. rhEPO treatment attenuated the decrease in compound muscle action potential in diabetic rats. In addition, rhEPO treatment was associated with a preservation of footpad cutaneous innervation, as assessed by protein gene product 9.5 immunostaining. Diabetic rats developed alterations in mechanical and thermal nociception, which were partially reversed by rhEPO given either in a preventative or therapeutic manner. These observations suggest that administration of rhEPO or its analogues may be useful in the treatment of diabetic neuropathy.

Animals↗
PubMed2004

Glutamate transporters in platelets: EAAT1 decrease in aging and in Alzheimer's disease.

Platelets release glutamate upon activation and are an important clearance system of the amino acid from blood, through high-affinity glutamate uptake, similar to that described in brain synaptosomes. Since platelet glutamate uptake is decreased in neurodegenerative disorders, we performed a morphological and molecular characterization of platelet glutamate transporters. The three major brain glutamate transporters EAAT1, EAAT2 and EAAT3 are expressed in platelets, with similar molecular weight, although at lower density than brain. A Na(+)-dependent-high-affinity glutamate uptake was competitively inhibited by known inhibitors but not by dihydrokainic acid, suggesting platelet EAAT2 does not play a major role in glutamate uptake at physiological conditions. We observed decreased glutamate uptake V(max), without modification of transporter affinity, in aging, which could be linked to the selective decrease of EAAT1 expression and mRNA. Moreover, in AD patients we found a further EAAT1 reduction compared to age-matched controls, which could explain the decrease of platelet uptake previously described. Platelet glutamate transporters may be used as peripheral markers to investigate the role of glutamate in patients with neuropsychiatric disorders.

Aged↗
PubMed2004

An unusual transthyretin gene missense mutation (TTR Phe33Val) linked to familial amyloidotic polyneuropathy.

Familial amyloidotic polyneuropathy is a rare autosomal dominant disease, with clinical symptoms beginning in most kindreds within the third to seventh decades of life. The primary defect results from one of a number of mutations in the transthyretin (TTR) gene. Over 80 mutations in the TTR gene have been described. Most mutations give rise to adult onset progressive peripheral and autonomic neuropathy, due to amyloid deposition within the nerves, and often subclinical cardiac amyloid and vitreous deposits. We report here the clinical and molecular characterization of a rare TTR missense mutation discovered in a young woman from Macedonia, showing severe axonal sensory-motor polyneuropathy, restrictive cardiomyopathy and bilateral vitreous deposits. The transthyretin gene, analyzed by direct nucleotide sequencing, demonstrated a T to G transversion at nucleotide 183 in the exon 2 which is predicted to cause a heterozygous valine for phenylalanine substitution at codon 33 (TTR Phe33Val). This mutation has been previously reported only twice, without complete clinical descriptions.

Adult↗
PubMed2004

Chemotherapy-induced peripheral neurotoxicity.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major clinical problem because it represents the dose-limiting side effects of a significant number of antineoplastic drugs. The incidence of CIPN varies depending on the drugs and schedules used, and this can be quite high, particularly when neurophysiological methods are used to make a diagnosis. However, even when CIPN is not a dose-limiting side effect, its onset may severely affect the quality of life of cancer patients and cause chronic discomfort. In this review the features of CIPN due to the administration of the most widely used drugs, such as platinum drugs, taxanes and vinca alkaloids, and of two old drugs with new clinical applications, suramin and thalidomide, will be discussed. Moreover, the earliest data regarding the neurotoxicity of some new classes of very promising antineoplastic agents, such as epothilones and proteasome inhibitors, will be discussed. Finally, the data available on neuroprotectants, evaluated in the attempt to prevent CIPN, will be summarised.

Animals↗
PubMed2003

Paclitaxel and Cisplatin-induced neurotoxicity: a protective role of acetyl-L-carnitine.

PURPOSE: Antineoplastic drugs belonging to platinum or taxane families are severely neurotoxic, inducing the onset of disabling peripheral neuropathies with different clinical signs. Acetyl-L-carnitine (ALC) is a natural occurring compound with a neuroprotective activity in several experimental paradigms. In this study we have tested the hypothesis that ALC may have a protective role on cisplatin and paclitaxel-induced neuropathy. EXPERIMENTAL DESIGN: Sensory nerve conduction velocity (SNCV) was measured in rats before, at end, and after an additional follow-up period from treatments with cisplatin, paclitaxel, or with the respective combination with ALC. In addition, serum from treated animals was collected to measure the levels of circulating NGF, and left sciatic nerves were processed for light and electron microscope observations. ALC interference on cisplatin and paclitaxel antitumor activity and protective mechanisms were investigated using several in vitro and in vivo models. RESULTS: ALC cotreatment was able to significantly reduce the neurotoxicity of both cisplatin and paclitaxel in rat models, and this effect was correlated with a modulation of the plasma levels of NGF in the cisplatin-treated animals. Moreover, experiments in different tumor systems indicated the lack of interference of ALC in the antitumor effects of cisplatin and paclitaxel. The transcriptional profile of gene expression in PC12 cells indicated that ALC, in the presence of NGF, was able to positively modulate NGFI-A expression, a gene relevant in the rescue from tissue-specific toxicity. Finally, the transcriptionally ALC-mediated effects were correlated to increase histone acetylation. CONCLUSION: In conclusion, our results indicate that ALC is a specific protective agent for chemotherapy-induced neuropathy after cisplatin or paclitaxel treatment without showing any interference with the antitumor activity of the drugs.

Acetylcarnitine↗
PubMedDate not supplied

Neurotoxicity of platinum compounds: comparison of the effects of cisplatin and oxaliplatin on the human neuroblastoma cell line SH-SY5Y.

The main dose-limiting side effect of cancer treatment with platinum compounds is peripheral neurotoxicity. To investigate the intracellular mechanisms of platinum drugs neurotoxicity we have studied the effects of cisplatin and oxaliplatin on the human neuroblastoma cell line SH-SY5Y. Both platinum compounds are toxic causing cellular death by inducing apoptosis but oxaliplatin is less neurotoxic than cisplatin. The study of the proteins involved in the intracellular transduction pathways that may cause apoptotic death, revealed a very similar pattern of changes after exposure to cisplatin or oxaliplatin. In particular, as demonstrated by densitometric analysis, after exposure to both platinum compounds the total amount of the anti-apoptotic protein Bcl-2 was significantly reduced. Conversely, the amount of the pro-apoptotic protein p53 significantly increased. Caspases 3 and 7 were activated, but their activation was a late event, indicating a secondary role in the apoptotic process. Among the mitogen activated protein kinases, only the p38 protein was activated (phosphorylated) early enough to have a possible role in inducing apoptosis, possibly through p53 stabilization. The results of the present study and the data of the literature demonstrate that the ways in which cisplatin and oxaliplatin are neurotoxic are very similar and include not only DNA damage, but also the modulation of specific molecules involved in regulating the cellular equilibrium between apoptotic death and the cell cycle.

Antineoplastic Agents↗
PubMedDate not supplied

Paclitaxel toxicity in post-mitotic dorsal root ganglion (DRG) cells.

Paclitaxel is an antineoplastic drug which acts by enhancing tubulin polymerization. The induction of peripheral neuropathy is the main dose-limiting side-effect of paclitaxel treatment. In this study, the neurotoxic effect of this drug in dorsal root ganglion (DRG) explants was analyzed by measuring the neurite length of DRG explants exposed to nerve growth factor (NGF). The neurotoxic effect of paclitaxel is dose- and time-dependent. Moreover, in DRG dissociated post-mitotic neurons, the molecular and morphological features of paclitaxel-induced cellular death were studied and the DRG neurons were observed to die by necrosis. On the contrary, the proliferating human neuroblastoma SH-SY5Y cells exposed to paclitaxel die by apoptosis, as reported for cortical neurons. The different response to the same stimulus of different neuronal populations underlines the importance of the biochemical and molecular phenotype of the neuronal population in determining cellular behavior and vulnerability to the same noxious stimulus.

Animals↗