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1.
J Peripher Nerv Syst ; 2024 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-39434652

RESUMO

BACKGROUND AND AIMS: Chemotherapy-induced peripheral neurotoxicity (CIPN), with paraesthesia, numbness, dysesthesia and neuropathic pain ranks among the most common dose-limiting toxicity of several widely used anticancer drugs. Recent studies revealed the microvascular angiogenesis as a new important actor, beside peripheral neurons, in the neurotoxicity and neuropathic pain development and chronicisation. The aim of this work is to elucidate the role of vascular alterations in CIPN. METHODS: We evaluated the severity of CIPN with neurophysiological, behavioural and neuropathological analysis together with the microvascular network in central and peripheral nervous systems of rats in order to correlate the features of the CIPN and the vascular abnormalities. The vascular network was quantitatively evaluated through synchrotron radiation-based X-ray phase-contrast micro-tomography imaging, measuring four specific parameters: vascular density, vessel diameter, vessel tortuosity and branching. RESULTS: Rats exposed to paclitaxel and affected by a severe painful sensory axonopathy showed an increased vascular density (putative sprouting angiogenesis) in the crucial districts of the central (somatosensory cortex and lumbar spinal cord) and peripheral nervous system (lumbar dorsal root ganglia). In addition, the complexity of the vascular network and the size of neo-formed vessels were significantly decreased in specific regions. On the other hand, less significant changes were observed in rats exposed to cisplatin, affected by a painless peripheral neuropathy, suggesting a specific involvement of neo-angiogenesis in the development of severe neurotoxicity and neuropathic pain. INTERPRETATIONS: These new ground-breaking results can shed light on new pathogenetic mechanisms and potential novel therapeutic approaches for painful-CIPN.

2.
Sci Rep ; 14(1): 19341, 2024 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-39164364

RESUMO

Peripheral neurotoxicity is a dose-limiting adverse reaction of primary frontline chemotherapeutic agents, including vincristine. Neuropathy can be so disabling that patients drop out of potentially curative therapy, negatively impacting cancer prognosis. The hallmark of vincristine neurotoxicity is axonopathy, yet its underpinning mechanisms remain uncertain. We developed a comprehensive drug discovery platform to identify neuroprotective agents against vincristine-induced neurotoxicity. Among the hits identified, SIN-1-an active metabolite of molsidomine-prevents vincristine-induced axonopathy in both motor and sensory neurons without compromising vincristine anticancer efficacy. Mechanistically, we found that SIN-1's neuroprotective effect is mediated by activating soluble guanylyl cyclase. We modeled vincristine-induced peripheral neurotoxicity in rats to determine molsidomine therapeutic potential in vivo. Vincristine administration induced severe nerve damage and mechanical hypersensitivity that were attenuated by concomitant treatment with molsidomine. This study provides evidence of the neuroprotective properties of molsidomine and warrants further investigations of this drug as a therapy for vincristine-induced peripheral neurotoxicity.


Assuntos
Molsidomina , Fármacos Neuroprotetores , Guanilil Ciclase Solúvel , Vincristina , Vincristina/efeitos adversos , Vincristina/farmacologia , Vincristina/toxicidade , Animais , Fármacos Neuroprotetores/farmacologia , Ratos , Guanilil Ciclase Solúvel/metabolismo , Molsidomina/farmacologia , Molsidomina/análogos & derivados , Humanos , Masculino , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Ratos Sprague-Dawley , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/prevenção & controle , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/etiologia
3.
Neuroscience ; 523: 1-6, 2023 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-37211082

RESUMO

Cerebral collaterals are recruited after arterial occlusion with a protective effect on tissue outcome in acute ischemic stroke. Head down tilt 15° (HDT15) is a simple, low cost and accessible procedure that could be applied as an emergency treatment, before recanalization therapies, with the aim to increase cerebral collateral flow. Spontaneously hypertensive rats have been shown to display anatomical differences in morphology and function of cerebral collaterals, compared to other rat strains, resulting in an overall poor collateral circulation. We investigate the efficacy and safety of HDT15 in spontaneously hypertensive (SHR) rats, which were considered as an animal stroke model with poor collaterals. Cerebral ischemia was induced by 90 minute endovascular occlusion of the middle cerebral artery (MCA). SHR rats were randomized to HDT15 or flat position (n = 19). HDT15 was applied 30 minutes after occlusion and lasted 60 minutes, until reperfusion. HDT15 application increased cerebral perfusion (+16.6% versus +6.1%; p = 0.0040) and resulted in a small reduction of infarct size (83.6 versus 107.1 mm3; - 21.89%; p = 0.0272), but it was not associated with early neurological improvement, compared to flat position. Our study suggests that the response to HDT15 during MCA occlusion is dependent on baseline collaterals. Nonetheless, HDT15 promoted a mild improvement of cerebral hemodynamics even in subjects with poor collaterals, without safety concerns.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Ratos , Circulação Cerebrovascular/fisiologia , Decúbito Inclinado com Rebaixamento da Cabeça , Ratos Endogâmicos SHR
4.
Toxics ; 11(2)2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36850969

RESUMO

Chemotherapy-induced peripheral neurotoxicity is one of the most common dose-limiting toxicities of several widely used anticancer drugs such as platinum derivatives (cisplatin) and taxanes (paclitaxel). Several molecular mechanisms related to the onset of neurotoxicity have already been proposed, most of them having the sensory neurons of the dorsal root ganglia (DRG) and the peripheral nerve fibers as principal targets. In this study we explore chemotherapy-induced peripheral neurotoxicity beyond the neuronocentric view, investigating the changes induced by paclitaxel (PTX) and cisplatin (CDDP) on satellite glial cells (SGC) in the DRG and their crosstalk. Rats were chronically treated with PTX (10 mg/Kg, 1qwx4) or CDDP (2 mg/Kg 2qwx4) or respective vehicles. Morpho-functional analyses were performed to verify the features of drug-induced peripheral neurotoxicity. Qualitative and quantitative immunohistochemistry, 3D immunofluorescence, immunoblotting, and transmission electron microscopy analyses were also performed to detect alterations in SGCs and their interconnections. We demonstrated that PTX, but not CDDP, produces a strong activation of SGCs in the DRG, by altering their interconnections and their physical contact with sensory neurons. SGCs may act as principal actors in PTX-induced peripheral neurotoxicity, paving the way for the identification of new druggable targets for the treatment and prevention of chemotherapy-induced peripheral neurotoxicity.

5.
Int J Mol Sci ; 24(2)2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36675203

RESUMO

Peripheral Neuropathies (PN) are common conditions whose treatment is still lacking in most cases. Animal models are crucial, but experimental procedures should be refined in some cases. We performed a detailed characterization of the ventral caudal nerve to contribute to a more effective assessment of axonal damage in future PN studies. PN was induced via weekly systemic injection of a neurotoxic drug (paclitaxel); we compared the control and PN-affected rats, performing serial neurophysiological evaluations of the caudal nerve for its entire length. On the same nerve portions, we performed light microscopy and ultrastructural pathological observations to assess the severity of damage and verify the integrity of the surrounding structures. Neurophysiological and morphological analyses confirmed that a severe axonopathy had ensued in the PN group, with a length-dependent modality, matching morphological observations. The site of neurophysiological recording (e.g., distance from the base of the tail) was critical for achieving useful data. A flexible experimental paradigm should be considered in animal studies investigating axonal PN, particularly if the expected severity is relevant; the mid-portion of the tail might be the most appropriate site: there damage might be remarkable but neither as extreme as at the tip of the tail nor as mild as at the base of the tail.


Assuntos
Tecido Nervoso , Síndromes Neurotóxicas , Doenças do Sistema Nervoso Periférico , Ratos , Animais , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Tecido Nervoso/patologia , Paclitaxel/efeitos adversos , Axônios/patologia , Síndromes Neurotóxicas/patologia
6.
Eur J Neurosci ; 57(12): 2149-2159, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36300727

RESUMO

Neurological outcome after ischemic stroke depends on residual salvageable brain tissue at the time of recanalization. Head down tilt 15° (HDT15) was proven effective in reducing infarct size and improving functional outcome in rats with transient middle cerebral artery occlusion (t-MCAO) by increasing cerebral perfusion within the ischemic penumbra. In this pooled analysis, individual animal-level data from three experimental series were combined in a study population of 104 t-MCAO rats (45 in HDT15 group and 59 in flat position group). Co-primary outcomes were infarct size and functional outcome at 24 h in both groups. The secondary outcome was hemodynamic change induced by HDT15 in ischemic and non-ischemic hemispheres in a subgroup of animals. Infarct size at 24 h was smaller in HDT15 group than in flat position group (absolute mean difference 31.69 mm3 , 95% CI 9.1-54.2, Cohen's d 0.56, p = 0.006). Functional outcome at 24 h was better in HDT15 group than in flat position group (median [IQR]: 13[10-16] vs. 11), with a shift in the distribution of the neurobehavioural scores in favour of HDT15. Mean cerebral perfusion in the ischemic hemisphere was higher during HDT15 than before its application (Perfusion Unit [P.U.], mean ± SD: 52.5 ± 19.52 P.U. vs. 41.25 ± 14.54 P.U., mean of differences 13.36, 95% CI 7.5-19.18, p = 0.0002). Mean cerebral perfusion in the non-ischemic hemisphere before and during HDT15 was unchanged (P.U., mean ± SD: 94.1 ± 33.8 P.U. vs. 100.25 ± 25.34 P.U., mean of differences 3.95, 95%, CI -1.9 to 9.6, p = 0.1576). This study confirmed that HDT15 improves the outcome in t-MCAO rats by promoting cerebral perfusion in the ischemic territory, without disrupting hemodynamics in non-ischemic areas.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Ratos , Humanos , Animais , Decúbito Inclinado com Rebaixamento da Cabeça , Encéfalo , Infarto da Artéria Cerebral Média , Hemodinâmica
7.
Front Pain Res (Lausanne) ; 3: 1066069, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36582196

RESUMO

Neuropathic pain is a frequent complication of chemotherapy-induced peripheral neurotoxicity (CIPN). Chemotherapy-induced peripheral neuropathies may serve as a model to study mechanisms of neuropathic pain, since several other common causes of peripheral neuropathy like painful diabetic neuropathy may be due to both neuropathic and non-neuropathic pain mechanisms like ischemia and inflammation. Experimental studies are ideally suited to study changes in morphology, phenotype and electrophysiologic characteristics of primary afferent neurons that are affected by chemotherapy and to correlate these changes to behaviors reflective of evoked pain, mainly hyperalgesia and allodynia. However, hyperalgesia and allodynia may only represent one aspect of human pain, i.e., the sensory-discriminative component, while patients with CIPN often describe their pain using words like annoying, tiring and dreadful, which are affective-emotional descriptors that cannot be tested in experimental animals. To understand why some patients with CIPN develop neuropathic pain and others not, and which are the components of neuropathic pain that they are experiencing, experimental and clinical pain research should be combined. Emerging evidence suggests that changes in subsets of primary afferent nerve fibers may contribute to specific aspects of neuropathic pain in both preclinical models and in patients with CIPN. In addition, the role of cutaneous neuroimmune interactions is considered. Since obtaining dorsal root ganglia and peripheral nerves in patients is problematic, analyses performed on skin biopsies from preclinical models as well as patients provide an opportunity to study changes in primary afferent nerve fibers and to associate these changes to human pain. In addition, other biomarkers of small fiber damage in CIPN, like corneal confocal microscope and quantitative sensory testing, may be considered.

8.
Int J Mol Sci ; 23(17)2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36077454

RESUMO

Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN) is a frequent adverse event of colorectal cancer treatment. OIPN encompasses a chronic and an acute syndrome. The latter consists of transient axonal hyperexcitability, due to unbalance in Na+ voltage-operated channels (Na+VOC). This leads to sustained depolarisation which can activate the reverse mode of the Na+/Ca2+ exchanger 2 (NCX2), resulting in toxic Ca2+ accumulation and axonal damage (ADa). We explored the role of NCX2 in in vitro and in vivo settings. Embryonic rat Dorsal Root Ganglia (DRG) organotypic cultures treated with SEA0400 (SEA), a NCX inhibitor, were used to assess neuroprotection in a proof-of-concept and pilot study to exploit NCX modulation to prevent ADa. In vivo, OHP treated mice (7 mg/Kg, i.v., once a week for 8 weeks) were compared with a vehicle-treated group (n = 12 each). Neurophysiological and behavioural testing were performed to characterise acute and chronic OIPN, and morphological analyses were performed to detect ADa. Immunohistochemistry, immunofluorescence, and western blotting (WB) analyses were also performed to demonstrate changes in NCX2 immunoreactivity and protein expression. In vitro, NCX inhibition was matched by ADa mitigation. In the in vivo part, after verifyingboth acute and chronic OIPN had ensued, we confirmed via immunohistochemistry, immunofluorescence, and WB that a significant NCX2 alteration had ensued in the OHP group. Our data suggest NCX2 involvement in ADa development, paving the way to a new line of research to prevent OIPN.


Assuntos
Síndromes Neurotóxicas , Trocador de Sódio e Cálcio , Animais , Axônios/metabolismo , Camundongos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Oxaliplatina/efeitos adversos , Projetos Piloto , Ratos , Trocador de Sódio e Cálcio/metabolismo
9.
Neurotherapeutics ; 19(6): 1942-1950, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36129603

RESUMO

Hypothermia is a promising therapeutic strategy for severe vasospasm and other types of non-thrombotic cerebral ischemia, but its clinical application is limited by significant systemic side effects. We aimed to develop an intraventricular device for the controlled cooling of the cerebrospinal fluid, to produce a targeted hypothermia in the affected cerebral hemisphere with a minimal effect on systemic temperature. An intraventricular cooling device (acronym: V-COOL) was developed by in silico modelling, in vitro testing, and in vivo proof-of-concept application in healthy Wistar rats (n = 42). Cerebral cortical temperature, rectal temperature, and intracranial pressure were monitored at increasing flow rate (0.2 to 0.8 mL/min) and duration of application (10 to 60 min). Survival, neurological outcome, and MRI volumetric analysis of the ventricular system were assessed during the first 24 h. The V-COOL prototyping was designed to minimize extra-cranial heat transfer and intra-cranial pressure load. In vivo application of the V-COOL device produced a flow rate-dependent decrease in cerebral cortical temperature, without affecting systemic temperature. The target degree of cerebral cooling (- 3.0 °C) was obtained in 4.48 min at the flow rate of 0.4 mL/min, without significant changes in intracranial pressure. Survival and neurological outcome at 24 h showed no significant difference compared to sham-treated rats. MRI study showed a transient dilation of the ventricular system (+ 38%) in a subset of animals. The V-COOL technology provides an effective, rapid, selective, and safe cerebral cooling to a clinically relevant degree of - 3.0 °C.


Assuntos
Hipotermia Induzida , Hipotermia , Animais , Ratos , Temperatura Corporal , Ratos Wistar , Bioengenharia , Encéfalo
10.
Cancers (Basel) ; 14(12)2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35740641

RESUMO

Glioblastoma is the most common and aggressive brain tumor, associated with poor prognosis and survival, representing a challenging medical issue for neurooncologists. Dysregulation of histone-modifying enzymes (HDACs) is commonly identified in many tumors and has been linked to cancer proliferation, changes in metabolism, and drug resistance. These findings led to the development of HDAC inhibitors, which are limited by their narrow therapeutic index. In this work, we provide the proof of concept for a delivery system that can improve the in vivo half-life and increase the brain delivery of Givinostat, a pan-HDAC inhibitor. Here, 150-nm-sized liposomes composed of cholesterol and sphingomyelin with or without surface decoration with mApoE peptide, inhibited human glioblastoma cell growth in 2D and 3D models by inducing a time- and dose-dependent reduction in cell viability, reduction in the receptors involved in cholesterol metabolism (from -25% to -75% of protein levels), and reduction in HDAC activity (-25% within 30 min). In addition, liposome-Givinostat formulations showed a 2.5-fold increase in the drug half-life in the bloodstream and a 6-fold increase in the amount of drug entering the brain in healthy mice, without any signs of overt toxicity. These features make liposomes loaded with Givinostat valuable as potential candidates for glioblastoma therapy.

11.
J Neurosci Methods ; 363: 109323, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34391792

RESUMO

BACKGROUND: Peripheral neuropathy treatment is not always satisfactory. To fill this gap, inferences from bench side are warranted, where morphological and pathogenetic determinations can be performed. Nerve conduction studies (NCS) are ideal to translate results from preclinical to clinical setting. NEW METHODS: We propose a comprehensive 8-minute protocol for sensory-motor neurophysiological assessment, similar to routine clinical practice: sensory proximal and distal caudal nerves, motor caudal nerve, and sensory digital nerve recordings were used and tested in 2 different experimental settings. In Experiment 1 we compared control (CTRL) animals to a severe sensory-motor polyneuropathy (animals treated with vincristine [VCR]), and in Experiment 2 CTRL animals were compared to a mild sensory polyneuropathy (animals treated with oxaliplatin [OHP]). NCS were performed after 1-month of chemotherapy and matched with confirmatory neuropathological analyses. RESULTS: VCR treated animals showed, at NCS, a relevant sensory-motor polyneuropathy ensued at the end of treatment; whereas, OHP animals showed a mild distal sensory neuropathy. These patterns were confirmed by neuropathological analysis. COMPARISON WITH EXISTING METHODS: In literature, the majority of proposed neurophysiological protocols relies mainly on a single nerve testing, rather than a combination of them, and only a few studies tested both caudal and sciatic nerve branches, nevertheless not aiming at fully reproduce clinical protocols (e.g., seeking for length-dependency); to provide evidence of appropriateness of our protocol we applied a gold standard: neuropathology. CONCLUSION: The simple and rapid protocol here presented can be suggested as a good translation outcome measure in preclinical setting.


Assuntos
Condução Nervosa , Doenças do Sistema Nervoso Periférico , Animais , Neurofisiologia , Nervos Periféricos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico
12.
Proc Natl Acad Sci U S A ; 118(4)2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33468672

RESUMO

The pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN) is poorly understood. Here, we report that the CIPN-causing drug bortezomib (Bort) promotes delta 2 tubulin (D2) accumulation while affecting microtubule stability and dynamics in sensory neurons in vitro and in vivo and that the accumulation of D2 is predominant in unmyelinated fibers and a hallmark of bortezomib-induced peripheral neuropathy (BIPN) in humans. Furthermore, while D2 overexpression was sufficient to cause axonopathy and inhibit mitochondria motility, reduction of D2 levels alleviated both axonal degeneration and the loss of mitochondria motility induced by Bort. Together, our data demonstrate that Bort, a compound structurally unrelated to tubulin poisons, affects the tubulin cytoskeleton in sensory neurons in vitro, in vivo, and in human tissue, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. The results reveal a previously unrecognized pathogenic role for D2 in BIPN that may occur through altered regulation of mitochondria motility.


Assuntos
Bortezomib/efeitos adversos , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/genética , Tubulina (Proteína)/genética , Animais , Antineoplásicos/efeitos adversos , Axônios/efeitos dos fármacos , Axônios/patologia , Modelos Animais de Doenças , Drosophila melanogaster/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Larva/efeitos dos fármacos , Larva/genética , Microtúbulos/efeitos dos fármacos , Microtúbulos/genética , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Dinâmica Mitocondrial/efeitos dos fármacos , Dinâmica Mitocondrial/genética , Neoplasias/genética , Neoplasias/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/patologia , Peixe-Zebra/genética
13.
Brain Sci ; 11(2)2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33499072

RESUMO

Peripheral neuropathies (PNs) are a type of common disease that hampers the quality of life of affected people. Treatment, in most cases, is just symptomatic and often ineffective. To improve drug discovery in this field, preclinical evidence is warranted. In vivo rodent models allow a multiparametric approach to test new therapeutic strategies, since they can allow pathogenetic and morphological studies different from the clinical setting. However, human readouts are warranted to promptly translate data from the bench to the bedside. A feasible solution would be neurophysiology, performed similarly at both sides. We describe a simple protocol that reproduces the standard clinical protocol of a neurophysiology hospital department. We devised the optimal montage for sensory and motor recordings (neurography) in mice, and we also implemented F wave testing and a short electromyography (EMG) protocol at rest. We challenged this algorithm by comparing control animals (BALB/c mice) with a model of mild neuropathy to grasp even subtle changes. The neurophysiological results were confirmed with neuropathology. The treatment group showed all expected alterations. Moreover, the neurophysiology matched the neuropathological analyses. Therefore, our protocol can be suggested to promptly translate data from the bench to the bedside and vice versa.

14.
Int J Mol Sci ; 22(3)2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33494384

RESUMO

The onset of chemotherapy-induced peripheral neurotoxicity (CIPN) is a leading cause of the dose reduction or discontinuation of cancer treatment due to sensory symptoms. Paclitaxel (PTX) can cause painful peripheral neuropathy, with a negative impact on cancer survivors' quality of life. While recent studies have shown that neuroinflammation is involved in PTX-induced peripheral neurotoxicity (PIPN), the pathophysiology of this disabling side effect remains largely unclear and no effective therapies are available. Therefore, here we investigated the effects of human intravenous immunoglobulin (IVIg) on a PIPN rat model. PTX-treated rats showed mechanical allodynia and neurophysiological alterations consistent with a severe sensory axonal polyneuropathy. In addition, morphological evaluation showed a reduction of intra-epidermal nerve fiber (IENF) density and evidenced axonopathy with macrophage infiltration, which was more prominent in the distal segment of caudal nerves. Three weeks after the last PTX injection, mechanical allodynia was still present in PTX-treated rats, while the full recovery in the group of animals co-treated with IVIg was observed. At the pathological level, this behavioral result was paralleled by prevention of the reduction in IENF density induced by PTX in IVIg co-treated rats. These results suggest that the immunomodulating effect of IVIg co-treatment can alleviate PIPN neurotoxic manifestations, probably through a partial reduction of neuroinflammation.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Imunoglobulinas Intravenosas/administração & dosagem , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/etiologia , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Axônios/efeitos dos fármacos , Axônios/metabolismo , Axônios/patologia , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Hiperalgesia/diagnóstico , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Síndromes Neurotóxicas/diagnóstico , Paclitaxel/uso terapêutico , Doenças do Sistema Nervoso Periférico/diagnóstico , Ratos , Resultado do Tratamento
15.
Front Pharmacol ; 12: 817236, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35126148

RESUMO

Chemotherapy-induced peripheral neurotoxicity is a common dose-limiting side effect of several cancer chemotherapeutic agents, and no effective therapies exist. Here we constructed a systems pharmacology model of intracellular signaling in peripheral neurons to identify novel drug targets for preventing peripheral neuropathy associated with proteasome inhibitors. Model predictions suggested the combinatorial inhibition of TNFα, NMDA receptors, and reactive oxygen species should prevent proteasome inhibitor-induced neuronal apoptosis. Dexanabinol, an inhibitor of all three targets, partially restored bortezomib-induced reduction of proximal action potential amplitude and distal nerve conduction velocity in vitro and prevented bortezomib-induced mechanical allodynia and thermal hyperalgesia in rats, including a partial recovery of intraepidermal nerve fiber density. Dexanabinol failed to restore bortezomib-induced decreases in electrophysiological endpoints in rats, and it did not compromise bortezomib anti-cancer effects in U266 multiple myeloma cells and a murine xenograft model. Owing to its favorable safety profile in humans and preclinical efficacy, dexanabinol might represent a treatment option for bortezomib-induced neuropathic pain.

16.
Int J Mol Sci ; 21(19)2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32998392

RESUMO

Oxaliplatin-induced peripheral neuropathy is characterized by an acute hyperexcitability syndrome triggered/exacerbated by cold. The mechanisms underlying oxaliplatin-induced peripheral neuropathy are unclear, but the alteration of ion channel expression and activity plays a well-recognized central role. Recently, we found that oxaliplatin leads to cytosolic acidification in dorsal root ganglion (DRG) neurons. Here, we investigated the early impact of oxaliplatin on the proton-sensitive TREK potassium channels. Following a 6-h oxaliplatin treatment, both channels underwent a transcription upregulation that returned to control levels after 42 h. The overexpression of TREK channels was also observed after in vivo treatment in DRG cells from mice exposed to acute treatment with oxaliplatin. Moreover, both intracellular pH and TREK channel transcription were similarly regulated after incubation with amiloride, an inhibitor of the Na+/H+ exchanger. In addition, we studied the role of oxaliplatin-induced acidification on channel behavior, and, as expected, we observed a robust positive modulation of TREK channel activity. Finally, we focused on the impact of this complex modulation on capsaicin-evoked neuronal activity finding a transient decrease in the average firing rate following 6 h of oxaliplatin treatment. In conclusion, the early activation of TREK genes may represent a mechanism of protection against the oxaliplatin-related perturbation of neuronal excitability.


Assuntos
Antineoplásicos/efeitos adversos , Gânglios Espinais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Oxaliplatina/efeitos adversos , Doenças do Sistema Nervoso Periférico/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Trocador 1 de Sódio-Hidrogênio/genética , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Amilorida/farmacologia , Animais , Capsaicina/farmacologia , Bloqueadores do Canal de Sódio Epitelial/farmacologia , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Biológicos , Neurônios/metabolismo , Neurônios/patologia , Técnicas de Patch-Clamp , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Canais de Potássio de Domínios Poros em Tandem/agonistas , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Cultura Primária de Células , Trocador 1 de Sódio-Hidrogênio/antagonistas & inibidores , Trocador 1 de Sódio-Hidrogênio/metabolismo , Ativação Transcricional
17.
Exp Neurol ; 334: 113458, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32889007

RESUMO

Chemotherapy-induced peripheral neurotoxicity represents one of the most relevant dose-limiting side effects that can affect cancer patients treated with the common antineoplastic agents. Since the severity of neurotoxicity often leads to dose reduction or early cessation of chemotherapy, the investigation of molecular mechanisms underlying chemotherapy-induced peripheral neurotoxicity is an urgent clinical need in order to better understand its physiopathology and find effective strategies for neuroprotection. Several in vivo preclinical models of chemotherapy-induced peripheral neurotoxicity have been developed but a great variability in mouse strain, dose, route of administration of the drug, treatment schedule and assessment of neurotoxicity is observed between the different published studies making difficult the comparison and interpretation of their results. In many of these studies only behavioural tests are used as outcome measures, while possible neurophysiological and neuropathological changes are not evaluated. In this study, focused on experimental oxaliplatin-induced peripheral neurotoxicity, we reproduced and compared four mouse models with very different drug dose (low or high dose-intensity) and treatment schedules (short or long-term treatment), selected from the literature. Using a multimodal assessment based on behavioural, neurophysiological and neuropathological methods, we evidenced remarkable differences in the results obtained in the selected animal models. This work suggests the importance of a multimodal approach including extensive pathological investigation to confirm the behavioural results.


Assuntos
Antineoplásicos/toxicidade , Oxaliplatina/toxicidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Doenças do Sistema Nervoso Periférico/psicologia , Distribuição Aleatória
18.
Antioxidants (Basel) ; 9(9)2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32882796

RESUMO

The comments sent by Stehr, Lundstom and Karlsson with reference to our article "Calmangafodipir reduces sensory alterations and prevents intraepidermal nerve fiber loss in a mouse model of oxaliplatin-induced peripheral neurotoxicity" are very interesting, since they suggest possible mechanisms of action of the compound, which might contribute to its protective action [...].

19.
Antioxidants (Basel) ; 9(7)2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32645985

RESUMO

Oxaliplatin (OHP) is an antineoplastic compound able to induce peripheral neurotoxicity. Oxidative stress has been suggested to be a key factor in the development of OHP-related peripheral neurotoxicity. Mangafodipir, a contrast agent possessing mitochondrial superoxide dismutase (MnSOD)-mimetic activity, has been tested as a cytoprotector in chemotherapy-induced peripheral neurotoxicity (CIPN). Calmangafodipir (PledOx®) has even better therapeutic activity. We investigated a BALB/c mouse model of OHP-related CIPN and the effects of the pre-treatment of calmangafodipir (2.5, 5, or 10 mg/kg intravenously) on sensory perception, and we performed a pathological study on skin biopsies to assess intraepidermal nerve fiber (IENF) density. At the end of the treatments, OHP alone or in pre-treatment with calmangafodipir 2.5 and 10 mg/kg, induced mechanical allodynia and cold thermal hyperalgesia, but calmangafodipir 5 mg/kg prevented these effects. Accordingly, OHP alone or in pre-treatment with calmangafodipir 2.5 and 10 mg/kg, induced a significant reduction in IENF density, but calmangafodipir 5 mg/kg prevented this reduction. These results confirm a protective effect of calmangafodipir against OHP-induced small fiber neuropathy. Interestingly, these results are in agreement with previous observations suggesting a U-shaped effect of calmangafodipir, with the 10 mg/kg dose less effective than the lower doses.

20.
Arch Toxicol ; 94(7): 2517-2522, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32333051

RESUMO

Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is a severe and long-lasting side effect of anticancer therapy, which can severely impair patients' quality of life. It is a sensory and length-dependent neuropathy, which predominantly affects large myelinated fibers. Easy and reliable monitoring of CIPN in patients is still an unmet clinical need. Since increasing clinical evidence supports the potential use of neurofilament light chain (NfL) as a biomarker of axonal injury, in this study we measured serum NfL levels in animals chronically treated with cisplatin (CDDP) and paclitaxel (PTX), two antineoplastic drugs with different neuronal targets. Wistar rats were treated with CDDP (2 mg/kg i.p. twice/week for 4 weeks) or PTX (10 mg/kg i.v. once/week for 4 weeks). Repeated serum NfL quantification was obtained using the Single Molecule Array (Simoa) technology. The onset and progression of peripheral neurotoxicity were evaluated through neurophysiology, morphological assessments and intraepidermal nerve fibers density quantification. Our results showed that serum NfL measurements correlated with the severity of axonal damage. In fact, both treatments induced serum NfL increase, but higher levels were evidenced in PTX-treated animals, compared with CDDP-treated rats, affected by a milder neurotoxicity. Notably, also the timing of the NfL level increase was associated with the severity of morphological and functional alterations of axonal structure. Therefore, NfL could be a useful biomarker for axonal damage in order to follow the onset and severity of axonal degeneration and possibly limit the occurrence of serious PNS disease.


Assuntos
Antineoplásicos , Axônios/metabolismo , Cisplatino , Proteínas de Neurofilamentos/sangue , Síndromes Neurotóxicas/sangue , Paclitaxel , Nervos Periféricos/metabolismo , Doenças do Sistema Nervoso Periférico/sangue , Animais , Axônios/patologia , Biomarcadores/sangue , Modelos Animais de Doenças , Feminino , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Nervos Periféricos/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia , Ratos Wistar , Índice de Gravidade de Doença , Regulação para Cima
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