Morphologic Features and Glial Activation in Rat Oxaliplatin-Dependent Neuropathic Pain

Mannelli, Lorenzo Di Cesare; Pacini, Alessandra; Bonaccini, Laura; Zanardelli, Matteo; Mello, Tommaso; Ghelardini, Carla

doi:10.1016/j.jpain.2013.08.002

Cited by 151 publications

(170 citation statements)

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“…To note, the pathophysiology of FOLFOX neurotoxicity has not been investigated yet and molecular mechanisms occurring in the chronic form of oxaliplatininduced neuropathy remain unclear. Morphological examination revealed that the primary target of oxaliplatin, and more in general of platinum compounds, is the dorsal root ganglia (DRGs), where the accumulation of the antineoplastic agent triggers nuclear damage [10,24]. Molecular modifications occurred both in DRGs and in peripheral nerves [10,25,26].…”

Section: Discussionmentioning

confidence: 99%

“…Morphological examination revealed that the primary target of oxaliplatin, and more in general of platinum compounds, is the dorsal root ganglia (DRGs), where the accumulation of the antineoplastic agent triggers nuclear damage [10,24]. Molecular modifications occurred both in DRGs and in peripheral nerves [10,25,26]. To note, despite the low oxaliplatin capability to cross the blood brain barrier [27,28], dramatic alterations of the CNS were shown.…”

Section: Discussionmentioning

confidence: 99%

“…Pain-related behaviours (i.e., lifting and licking of the hind paw) were observed and the time (s) of the first sign was recorded. The cutoff time of the latency of paw lifting or licking was set at 60 s [10].…”

Section: Cold Plate Testmentioning

confidence: 99%

“…Voluntary movements associated with locomotion were not taken as a withdrawal response. Stimuli were applied on each posterior paw with an interval of 5 s. The measure was repeated five times and the final value was obtained by averaging the five measures [10].…”

Section: Von Frey Testmentioning

confidence: 99%

“…The molecular bases of the neurotoxicity evoked by FOLFOX therapy in its entirety are unknown, even because the lack of a preclinical model of FOLFOX neuropathy. The currently available data about the most neurotoxic component oxaliplatin reveal a complex panel of damages (peripheral nerves, dorsal root ganglia, and central nervous system areas) and altered responses due to maladaptive plasticity (of both neurons and glia; [8][9][10][11]) that may be complicated by the presence of 5-FU and LV.…”

Section: Introductionmentioning

confidence: 99%

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A rat model of FOLFOX-induced neuropathy: effects of oral dimiracetam in comparison with duloxetine and pregabalin

Mannelli

Maresca

Micheli

et al. 2017

Cancer Chemother Pharmacol

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Results FOLFOX reduced the pain threshold in response to mechanical noxious and thermal (cold) non-noxious stimuli beginning from day 14 up to day 42 comparably to oxaliplatin alone. A fifth FOLFOX injection enhanced the severity but not the duration of painful alterations. Spontaneous activity, behavioural, autonomic, and neurological functions were also affected, whereas the motor coordination was not altered. On day 22, duloxetine (15 mg kg −1 , per os), morphine (10 mg kg −1 , subcutaneously), or pregabalin (20 mg kg −1 , per os), acutely administered, reduced the FOLFOX-dependent hypersensitivity. Repeated treatments with dimiracetam (150 mg kg −1 , per os, twice daily, from day 22) significantly protected rats from FOLFOX-induced alterations of pain threshold as well as from autonomic and neurological impairments taking effect after 7 days treatment. Pregabalin repeatedly administered (20 mg kg −1 , per os, twice daily, from day 22) was less effective in reducing mechanical hypersensitivity. Conclusion A clinically consistent model of FOL-FOX-induced neurotoxicity has been developed in rats. Dimiracetam fully reduced hypersensitivity and neurological alterations showing a relevant profile as anti-neuropathic resource.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cold Plate Testmentioning

confidence: 99%

Section: Von Frey Testmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A rat model of FOLFOX-induced neuropathy: effects of oral dimiracetam in comparison with duloxetine and pregabalin

Mannelli

Maresca

Micheli

et al. 2017

Cancer Chemother Pharmacol

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Development of Potent Inhibitors of Fatty Acid Amide Hydrolase Useful for the Treatment of Neuropathic Pain

et al. 2018

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The unique role of fatty acid amide hydrolase (FAAH) in terminating endocannabinoid (EC) signaling supports its relevance as a therapeutic target. Inhibition of EC metabolizing enzymes elicits indirect agonism of cannabinoid receptors (CBRs) and therapeutic efficacy devoid of psychotropic effects. Based on our previous ligands, and aiming at the discovery of new selective FAAH inhibitors, we developed a series of 12 new compounds characterized by functionalized tricyclic scaffolds. All the developed compounds display negligible activity on monoacylglycerol lipase (MAGL) and CBRs. The most potent FAAH inhibitors of the newly developed series, 6-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-6-phenylhexylcarbamate (5 h) and 4-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-(6-phenylhexyl)carbamate (5 i) (nanomolar FAAH inhibitors, the latter of which also shows micromolar affinity at the CB R), were selected for further studies. Results of cell-based studies on a neuroblastoma cell line (IMR32) demonstrated 5 h, 5 i, and our reference compound 3 ([3-(3-carbamoylpyrrol-1-yl)phenyl] N-(5-phenylpentyl)carbamate) to lack any cytotoxic effect, while all three showed the ability to decrease oxidative stress by reducing the expression of the redox-sensitive transcription factor NF-κB. Encouraged by these data, these compounds were studied in vivo and were dosed orally in a mouse model of neuropathic pain. At 10 mg kg all the compounds were able to relieve the hypersensitivity induced by oxaliplatin.

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Chemotherapy‐induced peripheral neuropathy: Identifying the research gaps and associated changes to clinical trial design

Germain

O’Mara

Robinson

et al. 2020

Cancer

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BACKGROUND: To the authors' knowledge, the empiric identification of agents and interventions to mitigate chemotherapy-induced peripheral neuropathy (CIPN) has resulted in only 1 agent that modestly mitigates it and no agents or interventions that prevent its development. This speaks to the need for a mechanistic understanding of CIPN to develop effective interventions. METHODS: To understand the extent to which mechanistic understanding of CIPN is being translated into the development of interventions, the National Cancer Institute conducted a review of the National Institutes of Health (NIH)'s portfolio of investigator-initiated grants, the literature regarding CIPN mechanisms, and the clinical trials listed in the ClinicalTrials.gov database from January 1, 2011, to May 22, 2019. RESULTS: A total of 69 NIH-supported grants and 95 published articles were identified that evaluated mechanistic pathways of 7 different chemotherapy agents that cause CIPN. The review also identified 35 clinical trials that investigated agents or devices with which to treat CIPN. Only 3 trials incorporated a mechanistic rationale to support the choice of the intervention. CONCLUSIONS: To the authors' knowledge, very little of the mechanistic understanding of the development of CIPN is being translated into intervention rationale in clinical trials that evaluate interventions to mitigate CIPN. Efforts to incentivize this translation are needed. Cancer 2020;126:4602-4613.

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Morphologic Features and Glial Activation in Rat Oxaliplatin-Dependent Neuropathic Pain

Cited by 151 publications

References 58 publications

A rat model of FOLFOX-induced neuropathy: effects of oral dimiracetam in comparison with duloxetine and pregabalin

A rat model of FOLFOX-induced neuropathy: effects of oral dimiracetam in comparison with duloxetine and pregabalin

Development of Potent Inhibitors of Fatty Acid Amide Hydrolase Useful for the Treatment of Neuropathic Pain

Chemotherapy‐induced peripheral neuropathy: Identifying the research gaps and associated changes to clinical trial design

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