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.

Ballarini, E., Malacrida, A., Rodriguez Menendez, V., Pozzi, E., Canta, A., Chiorazzi, A., et al. (2022). Sodium-Calcium Exchanger 2: A Pivotal Role in Oxaliplatin Induced Peripheral Neurotoxicity and Axonal Damage?. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 23(17), 1-18 [10.3390/ijms231710063].

Sodium-Calcium Exchanger 2: A Pivotal Role in Oxaliplatin Induced Peripheral Neurotoxicity and Axonal Damage?

Ballarini, E
Co-primo
;
Malacrida, A
Co-primo
;
Rodriguez Menendez, V
Secondo
;
Pozzi, E;Canta, A;Chiorazzi, A;Monza, L;Semperboni, S;Meregalli, C;Carozzi, V;Hashemi, M;Nicolini, G;Scuteri, A;Cavaletti, G
Penultimo
;
Alberti, P
Ultimo
2022

Abstract

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.
Si
Articolo in rivista - Articolo scientifico
Scientifica
axonal damage; axonal hyperexcitability; chemotherapy induced peripheral neuropathy; chemotherapy-induced peripheral neurotoxicity; immunofluorescence; immunohistochemistry; NCX2; nerve excitability testing; neuropathology; neuroprotection; voltage-operated ion channels;
English
1
18
18
Ballarini, E., Malacrida, A., Rodriguez Menendez, V., Pozzi, E., Canta, A., Chiorazzi, A., et al. (2022). Sodium-Calcium Exchanger 2: A Pivotal Role in Oxaliplatin Induced Peripheral Neurotoxicity and Axonal Damage?. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 23(17), 1-18 [10.3390/ijms231710063].
Ballarini, E; Malacrida, A; Rodriguez Menendez, V; Pozzi, E; Canta, A; Chiorazzi, A; Monza, L; Semperboni, S; Meregalli, C; Carozzi, V; Hashemi, M; Nicolini, G; Scuteri, A; Housley, S; Cavaletti, G; Alberti, P
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/391608
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