The Role of Microcirculatory Dysfunction During Paclitaxel Treatment as a Critical Co-Factor for the Development of Chemotherapy-Induced Peripheral Neuropathy

Abstract

Background

Chemotherapy-induced peripheral neuropathy (CIPN) has a lasting impact on quality of life with a high prevalence and the lack of preventive and causal treatment options. In addition, they are often dose-limiting for curative and palliative oncological therapy. The aim of this study was to systematically investigate the occurrence of paclitaxel-induced peripheral microcirculatory dysfunction and its potential impact on peripheral neuropathy using an experimental in vivo approach.

Methods

77 female 8-week-old mice were randomly assigned into three groups. Each group was exposed to the following intraperitoneal interventions in a blinded fashion: The therapy group was treated with six cycles of paclitaxel. In the control group, mice received six cycles of saline solution. In the vehicle group, animals received six cycles of cremophor. Various microscopic, neurological and biochemical analyses were performed to assess the effects on peripheral nerve function, microcirculation and inflammation.

Results

Von Frey’s neurological test showed a progressive peripheral neuropathy with a significant change in the sensitivity in the sense of hypesthesia of the hind paws in mice treated with paclitaxel. Beside signs of systemic inflammation, intravital microscopic analysis showed a significant reduction in functional capillary density, increased venular leukocyte adherence and endothelial permeability in the paclitaxel-treated mice compared to the control groups. In addition, serological tests and histopathological examinations underlined the paclitaxel-induced inflammation and nerve damage as well as the disturbance of the microcirculation.

Conclusion

The presented findings suggest that paclitaxel-induced microcirculatory disturbances may contribute to the development and severity of CIPN, highlighting the importance of considering microvascular and inflammatory mechanisms in the pathogenesis and management of chemotherapy-induced neuropathy.

Zusammenfassung

Hintergrund

Eine chemotherapieinduzierte periphere Neuropathie (CIPN) kann sich nachhaltig auf die Lebensqualität auswirken und ist mit einer hohen Prävalenz und einem Mangel an vorbeugenden und kausalen Behandlungsmöglichkeiten verbunden. Dazu kommt noch, dass sie nicht selten dosislimitierend ist für kurative und palliative onkologische Therapien. Ziel dieser Studie war die systematische Untersuchung des Auftretens einer Paclitaxel-induzierten peripheren mikrozirkulatorischen Dysfunktion und deren potenzieller Auswirkungen auf die periphere Neuropathie in einem experimentellen In-vivo-Tierversuch.

Methoden

Es wurden 77 weibliche 8 Wochen alte Mäuse in 3 Gruppen randomisiert. Es handelte sich dabei um eine Doppelblindstudie. Jede Gruppe wurde einer der folgenden intraperitonealen Interventionen ausgesetzt: Die Therapiegruppe erhielt 6 Zyklen mit Paclitaxel. Die Mäuse der Kontrollgruppe erhielten 6 Zyklen einer Kochsalzlösung. In der Vehikel-Kontrollgruppe erhielten die Tiere 6 Zyklen mit Cremophor. Verschiedene mikroskopische, neurologische und biochemische Analysen wurden durchgeführt, um die Auswirkungen auf die peripheren Nervenfunktionen, Mikrozirkulation und Inflammation zu evaluieren.

Ergebnisse

Die klinisch-neurologische Sensibilitätsprüfung zeigte eine progressive periphere Neuropathie mit signifikanten Sensibilitätsstörungen (Hypästhesien) der Hinterpfoten bei den mit Paclitaxel behandelten Mäusen. Neben Anzeichen einer systemischen Entzündung fanden intravitale mikroskopische Analysen auch eine signifikante Verringerung der funktionellen Kapillardichte, eine Zunahme der Leukozytenadhäsion in den Venolen und eine erhöhte endotheliale Durchlässigkeit in den mit Paclitaxel behandelten Mäusen verglichen mit den Kontrollgruppen. Auch die serologischen Tests und histopathologischen Untersuchungen wiesen Paclitaxel-induzierte Entzündungen und Nervenschädigungen sowie Störungen der Mikrozirkulation nach.

Schlussfolgerung

Die dargelegten Ergebnisse zeigen, dass Paclitaxel-induzierte mikrozirkulatorische Störungen zur Entwicklung und Schwere einer CIPN beitragen können. Damit wird auch klar, wie wichtig die Beachtung von mikrovaskulären und entzündlichen Mechanismen bei der Pathogenese und dem Management einer chemotherapieinduzierten Neuropathie ist.

Keywords

chemotherapy-induced peripheral neuropathy (CIPN) - paclitaxel - intravital fluorescence microscopy - microvascular damage - endothelial lesions - inflammation

Schlüsselwörter

chemotherapieinduzierte periphere Neuropathie (CIPN) - Paclitaxel - intravitale Fluoreszenzmikroskopie - mikrovaskuläre Schäden - endotheliale Läsion - Inflammation

Publikationsverlauf

Eingereicht: 29. August 2024

Angenommen nach Revision: 30. November 2024

Artikel online veröffentlicht:
17. März 2025

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