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This research investigates how carboplatin affects oligodendrocytes in a mouse model of neurofibromatosis type 1 (NF1).

July 23, 2026Neuro-Oncology0 citations

Carboplatin induces optic nerve oligodendrocyte loss and impairs myelin sheath microstructure in a mouse model of neurofibromatosis type 1 (NF1)

BABenjamin E. Aghoghovwia KBKechen Ban DSDimitrios Stavropoulos

Key Points

This research investigates how carboplatin affects oligodendrocytes in a mouse model of neurofibromatosis type 1 (NF1).
Nf1-mutant mice treated with carboplatin or vehicle were analyzed for optic nerve oligodendrocyte effects in vivo.
Pharmacological strategies were assessed for toxicity reduction using PLX5622 and clemastine treatments.
In vitro analysis was performed on Nf1-mutant optic glioma cells to evaluate tumor growth.
Carboplatin dosing led to oligodendrocyte loss and altered myelin sheath structure in Nf1+/- optic nerves.
Cholesterol biosynthesis genes were downregulated, and dietary cholesterol restored oligodendrocyte counts after treatment.
PLX5622 and clemastine treatments reduced both oligodendrocyte loss and Nf1-mutant glioma cell viability.

Abstract

Abstract Background Vision impairment is a significant concern for children with Neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG). While carboplatin-containing chemotherapy is often first-line therapy for NF1-OPG, it does not consistently improve visual function. Furthermore, chemotherapy is associated with altered white matter microstructure in individuals with NF1-OPG, suggesting a detrimental effect on oligodendroglia. We analyzed the tumor-independent effects of carboplatin on oligodendrocytes in Nf1-mutant mice and evaluated pharmacological strategies for reducing this chemotherapy-associated toxicity. Methods Carboplatin- or vehicle-treated Nf1+/- mice or Nf1-mutant optic glioma cells were employed to assess the effects of restorative interventions on optic nerve oligodendrocytes in vivo and tumor cell growth in vitro, respectively. Results Clinically relevant carboplatin dosing induced oligodendrocyte loss and impaired myelin sheath structure in the optic nerves of Nf1+/- mice, an effect not observed following vinca alkaloids or MEK inhibitor (selumetinib) treatment. Carboplatin downregulates genes essential for cholesterol biosynthesis and decreases cholesterol levels in carboplatin-exposed Nf1+/- optic nerves, such that dietary cholesterol supplementation after carboplatin exposure restored oligodendrocyte numbers. Carboplatin also increases the density of monocytes (microglia/macrophages) in the Nf1+/- optic nerves. Using PLX5622 (a CSF1R inhibitor) to reduce monocytes numbers or using clemastine to promote the generation and survival of oligodendrocytes, alleviated the oligodendrocyte loss caused by carboplatin treatment. Notably, PLX5622 and clemastine reduced the viability of Nf1-mutant optic glioma tumor cells. Conclusions Our findings demonstrate that carboplatin induces oligodendroglial toxicity in Nf1-mutant optic nerves, which can be mitigated by clemastine, PLX5622, or dietary cholesterol following carboplatin exposure.

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