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(PS13) Human and rodent in vitro models for Chemotherapy-induced peripheral neuropathy


Authors:

Christina Nodin, PhD – External Collaborations Manager, Cellectricon AB

Paul Karila

Susanne Lardell, MS – External Collaborations Manager, Cellectricon AB

Abstract:

Background and Aims : Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of several commonly used chemotherapeutic drugs such as platinum drugs and taxanes and includes symptoms as pain, numbness and tingling. Symptoms are often correlated with dose and duration of treatment. Today, there are limited options for treatment and also a limited mechanistic understanding of the currently used drugs. There is therefore a need for efficient and physiologically relevant screening methods identifying new putative compounds.
Our optical electrophysiology technology platform enables high capacity testing of changes in neuronal excitability in native neuronal cultures in a multi-well plate format. The aim of this study was to develop a cell model to investigate the effects of CIPN-inducing chemotherapeutic agents on neuronal excitability. Also, morphological parameters of neurons and supporting cells such as microglia and astrocytes were investigated. Successful assay development would enable efficient screening of compounds reversing the effects induced by CIPN-inducing compounds.


Methods : Human induced pluripotent stem cells (hiPSC) differentiated into sensory neurons were sourced from Censo (www.censobio.com; Karila et al. 2017). Rat dorsal root ganglia (rDRG) were dissected and cells were dissociated (Sidders et al. 2018). Both cell types were cultured and the CIPN-inducing compounds oxaliplatin and paclitaxel were added to the cultures up to 7 days prior to evaluating the compound effects in the optical electrophysiology platform. The cultures were subsequently fixed to enable immunocytochemical investigation on morphology of neurons and supporting cells.


Results : Neuronal excitability
Oxaliplatin induced increased neuronal excitability in both hiPSC sensory neurons and in rDRGs. The effects were most pronounced after three days at 30 µM for hiPSC sensory neurons and after 7 days at 3 µM for rDRGs.
In contrast, in presence of paclitaxel, neuronal excitability was reduced in a concentration and time-dependent manner in both cell systems. Neuronal excitability was decreased already after 2.5 hours of incubation and further decreased over time to be close to 0% of the response after 7 days.

Morphological parameters
In presence of oxaliplatin, the neurons in the hiPSC cultures were more dispersed and the bundles of neurites appeared thinner (i.e. the bundles may contain fewer neurites). In rDRG cultures the total number of cells in the cultures was decreased but not the number of neurons, nor the neurite density.
In hiPSC cultures exposed to paclitaxel, bundles of neurites appeared thinner and cell bodies appeared to be more intensely stained compared to control. Paclitaxel reduced the number of neurons as well as the total number of cells in rDRG cultures. In addition, cell bodies appeared to be intensely stained, similar to the observation in hiPSC cultures.


Conclusions : By using our optical electrophysiology platform, we have developed models to efficiently evaluate effects of CIPN-inducing compounds in both human and rodent neuronal cultures. These models can be used to address translational aspects as well as for large scale screening for compounds that are reversing the effects induced by CIPN-inducing compounds.


References : Karila P, Karlsson A, Tams D, Barnes A, Karlsson M, 2017; Development of a human high throughput neuronal activity assay for chronic pain. SfN meeting 2017; 486.14/AA9.

Sidders B, Karlsson A, Kitching L, Torella R, Karila P, Phelan A, 2018; J Mol Biol. 2018 Sep 14;430(18 Pt A):3005-3015. doi: 10.1016/j.jmb.2018.07.016. Epub 2018 Jul 18.

Conflicts of Interest : No conflict of interest

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