Abstract
Platinum-based chemotherapeutics still play an essential role in cancer treatment. Despite their high effectiveness, severe side effects such as chemotherapy-induced neuropathy (CIPN) occur frequently. The pathophysiology of CIPN by platinum-based chemotherapeutics is not fully understood yet, but primarily the disturbance of dorsal root ganglion cells is discussed. However, there is increasing evidence of central nervous system involvement with activation of spinal cord astrocytes after treatment with chemotherapeutics. We investigated the influence of cis- or oxaliplatin on the functionality of cultured rat spinal cord astrocytes by using immunocytochemistry and patch-clamp electrophysiology. Cis- or oxaliplatin activated spinal astrocytes and led to downregulation of the excitatory amino acid transporter 1 (EAAT1) expression. Furthermore, the expression and function of potassium channel Kir4.1 were modulated. Pre-exposure to a specific Kir4.1 blocker in control astrocytes led to a reduced immune reactivity (IR) of EAAT1 and a nearly complete block of the current density. When spinal astrocytes were pre-exposed to antibiotic minocycline, all effects of cis- or oxaliplatin were abolished. Taken together, the modulation of Kir4.1 and EAAT1 proteins in astrocytes could be linked to the direct impact of cis- or oxaliplatin, identifying spinal astrocytes as a potential target in the prevention and treatment of chemotherapy-induced neuropathy.
Highlights
Platinum-based chemotherapeutics as cis- or oxaliplatin still play an essential role in treating different cancer types today
We describe a direct relation between glutamate transporter excitatory amino acid transporter 1 (EAAT1) expression and the function of potassium channel
Our study demonstrates a direct influence of the chemotherapeutic drugs cis- and oxaliplatin on the expression and function of proteins such as GFAP, Kir4.1, and EAAT1 in spinal astrocytes, suggesting a potential role for those cells in CIPN
Summary
Platinum-based chemotherapeutics as cis- or oxaliplatin still play an essential role in treating different cancer types today. Besides its efficacy in tumor treatment, cis- or oxaliplatin leads to severe neurotoxic side effects, resulting in chemotherapy-induced neuropathy (CIPN) [1,2,3]. CIPN’s typical symptoms are impaired sensory function, manifested in numbness, tingling, spontaneous feeling of touch, and paresthesia [4,5] Painful sensations such as non-evoked burning, shooting, and mechanical or thermal allodynia or hyperalgesia occur frequently [1,4,6,7,8,9]. The drug-specific pathomechanisms leading to CIPN are not fully understood, but several are suggested, such as calcium disturbance in dorsal root ganglia neurons, mitochondrial dysfunctions, or activation of satellite glial cells [10,11,12,13,14,15]. Treatment with paclitaxel and oxaliplatin shows the involvement of the central nervous system (CNS) in the activation of spinal cord astrocytes [16,17]
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