Abstract
Glial cells actively maintain the homeostasis of brain parenchyma, regulating neuronal excitability and preserving the physiological composition of the extracellular milieu. Under pathological conditions, some functions of glial cells could be compromised, exacerbating the neurotoxic processes. We investigated if the homeostatic activities of astrocytes and microglia could be modulated by the voltage-gated K+ channel Kv1.3. To this end we used in vitro and in vivo systems to model cell-to-cell interactions in tumoral conditions, using a specific inhibitor of Kv1.3 channels, 5-(4-phenoxybutoxy) psoralen (PAP-1). We demonstrated that PAP-1 increases astrocytic glutamate uptake, reduces glioma-induced neurotoxicity, and decreases microglial migration and phagocytosis. We also found in a tumor blood brain barrier model that Kv1.3 activity is required for its integrity. The crucial role of Kv1.3 channels as modulators of glial cell activity was confirmed in a mouse model of glioma, where PAP-1 treatment reduces tumor volume only in the presence of active glutamate transporters GLT-1. In the same mouse model, PAP-1 reduces astrogliosis and microglial infiltration. PAP-1 also reduces tumor cell invasion. All these findings point to Kv1.3 channels as potential targets to re-instruct glial cells toward their homeostatic functions, in the context of brain tumors.
Highlights
Glial cells actively maintain the homeostasis of brain parenchyma, regulating neuronal excitability and preserving the physiological composition of the extracellular milieu
PAP-1 was still able to exert neuroprotection against glioma-induced toxicity (Fig. 1b), to a reduced extent, as the number of viable cells remained slightly but significantly reduced. This demonstrates the primary involvement of astrocytes in the PAP-1 mediated effects together with possible minor contribution by microglia. To investigate whether this astrocyte-dependent neuroprotection involved the activity of glutamate transporters, the experiments were performed in the presence of dihydrokainic acid (DHK, 500 μM, 18 h), a specific inhibitor of GLT-1
Kv1.3 channels are functionally expressed by microglial cells[20,22], and, as we reported in Figure1b, microglia are partially involved in PAP-1-mediated neuroprotection against glioma
Summary
Glial cells actively maintain the homeostasis of brain parenchyma, regulating neuronal excitability and preserving the physiological composition of the extracellular milieu. We investigated if the homeostatic activities of astrocytes and microglia could be modulated by the voltage-gated K+ channel Kv1.3 To this end we used in vitro and in vivo systems to model cell-to-cell interactions in tumoral conditions, using a specific inhibitor of Kv1.3 channels, 5-(4-phenoxybutoxy) psoralen (PAP-1). The crucial role of Kv1.3 channels as modulators of glial cell activity was confirmed in a mouse model of glioma, where PAP-1 treatment reduces tumor volume only in the presence of active glutamate transporters GLT-1. Astrocytic uptake of extracellular glutamate through the excitatory amino acid transporter 2 (GLT-1) is driven by intra/extra cellular ion balance, being favoured by higher intracellular K+ concentrations[7,8,9] In pathological microenvironments, such as those induced by epilepsy, neurodegenerative diseases or retinal inflammation, glial cells lose their ability to buffer glutamate[10] and to balance the interstitial concentration of K+ 11.
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