Therapeutic Potential of Astrocyte Purinergic Signalling in Epilepsy and Multiple Sclerosis

Abstract

Epilepsy and multiple sclerosis (MS), two of the most common neurological diseases, are characterized by the establishment of inflammatory environment in the central nervous system that drives disease progression and impacts on neurodegeneration. Current therapeutic approaches in the treatments of epilepsy and MS are targeting neuronal activity and immune cell response, respectively. However, the lack of fully efficient responses to the available treatments obviously shows the need to search for novel therapeutic candidates that will not exclusively target neurons or immune cells. Accumulating knowledge on epilepsy and MS in humans and analysis of relevant animal models, reveals that astrocytes are promising therapeutic candidates to target as they participate in the modulation of the neuroinflammatory response in both diseases from the initial stages and may play an important role in their development. Indeed, astrocytes respond to reactive immune cells and contribute to the neuronal hyperactivity in the inflamed brain. Mechanistically, these astrocytic cell to cell interactions are fundamentally mediated by the purinergic signalling and involve metabotropic P2Y1 receptors in case of astrocyte interactions with neurons, while ionotropic P2X7 receptors are mainly involved in astrocyte interactions with autoreactive immune cells. Herein, we review the potential of targeting astrocytic purinergic signalling mediated by P2Y1 and P2X7 receptors to develop novel approaches for treatments of epilepsy and MS at very early stages.

Keywords: P2X7; P2Y1; astroglia; disease; intercellular interaction; neuroinflammation.

FIGURE 1

Purinergic signalling between astrocytes, neurons, microglia and CNS-infiltrated immune cell in epilepsy and multiple sclerosis. The ATP release and the involvement of the specific astrocytic purinergic receptor (PR) type is depicted for the diseases. Activation of astrocytic P2Y1R and P2X7R induce the rise in intracellular Ca²⁺. Activation of P2Y1R promotes the release of glutamate, which acts on the presynaptic and postsynaptic glutamate receptors (NMDAR and mGluR). Activation of P2X7Rs is mediated by the release of ATP through connexin-43 hemichannels and/or pannexin-1 channels. Integrins are depicted as a putative link to the astrocytic P2X7R activation via connexin-43/pannexin-1-derived ATP.