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H2020Individual fellowship2018–2020

EpiBarrier · Control of the blood-brain barrier integrity during seizures via the ATP-gated P2X7 receptor

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2018-04-01 → 2020-03-31
EU contribution
€175,866
Participants
1
Scheme
MSCA-IF-EF-ST

Lines connect the coordinator with its partners.

Results in brief

Control of the blood-brain barrier integrity during seizures via the ATP-gated P2X7 receptor

EpiBarrier is focused on the study of epilepsy, a chronic neurological disease, that affects approximately 65 million people worldwide. Major challenges in epilepsy include social disadvantages, an increased risk for early mortality, and accompanying co-morbidities such as depression and anxiety. Currently, there are more than 25 drugs that suppress seizures, but they have little effect on epileptogenesis, the process leading to a reduced seizure threshold after transient brain insults. Therefore, there is an urgent need to develop new treatments targeting disease progression, based on a non-classical mechanism of action. In the last decades, special emphasis has been given to the dysfunction of cerebral vasculature and inflammatory processes as important players in epilepsy development, with particular attention on changes in the blood-brain barrier (BBB) functionality. The main objective of this project is to test whether P2X7 receptor signalling contributes to BBB opening during seizures and established epilepsy and whether P2X7 receptor inhibition ameliorates BBB disruption, thereby reducing seizure severity and the development of epilepsy.

Data: CORDIS, © European Union

Project objective

Epilepsy is the most common chronic neurological disorder, affecting ~50 million people. Major challenges in epilepsy include non-responsiveness to treatment and no effect on disease progression provided by anti-epileptic drugs. Over the past decade, particular attention has been paid to dysfunction of cerebral vasculature and inflammatory processes as important players in epileptogenic processes, with a specific emphasis on failure of the blood–brain barrier (BBB). The BBB is a complex cellular network forming a continuous cellular barrier separating the CNS from the bloodstream. A functional BBB is crucial in maintaining brain homeostasis and to prevent the entry of toxic compounds and immune cells into the CNS. During pathology, however, the permeability of the BBB may increase with the resulting entry into the CNS of blood-borne molecules and cells. Leakage of the BBB is one of the earliest characteristic pathophysiological disturbances following status epilepticus and may play an important role in the development of epilepsy. Consequently, drugs targeting BBB function may represent novel treatment strategies in epilepsy. The purinergic ATP-gated P2X7 receptor has gained much attention recently as novel target in the treatment of epilepsy. Expressed on all cell types in the CNS including endothelial cells, P2X7 has been associated with numerous damaging processes pertinent to epileptogenesis, such as inflammation and opening of the BBB. ATP and the P2X7 downstream target Interleukin-1β contribute to the disruption of the BBB and P2X7 antagonism protects against BBB disruption during intracerebral hemorrhage. To date, however, we do not know whether seizure-induced changes of the BBB are dependent on P2X7 signaling, and whether this process can be targeted. By using newly developed transgenic animal models, RNA sequencing and cutting edge imaging techniques we will determine how P2X7 impacts on BBB integrity during seizures and what genes are regulated by P2X7.

Original text from CORDIS.

Participants

  • ROYAL COLLEGE OF SURGEONS IN IRELAND · DUBLIN 2CoordinatorIreland

Links

Data: CORDIS, © European Union