Epilepsy, characterized by the occurrence of spontaneous seizures, is one of the most common chronic brain diseases affecting approximately 1% of the world population. Clinical challenges include drug- unresponsiveness (~30% of patients) and adverse side-effects to current medication, the lack of disease-modifying therapy and the fact that there are no biomarkers for seizure diagnosis and to predict disease progression.
The main focus of our research is to study pathological mechanisms underlying the development of epilepsy and to identify novel disease biomarkers for a better and faster diagnosis of seizures based on purinergic signalling.
Adenosine triphosphate (ATP), generally known as the universal cellular energy currency, also functions as an important extracellular signalling molecule. Usually found in very low concentrations outside the cell, extracellular ATP increases rapidly under pathological conditions, including neuronal hyperexcitability. Once released, ATP activates specific purinergic P2 receptors, including metabotropic P2Y and ionotropic P2X receptors.
Demonstrating the therapeutic potential of treatments based on purinergic signalling, we have been the first to show the anticonvulsive and anti-epileptogenic potential of targeting the ATP-gated P2X7 channel (Engel et al., 2012, FASEBJ; Jimenez-Pacheco et al., 2016, J Neurosci).
P2X7 receptor expression and function increases following status epilepticus and during epilepsy, both in animal models and the patient brain.
On the other hand, blocking P2X7 receptor activitiy reduces seizure severity and brain damage during status epilepticus in adults and during early life seizures (Mesuret et al., 2014, CNS Neurosci Ther).
During epilepsy, P2X7 antagonism decreases seizure frequency and accompanying neuroinflammation. Critically, anti-epileptogenic effects provided by P2X7 antagonism persist beyond drug-washout, suggesting a disease-modifying potential (Jimenez-Pacheco et al., 2016, J Neurosci).
Further research by our group has identified the transcription factor SP1 and microRNA-22 as controlling P2X7 expression in the brain during seizures, dependent on seizure severity and intracellular calcium (Jimenez-Mateos et al., Sci Rep, 2015; Engel et al., 2017, Biochim Biophys Acta Mol Cell Res).
More recently, our group has also shown a role for the metabotropic P2Y receptor family in epilepsy (Alves et al., 2018, Epilepsia) with antagonists blocking the P2Y1 receptor reducing seizures during status epilepticus and during chronic epilepsy.