Neonatal Seizures and Purinergic Signalling

Abstract

Neonatal seizures are one of the most common comorbidities of neonatal encephalopathy, with seizures aggravating acute injury and clinical outcomes. Current treatment can control early life seizures; however, a high level of pharmacoresistance remains among infants, with increasing evidence suggesting current anti-seizure medication potentiating brain damage. This emphasises the need to develop safer therapeutic strategies with a different mechanism of action. The purinergic system, characterised by the use of adenosine triphosphate and its metabolites as signalling molecules, consists of the membrane-bound P1 and P2 purinoreceptors and proteins to modulate extracellular purine nucleotides and nucleoside levels. Targeting this system is proving successful at treating many disorders and diseases of the central nervous system, including epilepsy. Mounting evidence demonstrates that drugs targeting the purinergic system provide both convulsive and anticonvulsive effects. With components of the purinergic signalling system being widely expressed during brain development, emerging evidence suggests that purinergic signalling contributes to neonatal seizures. In this review, we first provide an overview on neonatal seizure pathology and purinergic signalling during brain development. We then describe in detail recent evidence demonstrating a role for purinergic signalling during neonatal seizures and discuss possible purine-based avenues for seizure suppression in neonates.

Targeting Neuroinflammation via Purinergic P2 Receptors for Disease Modification in Drug-Refractory Epilepsy

“…Therefore, the targeting of P2X 7 , thought to be mainly activated during pathological release of ATP, 201 may represent a promising novel treatment strategy for neonates. 202 Other studies, however, have shown only a moderate or no anticonvulsant effect of P2X 7 antagonism. Using the maximal electroshock seizurethreshold test and the Ptz (87 mg/kg, IP) seizure-threshold test in mice, Fischer et al showed no anticonvulsant effects provided by P2X 7 antagonism using four antagonists (JNJ47965567, AFC5128, BBG, and tanshinone IIA sulfonate).…”

Hypoxia‐inducible factor 1 alpha (HIF‐1α) stimulated and P2X7 receptor activated by COVID-19, as a potential therapeutic target and risk factor for epilepsy

“…In turn, adenosine generated by the ectonucleotidases, such as NTPDases, NPPases, and alkaline, phosphatase activate P1 (G protein-coupled) receptors as a result of the nucleotide hydrolysis (Fig. 1 ) [ 33 – 36 ].

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Novel Point-of-Care Diagnostic Method for Neonatal Encephalopathy Using Purine Nucleosides

“…Purinergic signaling, characterized as a complex regulatory system governed by purine nucleotides such as ATP and nucleosides, is involved in many critical processes of brain development, such as cell proliferation and differentiation, neuron-glia communication, neurotransmitter modulation and inflammatory processes ( Rodrigues et al, 2019 ). In animal models of NE, inflammatory signaling is enhanced in conjunction with upregulation of purine receptors, which can be targeted therapeutically to reduce pathology ( Rodriguez-Alvarez et al, 2017 ; Menendez Mendez et al, 2020 ). Normally, purine signaling molecules (e.g., ATP, adenosine) have relatively low extracellular concentrations, and are also actively released following cellular stress such as inflammation and hypoxia ( Takahashi et al, 2010 ; Thauerer et al, 2012 ).…”