Variations of ATP and its metabolites in the hippocampus of rats subjected to pilocarpine-induced temporal lobe epilepsy

Doná, Flávia; Conceição, Isaltino Marcelo; Ulrich, Henning; Ribeiro, Eliane; Freitas, Thalma Ariani; Nencioni, Ana Leonor Abrahão; Fernandes, Maria José da Silva

doi:10.1007/s11302-016-9504-9

Cited by 30 publications

(19 citation statements)

References 35 publications

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“…(ii) We still do not know when ATP is released and what local concentrations are reached. Attempts have been made (Doná et al, 2016 ), however, the techniques used may lack sufficient temporal resolution to detect seizure-induced ATP release in the brain. (iii) What are the cell-specific contributions of P2X7 to disease progression?…”

Section: Discussionmentioning

confidence: 99%

The ATP-Gated P2X7 Receptor As a Target for the Treatment of Drug-Resistant Epilepsy

2017

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Despite the progress made in the development of new antiepileptic drugs (AEDs), the biggest challenges that epilepsy presents to drug development have remained unchanged for the last 80 years: finding a treatment with potential for modifying disease progression and reducing the percentage of patients resistant to all pharmacological interventions. The mechanism of action of the majority of AEDs is based on blocking Na+ and/or Ca2+ channels, promotion of GABA or inhibition of glutamate signaling. In order for further progress to be made, however, a fuller picture of epilepsy will need to be considered, including changes to blood–brain barrier permeability, synaptic plasticity, network reorganization, and gliosis. In particular, brain inflammation has attracted much attention over recent years. Emerging evidence demonstrates a causal role for brain inflammation in lowering seizure thresholds and driving epileptogenesis. Consistent with this, intervening in pro-inflammatory cascades has shown promise in animal models of epilepsy, with clinical trials of anti-inflammatory agents already underway. The ATP-gated purinergic P2X7 receptor (P2X7) has been proposed as a novel drug target for a host of neurological conditions, including epilepsy. Constitutive expression of P2X7 in the CNS is mainly on microglia, but neuronal and astroglial expression has also been suggested. Its function as a gatekeeper of inflammation is most clearly understood, however, it also plays a number of other important roles pertinent to icto- and epileptogenesis: depolarization of the cell membrane, release of macromolecules, induction of apoptosis and synaptic reorganization. Changes in P2X7 expression have been reported following prolonged seizures (status epilepticus) and during chronic epilepsy in both experimental models and patients. While much of the early work focused on the study of P2X7 during status epilepticus, there is now mounting data showing involvement of this receptor during epilepsy. The present short review will discuss the most recent findings concerning P2X7 expression and function during epilepsy and the clinical potential for P2X7 antagonists as novel AEDs.

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Section: Discussionmentioning

confidence: 99%

The ATP-Gated P2X7 Receptor As a Target for the Treatment of Drug-Resistant Epilepsy

2017

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“…However, evidence suggests that extracellular nucleotides are involved. For example, altered levels of extracellular ATP 7,8 and adenosine [9][10][11] as well as ectonucleotidase activity 12,13 are found in the brains of rat epilepsy models. In addition, levels of extracellular adenosine increased in the hippocampus of epilepsy patients during seizures.…”

Section: Introductionmentioning

confidence: 99%

Disruption of theATP/adenosine balance inCD39^−/−mice is associated with handling‐induced seizures

et al. 2017

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Seizures are due to excessive, synchronous neuronal firing in the brain and are characteristic of epilepsy, the fourth most prevalent neurological disease. We report handling-induced and spontaneous seizures in mice deficient for CD39, a cell-surface ATPase highly expressed on microglial cells. CD39 mice with handling-induced seizures had normal input-output curves and paired-pulse ratio measured from hippocampal slices and lacked microgliosis, astrogliosis or overt cell loss in the hippocampus and cortex. As expected, however, the cerebrospinal fluid of CD39 mice contained increased levels of ATP and decreased levels of adenosine. To determine if immune activation was involved in seizure progression, we challenged mice with lipopolysaccharide (LPS) and measured the effect on microglia activation and seizure severity. Systemic LPS challenge resulted in increased cortical staining of Iba1/CD68 and gene array data from purified microglia predicted increased expression of interleukin-8, triggering receptor expressed on myeloid cells 1, p38, pattern recognition receptors, death receptor, nuclear factor-κB , complement, acute phase, and interleukin-6 signalling pathways in CD39 versus CD39 mice. However, LPS treatment did not affect handling-induced seizures. In addition, microglia-specific CD39 deletion in adult mice was not sufficient to cause seizures, suggesting instead that altered expression of CD39 during development or on non-microglial cells such as vascular endothelial cells may promote the seizure phenotype. In summary, we show a correlation between altered extracellular ATP/adenosine ratio and a previously unreported seizure phenotype in CD39 mice. This work provides groundwork for further elucidation of the underlying mechanisms of epilepsy.

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“…This also included an approximately fourfold increase in extracellular ATP levels. 183 nucleotides, injection of ATP, the ATP analogue 2,3-O-(4benzoylbenzoyl) ATP (BzATP) or ADP, into the lateral ventricle of mice caused high-amplitude, high-frequency polyspiking on electroencephalography (ATP) 184 and increased seizure severity during KA (0.3 µg, IA)-induced status epilepticus (BzATP and ADP). 119,185 In contrast to a proconvulsant function of extracellular ATP, injection of uridine-5′-triphosphate into the lateral ventricle of mice reduced seizure severity during IA KA-induced status epilepticus.…”

Section: Purinergic Signaling During Seizures and Epilepsy Atp Release During Seizures And Epilepsymentioning

confidence: 99%

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

Engel¹,

Smith²,

Alves³

2021

JIR

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Treatment of epilepsy remains a clinical challenge, with >30% of patients not responding to current antiseizure drugs (ASDs). Moreover, currently available ASDs are merely symptomatic without altering significantly the progression of the disease. Inflammation is increasingly recognized as playing an important role during the generation of hyperexcitable networks in the brain. Accordingly, the suppression of chronic inflammation has been suggested as a promising therapeutic strategy to prevent epileptogenesis and to treat drug-refractory epilepsy. As a consequence, a strong focus of ongoing research is identification of the mechanisms that contribute to sustained inflammation in the brain during epilepsy and whether these can be targeted. ATP is released in response to several pathological stimuli, including increased neuronal activity within the central nervous system, where it functions as a neuro-and gliotransmitter. Once released, ATP activates purinergic P2 receptors, which are divided into metabotropic P2Y and ionotropic P2X receptors, driving inflammatory processes. Evidence from experimental models and patients demonstrates widespread expression changes of both P2Y and P2X receptors during epilepsy, and critically, drugs targeting both receptor subtypes, in particular the P2Y 1 and P2X 7 subtypes, have been shown to possess both anticonvulsive and antiepileptic potential. This review provides a detailed summary of the current evidence suggesting ATP-gated receptors as novel drug targets for epilepsy and discusses how P2 receptor-driven inflammation may contribute to the generation of seizures and the development of epilepsy.

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Variations of ATP and its metabolites in the hippocampus of rats subjected to pilocarpine-induced temporal lobe epilepsy

Cited by 30 publications

References 35 publications

The ATP-Gated P2X7 Receptor As a Target for the Treatment of Drug-Resistant Epilepsy

The ATP-Gated P2X7 Receptor As a Target for the Treatment of Drug-Resistant Epilepsy

Disruption of theATP/adenosine balance inCD39^−/−mice is associated with handling‐induced seizures

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

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Variations of ATP and its metabolites in the hippocampus of rats subjected to pilocarpine-induced temporal lobe epilepsy

Cited by 30 publications

References 35 publications

The ATP-Gated P2X7 Receptor As a Target for the Treatment of Drug-Resistant Epilepsy

The ATP-Gated P2X7 Receptor As a Target for the Treatment of Drug-Resistant Epilepsy

Disruption of theATP/adenosine balance inCD39−/−mice is associated with handling‐induced seizures

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

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Disruption of theATP/adenosine balance inCD39^−/−mice is associated with handling‐induced seizures