Genetic variation in the adenosine regulatory cycle is associated with posttraumatic epilepsy development

Diamond, Matthew L.; Ritter, Anne C.; Jackson, Edwin K.; Conley, Yvette P.; Kochanek, Patrick M.; Boison, Detlev; Wagner, Amy K.

doi:10.1111/epi.13044

Cited by 54 publications

(39 citation statements)

References 48 publications

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“…However, previous work developing prognostic models for PTS using a more recent cohort from the TBIMS‐NDB did not find race to be associated with PTS and did not investigate race as a PTS predictor in multivariable modeling . Differences in late PTS risk by race may also potentially reflect genetic differences thought to influence PTS risk . Future work might investigate racial/ethnic differences in epilepsy‐related outcomes and comorbidity burden …”

Section: Discussionmentioning

confidence: 96%

Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study

et al. 2016

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SUMMARYObjective: Determine incidence of posttraumatic seizure (PTS) following traumatic brain injury (TBI) among individuals with moderate-to-severe TBI requiring rehabilitation and surviving at least 5 years. Methods: Using the prospective TBI Model Systems National Database, we calculated PTS incidence during acute hospitalization, and at years 1, 2, and 5 postinjury in a continuously followed cohort enrolled from 1989 to 2000 (n = 795). Incidence rates were stratified by risk factors, and adjusted relative risk (RR) was calculated. Late PTS associations with immediate (<24 h), early (24 h-7 day), or late seizures (>7 day) versus no seizure prior to discharge from acute hospitalization was also examined. Results: PTS incidence during acute hospitalization was highest immediately (<24 h) post-TBI (8.9%). New onset PTS incidence was greatest between discharge from inpatient rehabilitation and year 1 (9.2%). Late PTS cumulative incidence from injury to year 1 was 11.9%, and reached 20.5% by year 5. Immediate/early PTS RR (2.04) was increased for those undergoing surgical evacuation procedures. Late PTS RR was significantly greater for individuals who self-identified as a race other than black/white (year 1 RR = 2.22), and for black individuals (year 5 RR = 3.02) versus white individuals. Late PTS was greater for individuals with subarachnoid hemorrhage (year 1 RR = 2.06) and individuals age 23-32 (year 5 RR = 2.43) and 33-44 (year 5 RR = 3.02). Late PTS RR years 1 and 5 was significantly higher for those undergoing surgical evacuation procedures (RR: 3.05 and 2.72, respectively).

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Section: Discussionmentioning

confidence: 96%

Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study

et al. 2016

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“…Consistent with these human data, increases in CD73 activity were also found in rodent models of epilepsy (Bonan et al, 2000a; Bonan et al, 2000b; Schoen et al, 1999). More recently, genetic variants of both CD73 and ADK were associated with the development of posttraumatic epilepsy in a human study involving samples from 162 subjects (Diamond et al, 2015). …”

Section: Disruption Of Adenosine Homeostasismentioning

confidence: 99%

Adenosinergic signaling in epilepsy

Boison

2016

Neuropharmacology

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Despite the introduction of at least 20 new antiepileptic drugs (AEDs) into clinical practice over the past decades, about one third of all epilepsies remain refractory to conventional forms of treatment. In addition, currently used AEDs have been developed to suppress neuronal hyperexcitability, but not necessarily to address pathogenic mechanisms involved in epilepsy development or progression (epileptogenesis). For those reasons endogenous seizure control mechanisms of the brain may provide alternative therapeutic opportunities. Adenosine is a well characterized endogenous anticonvulsant and seizure terminator of the brain. Several lines of evidence suggest that endogenous adenosine-mediated seizure control mechanisms fail in chronic epilepsy, whereas therapeutic adenosine augmentation effectively prevents epileptic seizures, even those that are refractory to conventional AEDs. New findings demonstrate that dysregulation of adenosinergic mechanisms are intricately involved in the development of epilepsy and its comorbidities, whereas adenosine-associated epigenetic mechanisms may play a role in epileptogenesis. The first goal of this review is to discuss how maladaptive changes of adenosinergic mechanisms contribute to the expression of seizures (ictogenesis) and the development of epilepsy (epileptogenesis) by focusing on pharmacological (adenosine receptor dependent) and biochemical (adenosine receptor independent) mechanisms as well as on enzymatic and transport based mechanisms that control the availability (homeostasis) of adenosine. The second goal of this review is to highlight innovative adenosine-based opportunities for therapeutic intervention aimed at reconstructing normal adenosine function and signaling for improved seizure control in chronic epilepsy. New findings suggest that transient adenosine augmentation can have lasting epigenetic effects with disease modifying and antiepileptogenic outcome.

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“…Knowing that the A 2A receptor is preferentially activated by adenosine originated from released ATP in the hippocampus [31], we also evaluated the expression and localization of ecto-5′-nucleotidase/ CD73 (EC3.1.3.5), the rate-limiting enzyme for extracellular adenosine formation in the brain. It is worth noting that genetic variations in enzymes and/or transporters influencing extracellular adenosine homeostasis, including ecto-5′-nucleotidase/CD73, have been significantly associated with epileptogenesis and posttraumatic epilepsy risk and are, therefore, worth to be explored as therapeutic targets for pharmacological development [32].…”

Section: Introductionmentioning

confidence: 99%

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

Barros‐Barbosa

Ferreirinha

Oliveira

et al. 2016

Purinergic Signalling

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Refractoriness to existing medications of up to 80 % of the patients with mesial temporal lobe epilepsy (MTLE) prompts for finding new antiepileptic drug targets. The adenosine A 2A receptor emerges as an interesting pharmacological target since its excitatory nature partially counteracts the dominant antiepileptic role of endogenous adenosine acting via inhibitory A 1 receptors. Gain of function of the excitatory A 2A receptor has been implicated in a significant number of brain pathologies commonly characterized by neuronal excitotoxicity. Here, we investigated changes in the expression and cellular localization of the A 2A receptor and of the adenosine-generating enzyme, ecto-5′-nucleotidase/ CD73, in the hippocampus of control individuals and MTLE human patients. Western blot analysis indicates that the A 2A receptor is more abundant in the hippocampus of MTLE patients compared to control individuals. Immunoreactivity against the A 2A receptor predominates in astrocytes staining positively for the glial fibrillary acidic protein (GFAP). No colocalization was observed between the A 2A receptor and neuronal cell markers, like synaptotagmin 1/2 (nerve terminals) and neurofilament 200 (axon fibers). Hippocampal astrogliosis observed in MTLE patients was accompanied by a proportionate increase in A 2A receptor and ecto-5′-nucleotidase/CD73 immunoreactivities. Given our data, we hypothesize that selective blockade of excessive activation of astrocytic A 2A receptors and/or inhibition of surplus adenosine formation by membrane-bound ecto-5′-nucleotidase/CD73 may reduce neuronal excitability, thus providing a novel therapeutic target for drug-refractory seizures in MTLE patients. • Ecto-5′-nucleotidase/CD73 localizes in close proximity with adenosine A 2A receptors in astrocytes of the human hippocampus. Keywords Mesial temporal lobe epilepsy (MTLE• Up-regulation of A 2A receptors and ecto-5′-nucleotidase/CD73 associates with astrogliosis of the hippocampus of MTLE patients.• Targeting astrocytic A 2A activation and/or adenosine formation via ecto-5′-nucleotidase/CD73 may control neuronal excitability.• Inhibitors of astrocytic A 2A receptors and ecto-5′-nucleotidase/CD73 may be a novel therapeutic strategy to control drug-refractory MTLE.

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Genetic variation in the adenosine regulatory cycle is associated with posttraumatic epilepsy development

Cited by 54 publications

References 48 publications

Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study

Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study

Adenosinergic signaling in epilepsy

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

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