NNS 2015 Program & Abstract Book

brain 2

-cAMP-adenosine pathway; similar experiments in CNPase

knockout mice suggest that CNPase is involved in the metabolism of

endogenous 2

-cAMP to 2

-AMP and to adenosine and provides

neuroprotection. In CSF from TBI patients, 2

-cAMP is increased in

the initial 12 hours after injury and correlates with CSF levels of 2

-AMP

and adenosine. We conclude that the 2

-cAMP-adenosine pathway

exists in the brain and is likely neuroprotective.

Keywords: 2’, 3’-cAMP, 2’-AMP, 3’-AMP, Adenosine, CNPase

S14-02

ROLE OF ADENOSINE IN POSTTRAUMATIC SEIZURES

AND EPILEPSY: A POTENTIAL NEW TARGET

Detlev Boison

Legacy Research Institute, Robert Stone Dow Neurobiology Labora-

tories, Portland, USA

Brain trauma and related injuries trigger a sequela of events that cause

glial activation. Astrogliosis is a major consequence of traumatic brain

injury and associated with increased expression of the major adenosine

metabolizing enzyme adenosine kinase (ADK); those changes result in

adenosine deficiency as characteristic chronic response of affected brain

areas to a prior injury. In rodent models of neuronal injury and epilepsy

we have demonstrated that

(i)

overexpression of ADK and resulting

adenosine deficiency can be a direct cause for epileptic seizures, and

(ii)

that adenosine deficiency induces changes to the epigenome resulting in

increased DNA methylation status. Based on those mechanisms, adeno-

sine augmentation therapies hold promise for the treatment, as well as

prevention, of posttraumatic epilepsy. Data are presented showing that

therapies that reconstruct adenosine homeostasis locally (e.g. by adeno-

sine releasing bioengineered brain implants, or gene therapy) can effec-

tively suppress epileptic seizures in rodent models of epilepsy.

Furthermore, transient therapeutic adenosine augmentation affects path-

ogenic changes of the epigenome (i.e., hypermethylation of DNA) long-

term and thereby prevents the development and progression of epilepsy.

Keywords: adenosine, adenosine kinase, silk, epigenetics, DNA

methylation, epileptogenesis

S14-03

URATE - A NOVEL POTENTIAL THERAPY IN CNS INJURY

AND NEURODEGENERATION

Michael Schwarzschild

Massachusetts General Hospital, Neurology, Boston, USA

Urate elevation has recently emerged as a promising and realistic neu-

roprotective strategy for the treatment neurodegenerative diseases and

acute neuronal injury. Urate (a.k.a. uric acid) circulates at higher levels in

humans and other hominoids due to mutations in the gene encoding the

urate-catabolizing enzyme urate oxidase (UOx) during primate evolu-

tion. Although the increased levels now predispose humans to urate

crystal disorders like gout, they likely conferred an evolutionary ad-

vantage to our ancestors. The discovery that urate has potent antioxidant

properties equivalent to those of ascorbate and is the main source of

antioxidant capacity in human plasma led to the theory that urate serves

as an endogenous protectant against diseases characterized by oxidative

damage, including Parkinson’s disease (PD). Higher urate has been

identified as a robust inverse risk factor for PD and as a favorable

prognostic biomarker among people already diagnosed with PD. Simi-

larly, lower urate levels have been linked to the development or more

rapid progression of other neurodegenerative diseases including ALS.

Laboratory studies in cellular and animal models of PD have further

substantiated the neuroprotective potential of urate, and interestingly

have implicated an astrocyte-dependent mechanism through the Nrf2

antioxidant response pathway. Of note, the urate precursor inosine has

been found to be improve recovery in animal models of spinal cord and

traumatic brain injury (TBI), and both inosine and urate are markedly

increased locally after TBI. Based on convergent lines of evidence

suggesting that urate may be a mediator as well as a marker for slower

disease progression, a randomized double-blind placebo-controlled

phase 2 clinical trial of the inosine in early PD was conducted, finding

that urate levels in blood and CSF could be effectively, safely and

chronically elevated in this population. In parallel, urate itself has been

shown to confer protection against acute cerebral ischemia in rodent

models of stroke and led to a phase 2 randomized double-blind placebo-

controlled phase 2 clinical trial of intravenous urate in the setting of an

acute ischemic stroke, with encouraging safety and efficacy results.

Keywords: Urate, Inosine, Nrf-2, Parkinson’s disease, TBI, stroke

S15 Post-Traumatic Epilepsy: Mechanisms and Man-

ifestations

S15-01

CLINICAL RESEARCH INSIGHTS INTO PERSONAL BIOL-

OGY AND BIOSUSCEPTIBILTIY WITH EPILEPTOGENESIS

AND POST-TRAUMATIC EPILEPSY

Amy Wagner

Univ. of Pittsburgh, Dept Phys Medicine and Rehab, Pittsburgh, USA

Epileptogenesis and the development of Post-traumatic Epilepsy (PTE)

is relatively common after moderate to severe traumatic brain injury

(TBI). Clinical predictors are limited in their ability to identify those at

highest risk for PTE development and to identify who may benefit most

from prophylactic treatment strategies. We will review the latest evi-

dence for clinical predictors of PTE risk, summarize points of over-

lapping pathophysiology with TBI and epilepsy, and explore the current

evidence for genetic and proteomic biomarkers with informing the

process of epileptogenesis and epilepsy development for those with

TBI. Contemporary work from our laboratory will be reviewed that

identifies biomarkers within inflammatory pathways as well as excit-

atory and neuroinbitory pathways as possible contributors to epilepto-

genesis and PTE. Future directions for advancing this work, including

validation studies and therapeutic target exploration, will be discussed.

Future opportunities for Rehabilomics based approaches to exploring

biological associations with recovery based outcomes will be discussed.

Keywords: biosusceptibility, Rehabilomics, epileptogenesis, risk

assessment

S15-02

SEIZURE SUSCEPTIBILITY AFTER TRAUMATIC INJURY

TO THE PEDIATRIC BRAIN

Bridgette Semple

University of Melbourne (Royal Melbourne Hospital), Department of

Medicine, Parkville, Australia

The occurrence of post-traumatic epilepsy is particularly high after injury

at a young age, and has been associated with poorer functional outcomes,

suggesting that the developing brain may show elevated vulnerability to

post-traumatic epileptogenesis. However, most existing models of post-

traumatic epileptogenesis focus on injury to the adult brain. Here, we

have investigated seizure susceptibility in mice after injury at postnatal

day 21, using a well-characterized model of controlled cortical impact to

approximate a toddler-aged child. Within weeks, brain-injured mice

A-150