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Targeting Neurodegeneration to Prevent Post-Traumatic Epilepsy T Idrish Alia,B, Juliana C

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Targeting Neurodegeneration to Prevent Post-Traumatic Epilepsy T Idrish Alia,B, Juliana C Neurobiology of Disease 123 (2019) 100–109 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi Review Targeting neurodegeneration to prevent post-traumatic epilepsy T Idrish Alia,b, Juliana C. Silvaa,b, Shijie Liua,b, Sandy R. Shultza,b, Patrick Kwana,b, ⁎ Nigel C. Jonesa,b, Terence J. O'Briena,b, a Department of Neuroscience, Central Clinical School, Monash University, The Alfred Hospital, Melbourne, Australia b Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Melbourne, Australia ARTICLE INFO ABSTRACT Keywords: In the quest for developing new therapeutic targets for post-traumatic epilepsies (PTE), identifying mechanisms Neurodegeneration relevant to development and progression of disease is critical. A growing body of literature suggests involvement Tauopathies of neurodegenerative mechanisms in the pathophysiology of acquired epilepsies, including following traumatic β amyloid brain injury (TBI). In this review, we discuss the potential of some of these mechanisms to be targets for the Neuroinflammation development of a therapy against PTE. Traumatic brain injury Post-traumatic epilepsy 1. Introduction In the quest to develop antiepileptic treatments that are disease- modifying - as opposed to those providing only symptomatic relief - it is Epilepsy is a common chronic group of neurological disorders that is necessary to identify new biological targets that are critical to the de- characterized by the occurrence of recurrent unprovoked seizures. Post- velopment and maintenance of the epileptic state. In this regard, new traumatic epilepsy (PTE) accounts for up to 20% of epilepsies due to an insights can be obtained from the overlapping mechanisms of neuro- identifiable acquired cause, i.e. “acquired epilepsies”, and follows a degeneration that may be involved in epilepsy and neurodegenerative traumatic brain injury that initiates a process of epileptogenesis, often diseases such as Alzheimer's (AD). Patients with neurodegenerative lasting months to years, before the first epileptic seizures are observed. conditions such as AD have a significantly increased risk to develop The mechanisms underlying epileptogenesis are not clearly understood, epilepsy compared to age matched controls (Abou-Khalil, 2010; but probably involve many structural and molecular alterations that Friedman et al., 2012; Nicastro et al., 2016). The accuracy of pre- alter neuronal excitation-inhibition balance and render the brain prone valence rates of epilepsy in AD are limited due to methodological dif- to generate recurrent spontaneous seizures (Avoli et al., 2016). The ficulties of performing such studies (Friedman et al., 2012; Giorgi et al., long duration of the pathogenesis of PTE makes it challenging to se- 2017). Studies have reported that up to 64% of AD patients will un- parate causal mechanisms contributing to epilepsy development from dergo at least one unprovoked seizures with prevalence of epilepsy in other pathological events associated with the neurotrauma which are AD patients to be up to 10 fold higher than in age matched controls unrelated to epileptogenesis. (Forsgren et al., 1996; Hauser et al., 1986; Risse et al., 1990). The Neurodegeneration is one of the characteristic brain pathologies pathological mechanisms frequently described in neurodegenerative associated with acquired epilepsies such as PTE, although the direct conditions such as hyperphosphorylated tau, ß-amyloid pathology, relationship with the development of spontaneous recurrent seizures is chronic neuroinflammation are all associated with epileptic disorders. ambiguous (eg: (Brandt et al., 2006; Pitkanen et al., 2005). Never- This evidence comes from studies of specimens from resected epi- theless, neurodegeneration within epileptogenic regions may trigger leptogenic brain tissue from epilepsy patients who have undergone neuroinflammation (or vice versa), network re-organization and/or surgery for drug resistant temporal lobe epilepsy, as well as consistent cascades of molecular changes, some or all of which may contribute to robust evidences from the animal models of acquired epilepsy (Liu the transformation from a normal to an epileptic brain network et al., 2016; Thom et al., 2011) The possibility of involvement of (Acharya et al., 2008). The purpose of this review is to summarise and common underlying neurodegenerative mechanisms is further sup- critically analyse neurodegenerative processes as potential casual ported by the alteration of epilepsy outcomes on modification of these mediators of acquired epilepsy following a traumatic brain injury. pathways (discussed in next section). However, it remains to be seen ⁎ Corresponding author at: Department of Neuroscience, Central Clinical School, Monash University, The Alfred Hospital, Melbourne, Australia. E-mail address: [email protected] (T.J. O'Brien). https://doi.org/10.1016/j.nbd.2018.08.006 Received 11 June 2018; Received in revised form 31 July 2018; Accepted 8 August 2018 Available online 09 August 2018 0969-9961/ © 2018 Elsevier Inc. All rights reserved. I. Ali et al. Table 1 Summarizing the neurodegenerative mechanisms including Tauopathies, amyloid pathology and neuroinflammation in patients and animal models with TBI. Model Mechanism/s investigated Intervention/s Outcomes Reference TBI patients Hyper-phosphorylated-Tau Not evaluated Increased Hyperphophorylated-Tau (Shultz et al., 2015) Repeatative TBI in patients Hyper-phosphorylated-Tau Not evaluated Increased phosphorylated tau in rTBI patients that were similar to observation (Puvenna et al., 2016) in temporal lobe epilepsy patients TBI patients Hyper-phosphorylated-Tau Not evaluated Phopho-Tau associated with TBI history but not seizures (Thom et al., 2011) Traumatic encephalopathy patients PP2A activity Not evaluated Decreased PP2A activity and associated genes in patients (Seo et al., 2017) Military personnel with TBI Total Tau Not evaluated Increased total tau in blood that related to increased post concussive (Olivera et al., 2015) neurological symptoms TBI patients Cis-Tau Not evaluated Cis-Phospho-Tau increased in cortical axons and CSF and correlated with (Albayram et al., 2017) rTBI in mice Specific neutralizing antibody against cis axonal injury and clinical outcomes phosho-Tau Attenuates neuropathology and brain dysfunction. Lateral fluid percussion injury model PR55 and PP2A levels regulating Hyper- Tau phosphatase activator‑sodium selenate TBI reduced PR55 and PP2A activity and increased phosphor-Tau expression (Shultz et al., 2015) in Long-Evans rat phosphorylated-Tau that was reversed by sodium selenate. Reduced brain damage and improved behavioural outcomes. Lateral fluid percussion injury model Hyper-phosphorylated-Tau Tau phosphatase activator‑sodium selenate Reduced epileptic seizure frequency and duration in treated rats with effects (Liu et al., 2016) in Long-Evans rat observable even following washout period Parasagittal FPI model in rats Hyper-phosphorylated-Tau Not evaluated Increased oligomeric and Phospho-Tau (Hawkins et al., 2013) Mechanical compression in rats Hyper-phosphorylated-Tau and Not evaluated Increased phosphorylation of Tau and MAP2 with decrease PP2A activity (Chen et al., 2010) microtubule associated protein-2 within minutes Mild rTBI in mice Total Tau Complete ablation/partial reduction of Tau Reduced spatial learning and memory deficits along with reduced level of (Cheng et al., 2014) axonopathy Surgical excision of human temporal APP overexpression Not evaluated Increase in APP levels after TBI in patients. (Ikonomovic et al., 2004) cortex after TBI (Roberts et al., 1994) Post-mortem study with 152 101 patients that had severe TBI Needle stabbing or weight drop in rats APP overexpression Not evaluated Increase in APP levels after TBI in different animal models. (Lewen et al., 1995)/ Midline fluid percussion model in (Otsuka et al., 1991) rats (Murakami et al., 1998) Weight fall model of brainstem (Yang et al., 2014) injury in rats (Van den Heuvel et al., Ovine TBI model 1999) Severe controlled cortical impact in APP processing after injury Not evaluated Up-regulation in the expression of genes encoding proteins related to Aß (Miszczuk et al., 2016) APP/PS1 mice clearance. Controlled cortical impact in young APP processing after injury Not evaluated Reduction in Aß deposit after injury while sham animals displayed increasing (Nakagawa et al., 1999) PDAPP mice amyloid burden. (Nakagawa et al., 2000) Controlled cortical impact in aged Reduction in Aß burden in the ipsilateral hippocampus after injury in mice PDAPP mice with abundant plaques. Mild controlled cortical impact in APP- APP role after injury Not evaluated APP-KO mice exhibit worst outcomes after injury compared to wild-type (Corrigan et al., 2012a) KO mice controls. Moderate controlled cortical impact in APP role after injury Intracerebroventricular injection of sAPPα sAPPα treatment rescued damage and functional deficits in APP-KO mice. (Corrigan et al., 2012b) APP-KO mice 15 min after injury Neurobiology ofDisease123(2019)100–109 Controlled cortical impact in mice APP metabolites γ-secretase inhibitor Reduced Aß levels by 25%, reduced neurodegeneration and improved motor (Loane et al., 2009) and cognitive recovery after TBI. Controlled cortical impact in APP-KO APP metabolites Intracerebroventricular injection of APP Improvement of outcomes post-injury similar to the treatment with sAPPα.(Corrigan et al., 2011) mice 96–110 peptide Diffuse TBI in Sprague-Dawley
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