Epilepsy is one of the most common neurological disorders. It has long been known that brain injuries (e.g. traumatic, ischemic, and infectious) often result in seizures and epilepsy (AKA "post traumatic epilepsy"). Post-traumatic epilepsy (PTE) accounts for 20% of symptomatic epilepsy in the general population, and up to 50% in the military population. The mechanisms by which injury to the brain leads to epileptogenesis are mostly unknown, and consequently we are unable to identify patients at risk, or offer them therapies that can bock the development of epilepsy. Here, we propose to identify therapeutic agents able to block epileptogenesis by exploring: 1. Albumin-induced synaptogenesis and neurogenesis and the contribution to excitatory/inhibitory imbalance. 2. Downstream effects of albumin exposure on neuronal network reorganization. 3. The potential of BBB imaging as a biomarker for epilepsy risk and anti-TGF beta therapeutics to prevent epileptogenesis following traumatic brain injury. Brain injuries are often associated with vascular pathology, specifically with opening of the blood-brain barrier (BBB). Under the previous RO1 we have identified a novel mechanism for the development of epilepsy following BBB compromise: we have shown that chemical opening of the BBB leads to the delayed development of focal epileptiform activity, and that serum albumin is a critical factor in the subsequent process of epileptogenesis. Specifically, we have found that albumin interacts with transforming growth factor-beta (TGF beta receptors in astrocytes and activates the TGF beta signaling pathway, induces an epilepsy-promoting transcriptional program, and subsequently leads to the early dysfunction of astrocytes and delayed pathological hyper-excitability and seizures. The present proposal combines cellular, circuit, molecular/genetic, and MR imaging approaches to investigate network reorganization that follows the exposure of the brain to the serum protein albumin and promotes epilepsy. The proposed work unravels a novel epileptogenic cascade and demonstrates profound clinical implications for diagnosing epilepsy risk, and developing a safe/effective anti-epileptogenic drugs for treatment of acquired epilepsies in humans.
Acquired epilepsies that develop after traumatic or ischemic brain injuries are difficult to treat with conventional antiepileptic drugs, and currently no drug exists that has the most clinically desired capability of blocking the development of epilepsy. This project will impact public health in three major ways. Firstly, the project will elucidate the pathways that lead to epileptogenesis following traumatic brain injury. Secondly, the project will assess the efficacy of targeting these pathways for therapeutic intervention and prevention of epileptogenesis. Finally, the project will test the efficacy of blood brain barrier imaging as a biomarker to predict patients at risk to develop epilepsy. Since such insults are one of the primary causes of disability with no means of prevention as of yet, this proposal represents an important advancement toward resolving this unmet medical need.
|Vazana, Udi; Veksler, Ronel; Pell, Gaby S et al. (2016) Glutamate-Mediated Blood-Brain Barrier Opening: Implications for Neuroprotection and Drug Delivery. J Neurosci 36:7727-39|