Discovering novel strategies to prevent epilepsy by targeting autophagy and mitophagy pathways

banner prin def.jpeg

Abstract:

Epilepsy prevention is an urgent and global unmet need today. With about 1% of people affected worldwide, epilepsy is one of the most common and severe brain disorders. A recent WHO report states that about a quarter of epilepsy episodes are preventable and that only many symptomatic antiepileptic drugs (AEDs) and other therapeutic approaches (surgery, brain stimulation, ketogenic diet, etc.) are available. Thus, to date, primary prevention is represented by efforts to minimize the main factors that can trigger seizures, such as perinatal insults, CNS infections, traumatic brain injury, and stroke, but is often insufficient. An interesting strategy for secondary prevention is the use of therapies that intervene early after an insult to limit the extent of brain damage or to interrupt epileptogenesis: this type of approach needs further study on the molecular and cellular mechanisms of epileptogenesis, which are extremely complex and poorly understood. Therefore, translational studies are needed to understand the mechanisms underlying epileptogenesis and to identify new antiepileptogenic molecules that can then be tested in randomized controlled trials. In this regard, the development of new antiepileptogenic drugs has been greatly hindered by several problems, including the long timeframe of the drug discovery process, the ethical issues of conducting studies on apparently healthy individuals and exposing them to risks of side effects, high costs, and regulatory hurdles on drug safety. To avoid these obstacles, drugs already approved, with a good safety and tolerability profile and known to target a pathway that is also altered in epilepsy are being considered as candidates for drug repositioning. In this scenario, our first goal is to study one of the biological processes that may be altered during epileptogenesis, namely the modulation of autophagy and mitophagy, delving into the intrinsic mechanisms that could lead to a chronic epileptic state. Two different animal models of epilepsy, one ex vivo, such as organotypic cultures and one in vivo lesional model, will be validated for the presence of classic hallmarks of epilepsy such as altered electrical activity and biochemical and morphological markers and will be characterized through careful assessment of autophagy and mitophagy flux during epileptogenesis, from the early latency period to the onset of a chronic epileptic state. Our second aim is to identify new treatment strategies that could be beneficial in blocking epileptogenesis, having therefore a disease-modifying effect. To this end, the therapeutic potential of repurposed drugs that promote autophagy will be evaluated in our ex vivo and in vivo models. Considering that the social and economic burden of epilepsy worldwide is steadily increasing, the advancement in mechanistic understanding of disease processes and new therapeutic strategies to prevent epilepsy represent an important breakthrough for public health.

Dettagli progetto:

Referente scientifico: Zucchini Silvia

Fonte di finanziamento: Bando PRIN 2022 PNRR

Data di avvio: 30/11/2023

Data di fine: 30/11/2025

Contributo MUR: 117.714 €

Partner:

  • Università degli Studi di FERRARA (capofila)
  • Università Politecnica delle MARCHE