Basic mechanisms of epileptogenesis and novel therapeutic targets for symptomatic epilepsies

Cibio Seminar
6 May 2019
May 6th
Contatti: 
Department of Cellular, Computational and Integrative Biology (CIBIO)
Via Sommarive 9, 38123 Povo (TN)
Tel. 
+39 0461 283163 - 1203 - 3995 - 1622 - 3706

Annamaria Vezzani
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy

3.00 p.m - Aula B104
Via Sommarive, 9 - Povo, Trento 

Epileptogenesis is a complex pathophysiological phenomenon ignited by various brain or metabolic injuries or by gene mutations that leads to the onset of epilepsy. Animal studies have shown that various molecular and cellular mechanisms are activated during epileptogenesis in seizure-generating brain areas. Some mechanisms are ignited to re-establish tissue homeostasis while others promote disease development. Their identification is instrumental for finding novel targets for therapeutic interventions and mechanistic biomarkers. Animal models of epileptogenesis, induced by stroke, neurotrauma, CNS infections, status epilepticus, brain tumors share the common activation of microglia and astrocytes, and the release from these cells of inflammatory mediators, in brain regions involved in seizures. These glial cells changes are accompanied by alterations in cells physiology and blood-brain barrier functions which contribute to the onset and progression of the disease. We showed that both IL-1beta, TNF-alpha and High-Mobility Group Box1 are inflammatory molecules released by activated astrocytes and microglia in epileptogenic brain regions, and together with reactive oxygen and nitrogen species, they contribute to the generation and recurrence of seizures, neuronal cell loss and neurological comorbidities. Epigenetic and pharmacological interventions that block specific inflammatory signalings or oxidative stress greatly improved pathologic disease outcomes. Conversely, astrocitic activation or enhanced neuroinflammation is sufficient to trigger epileptogenesis. Brain imaging of glia highlighted prognostic biomarkers of disease development. Based on this evidence, clinical studies are testing novel anti-inflammatory treatments in epilepsy and are validating new inflammatory biomarkers for patient stratification.

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