Antiepileptogenesis, neuroprotection, and disease modification in the treatment of epilepsy: focus on levetiracetam.
The search for antiepileptic drugs (AEDs) using drug screens that test for the ability to suppress paroxysmal events has primarily resulted in the discovery of AEDs that inhibit neuronal excitability. While profoundly reducing expression of epileptic seizures, current pharmacologic treatments have not been able to completely control seizures in all patients, and can impair normal neuronal excitation underlying cognition. A new approach to drug screening, including the process of epileptogenesis, may yield new classes of drugs that not only suppress seizures but also specifically act to protect against the neurobiological changes that contribute to the development of epilepsy. By preventing or reversing the neuronal circuit reorganizations that produce lowered seizure thresholds following brain insults such as head trauma or status epilepticus, these antiepileptogenic drugs could prevent, or reverse, progressive worsening of the epileptic process. It is likely that antiepileptogenic drugs will have mechanisms of action distinct from traditional AEDs, as the molecular mechanisms underlying epileptogenesis and ictogenesis probably differ. One new AED with potential antiepileptogenic properties is levetiracetam, which was discovered using non-conventional drug screens. It markedly suppresses kindling development at doses devoid of adverse effects, with persistent suppression of kindled seizures even after termination of treatment. Further design and implementation of antiepileptogenic drug screens are needed for the discovery of other novel disease-modifying agents.
Klitgaard
Henrik
H
Preclinical CNS Research, UCB S.A. Pharma Sector, Braine L'Alleud, Belgiun. Henrik.Klitgaard@ucb-group.com
Pitkänen
Asla
A
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000188:drug therapy*; D006801:Humans; D007696:Kindling, Neurologic / Q000187:drug effects; D000077287:Levetiracetam; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*
D000927:Anticonvulsants; D018696:Neuroprotective Agents; D000077287:Levetiracetam; D010889:Piracetam