Antiepileptic drugs in neuroprotection.
Antiepileptic drugs (AEDs) are designed to prevent and suppress seizure activity. Their effects on calcium influx and molecular cascades contributing to necrotic and apoptotic neuronal death, however, suggests that they have functions other than just suppression of excitability. The neuroprotective effects of 20 AEDs currently in use or being investigated in Phase II - III clinical trials for treatment of epilepsy are reviewed. Data analyses is complicated by several factors. Firstly, the available data on the neuroprotective effects of different AEDs varies largely. Secondly, most of the evidence demonstrating neuroprotective effects comes from stroke models and it is uncertain whether these data can be extrapolated to other conditions, such as status epilepticus (SE) or traumatic brain injury. Thirdly, data obtained in adult animals cannot be extrapolated to young animals without caution. For example, AEDs protecting adult brain from stroke or SE-induced injury can cause apoptosis in immature brain. Finally, data comparison is complicated by the variability in study designs and methodologies between studies. With these caveats in mind, an analysis of the available data suggests that AEDs with different mechanisms of action can have mild-to-moderate neuroprotective effects. It is difficult, however, to associate the neuroprotective effects with a favourable functional outcome. For example, it is difficult to conclude that administration of AEDs during the latency phase would have an effect on the molecular cascades underlying epileptogenesis. The few favourable data demonstrating a decrease in the incidence of epilepsy after SE are probably related to the administration of AEDs during SE, which resulted in modification/alleviation of the insult itself and consequently, reduced its epileptogenecity. These experimental data, however, are clinically important because they show that early intervention of SE has an effect on long-term functional outcome. These observations emphasise the need to use additional outcome measures, such as markers of normal development or cognitive performance, when the benefits of neuroprotection achieved by the use of neuroprotective AEDs are assessed.
Pitkänen
Asla
A
A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland. asla.pitkanen@uku.fi
Kubova
Hana
H
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D004827:Epilepsy / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D009336:Necrosis; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use
D000927:Anticonvulsants; D018696:Neuroprotective Agents