- Email: [email protected]
Neuroprotection in epilepsy: The Holy Grail of antiepileptogenic therapy
Epilepsy & Behavior 7 (2005) S1–S2 www.elsevier.com/locate/yebeh
Foreword
Neuroprotection in epilepsy: The Holy Grail of antiepileptogenic therapy The recent availability of a large number of new antiepileptic drugs (AEDs) has raised the hope and anticipation that some of these agents may possess pharmacological properties that provide a measure of neuroprotection, and perhaps, antiepileptogenic potential. This optimistic expectation is moderated by the long trail of failed clinical neuroprotection trials in stroke. Indeed, results of human trials involving traditional AEDs for prophylaxis against posttraumatic epilepsy have been disappointing [1,2]. There are important differences between the neuroprotective approaches in stroke and epilepsy. Protecting the cells in the ischemic penumbra after a stroke imposes strict requirements for the timing of intervention when a window of opportunity still exists. In epilepsy, a chronic condition that is increasingly seen as a progressive disease, the ability of an AED to contribute to disease modification over a period of time can be construed as effective neuroprotection. Accumulating laboratory evidence suggests that an epileptogenic cascade, resulting in altered network excitability, may be triggered by sustained neuronal activity, even in the absence of discernible neuronal injury [3]. Thus, neuroprotection in the narrow definition of protecting neurons from death, even if necessary, may not be sufficient for antiepileptogenic therapy. On the other hand, what if AEDs used to limit neuronal activity were to result in neuronal injury, as demonstrated in the immature brain by Bittigau et al. [4]? Approaches to neuroprotection should include consideration of the unique response of the immature brain, in which blockade of N-methyl-D-aspartate (NMDA) receptor-mediated currents may be proapoptotic [5] rather than neuroprotective. However, it appears that antagonism of non-NMDA receptor (e.g., a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptor) sites may be neuroprotective in the mature [6,7] brain, as well as neuroprotective and antiepileptogenic in the immature brain [8,9]. In addition to the targets of AEDs, constituted by extracellular ion channel-coupled receptors and channel proteins, there is emerging knowledge that pertains to targets involving intracellular processes. Understanding of such processes and new insights into the role played by genetic diversity in defining cellular vulnerability will help us get closer to achieving effective neuroprotection. 1525-5050/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2005.08.002
In the articles in this special supplement, Dr. Fujikawa describes the advances and the gaps in our knowledge of the detailed steps involved in seizure-induced cell death. His article emphasizes the role of numerous biochemical steps involved in neuronal injury, even when the morphology of cell death appears necrotic. Detailed studies of the death cascade help define numerous potential targets for neuroprotective strategies. Dr. Stafstrom and Dr. Sutula review the progressive nature of recurrent seizures in the immature and adult brain, concentrating on studies that involve the kindling model. The article by Dr. Sullivan highlights the crucial role played by mitochondria in mediating neuronal injury and describes the potential for neuroprotection by dietary strategies that induce greater expression of mitochondrial uncoupling proteins. Finally, Dr. Willmore summarizes the evidence for neuroprotection by available AEDs. I invoke the editorÕs prerogative to highlight a few ideas. The first idea is to recognize that not all the actions of available AEDs are connected to ion channels or ion channel-coupled receptors on the cell surface. Dr. SullivanÕs article notes the evidence that zonisamide may scavenge free radicals and may also have antioxidant abilities. A recent article attributes the neuroprotective effect of topiramate to its inhibitory effect on the mitochondrial transition pore [10]. Evidence has also been presented that levetiracetam modifies kindling-induced alterations in gene expression in the temporal lobes of rats [11]. This type of investigation begins to address concerns pertaining to the potential for pharmacological actions that can reasonably be expected to prevent epileptogenicity that is seen even in the absence of neuronal loss, such as is suspected in the very immature brain. The second idea pertains to speculating on the possibility that, in the near future, we may leverage the knowledge emerging from investigations on the basis of the genetic background in modifying neuronal vulnerability to excitotoxic insults. Schauwecker and Steward [12] found that certain strains of mice (i.e., 129/SvEMS and FVB/N) were highly susceptible to kainic acid-induced damage in the CA3 and CA1 subfields of the hippocampus, while other strains (i.e., C57BL/6 and BALB/c) were
S2
Foreword / Epilepsy & Behavior 7 (2005) S1–S2
highly resistant, even though kainic acid produced seizures of similar severity in all these strains. More recently, Schauwecker [13] reported that the differences in apparent kainic acid-induced cell death between FVB/N and C57BL/6 mice are conferred by a single gene locus. This is an extremely important concept that is bound to have applications in the development of neuroprotective strategies. Clinicians have known that genetic endowment influences the development of posttraumatic epilepsy in humans. In the future, exploiting such differences to engineer stem cells for antiepileptogenic therapy may become a reality. Finally, clinicians concerned about neuroprotection in epilepsy must more vigorously embrace the presently feasible approaches that can contribute to neuroprotection. Shinnar and colleagues concluded that when seizures in children last more than 5 to 10 minutes, the probability of those seizures stopping spontaneously on their own diminishes rapidly and that specific intervention is indicated [14]. It is likely that a threshold exists for children and adults with chronic epilepsy beyond which seizures may become prolonged enough to trigger adverse plasticity and/or cell death. The corollary to this argument is that families need to be provided with a strategy, such as rectal diazepam, to promptly terminate seizures that have a tendency to become prolonged. Acknowledgment Supported by NINDS-NIH grant RO1 NS046516. References [1] Temkin NR, Dikmen SS, Wilensky AJ, et al. A randomized, doubleblind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med 1990;323:497–502. [2] Temkin NR, Dikmen SS, Anderson GD, et al. Valproate therapy for prevention of posttraumatic seizures: a randomized trial. J Neurosurg 1999;91:593–600.
[3] Baram TZ, Eghbal-Ahmadi M, Bender RA. Is neuronal death required for seizure-induced epileptogenesis in the immature brain? Prog Brain Res 2002;135:365–75. [4] Bittigau P, Sifringer M, Genz K, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci USA 2002;99:15089–94. [5] Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999;283:70–4. [6] Niebauer M, Gruenthal M. Topiramate reduces neuronal injury after experimental status epilepticus. Brain Res 1999;837:263–9. [7] Rigoulot MA, Koning E, Ferrandon A, et al. Neuroprotective properties of topiramate in the lithium–pilocarpine model of epilepsy. J Pharmacol Exp Ther 2004;308:787–95. [8] Koh S, Tibayan FD, Simpson JN, et al. NBQX or topiramate treatment after perinatal hypoxia-induced seizures prevents later increases in seizure-induced neuronal injury. Epilepsia 2004;45:569–75. [9] Suchomelova L, Baldwin RA, Kubova H, et al. Treatment of experimental status epilepticus in immature rats: dissociation between anticonvulsant and antiepileptogenic effects. Pediatr Res, in press. [10] Kudin AP, Debska-Vielhaber G, Vielhaber S, et al. The mechanism of neuroprotection by topiramate in an animal model of epilepsy. Epilepsia 2004;45:1478–87. [11] Gu J, Lynch BA, Anderson D, et al. The antiepileptic drug levetiracetam selectively modifies kindling-induced alterations in gene expression in the temporal lobe of rats. Eur J Neurosci 2004;19:334–45. [12] Schauwecker PE, Steward O. Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. Proc Natl Acad Sci USA 1997;94:4103–8. [13] Schauwecker PE. Genetic basis of kainate-induced excitotoxicity in mice: phenotypic modulation of seizure-induced cell death. Epilepsy Res 2003;55:201–10. [14] Shinnar S, Berg AT, Moshe SL, et al. How long do new-onset seizures in children last? Ann Neurol 2001;49:659–64.
Raman Sankar Division of Pediatric Neurology David Geffen School of Medicine University of California at Los Angeles Los Angeles, CA, USA E-mail address: [email protected] Received 17 August 2005; accepted 17 August 2005 Available online 20 October 2005
Fax: +1 310 825 5834.
Foreword
Neuroprotection in epilepsy: The Holy Grail of antiepileptogenic therapy The recent availability of a large number of new antiepileptic drugs (AEDs) has raised the hope and anticipation that some of these agents may possess pharmacological properties that provide a measure of neuroprotection, and perhaps, antiepileptogenic potential. This optimistic expectation is moderated by the long trail of failed clinical neuroprotection trials in stroke. Indeed, results of human trials involving traditional AEDs for prophylaxis against posttraumatic epilepsy have been disappointing [1,2]. There are important differences between the neuroprotective approaches in stroke and epilepsy. Protecting the cells in the ischemic penumbra after a stroke imposes strict requirements for the timing of intervention when a window of opportunity still exists. In epilepsy, a chronic condition that is increasingly seen as a progressive disease, the ability of an AED to contribute to disease modification over a period of time can be construed as effective neuroprotection. Accumulating laboratory evidence suggests that an epileptogenic cascade, resulting in altered network excitability, may be triggered by sustained neuronal activity, even in the absence of discernible neuronal injury [3]. Thus, neuroprotection in the narrow definition of protecting neurons from death, even if necessary, may not be sufficient for antiepileptogenic therapy. On the other hand, what if AEDs used to limit neuronal activity were to result in neuronal injury, as demonstrated in the immature brain by Bittigau et al. [4]? Approaches to neuroprotection should include consideration of the unique response of the immature brain, in which blockade of N-methyl-D-aspartate (NMDA) receptor-mediated currents may be proapoptotic [5] rather than neuroprotective. However, it appears that antagonism of non-NMDA receptor (e.g., a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptor) sites may be neuroprotective in the mature [6,7] brain, as well as neuroprotective and antiepileptogenic in the immature brain [8,9]. In addition to the targets of AEDs, constituted by extracellular ion channel-coupled receptors and channel proteins, there is emerging knowledge that pertains to targets involving intracellular processes. Understanding of such processes and new insights into the role played by genetic diversity in defining cellular vulnerability will help us get closer to achieving effective neuroprotection. 1525-5050/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2005.08.002
In the articles in this special supplement, Dr. Fujikawa describes the advances and the gaps in our knowledge of the detailed steps involved in seizure-induced cell death. His article emphasizes the role of numerous biochemical steps involved in neuronal injury, even when the morphology of cell death appears necrotic. Detailed studies of the death cascade help define numerous potential targets for neuroprotective strategies. Dr. Stafstrom and Dr. Sutula review the progressive nature of recurrent seizures in the immature and adult brain, concentrating on studies that involve the kindling model. The article by Dr. Sullivan highlights the crucial role played by mitochondria in mediating neuronal injury and describes the potential for neuroprotection by dietary strategies that induce greater expression of mitochondrial uncoupling proteins. Finally, Dr. Willmore summarizes the evidence for neuroprotection by available AEDs. I invoke the editorÕs prerogative to highlight a few ideas. The first idea is to recognize that not all the actions of available AEDs are connected to ion channels or ion channel-coupled receptors on the cell surface. Dr. SullivanÕs article notes the evidence that zonisamide may scavenge free radicals and may also have antioxidant abilities. A recent article attributes the neuroprotective effect of topiramate to its inhibitory effect on the mitochondrial transition pore [10]. Evidence has also been presented that levetiracetam modifies kindling-induced alterations in gene expression in the temporal lobes of rats [11]. This type of investigation begins to address concerns pertaining to the potential for pharmacological actions that can reasonably be expected to prevent epileptogenicity that is seen even in the absence of neuronal loss, such as is suspected in the very immature brain. The second idea pertains to speculating on the possibility that, in the near future, we may leverage the knowledge emerging from investigations on the basis of the genetic background in modifying neuronal vulnerability to excitotoxic insults. Schauwecker and Steward [12] found that certain strains of mice (i.e., 129/SvEMS and FVB/N) were highly susceptible to kainic acid-induced damage in the CA3 and CA1 subfields of the hippocampus, while other strains (i.e., C57BL/6 and BALB/c) were
S2
Foreword / Epilepsy & Behavior 7 (2005) S1–S2
highly resistant, even though kainic acid produced seizures of similar severity in all these strains. More recently, Schauwecker [13] reported that the differences in apparent kainic acid-induced cell death between FVB/N and C57BL/6 mice are conferred by a single gene locus. This is an extremely important concept that is bound to have applications in the development of neuroprotective strategies. Clinicians have known that genetic endowment influences the development of posttraumatic epilepsy in humans. In the future, exploiting such differences to engineer stem cells for antiepileptogenic therapy may become a reality. Finally, clinicians concerned about neuroprotection in epilepsy must more vigorously embrace the presently feasible approaches that can contribute to neuroprotection. Shinnar and colleagues concluded that when seizures in children last more than 5 to 10 minutes, the probability of those seizures stopping spontaneously on their own diminishes rapidly and that specific intervention is indicated [14]. It is likely that a threshold exists for children and adults with chronic epilepsy beyond which seizures may become prolonged enough to trigger adverse plasticity and/or cell death. The corollary to this argument is that families need to be provided with a strategy, such as rectal diazepam, to promptly terminate seizures that have a tendency to become prolonged. Acknowledgment Supported by NINDS-NIH grant RO1 NS046516. References [1] Temkin NR, Dikmen SS, Wilensky AJ, et al. A randomized, doubleblind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med 1990;323:497–502. [2] Temkin NR, Dikmen SS, Anderson GD, et al. Valproate therapy for prevention of posttraumatic seizures: a randomized trial. J Neurosurg 1999;91:593–600.
[3] Baram TZ, Eghbal-Ahmadi M, Bender RA. Is neuronal death required for seizure-induced epileptogenesis in the immature brain? Prog Brain Res 2002;135:365–75. [4] Bittigau P, Sifringer M, Genz K, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci USA 2002;99:15089–94. [5] Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999;283:70–4. [6] Niebauer M, Gruenthal M. Topiramate reduces neuronal injury after experimental status epilepticus. Brain Res 1999;837:263–9. [7] Rigoulot MA, Koning E, Ferrandon A, et al. Neuroprotective properties of topiramate in the lithium–pilocarpine model of epilepsy. J Pharmacol Exp Ther 2004;308:787–95. [8] Koh S, Tibayan FD, Simpson JN, et al. NBQX or topiramate treatment after perinatal hypoxia-induced seizures prevents later increases in seizure-induced neuronal injury. Epilepsia 2004;45:569–75. [9] Suchomelova L, Baldwin RA, Kubova H, et al. Treatment of experimental status epilepticus in immature rats: dissociation between anticonvulsant and antiepileptogenic effects. Pediatr Res, in press. [10] Kudin AP, Debska-Vielhaber G, Vielhaber S, et al. The mechanism of neuroprotection by topiramate in an animal model of epilepsy. Epilepsia 2004;45:1478–87. [11] Gu J, Lynch BA, Anderson D, et al. The antiepileptic drug levetiracetam selectively modifies kindling-induced alterations in gene expression in the temporal lobe of rats. Eur J Neurosci 2004;19:334–45. [12] Schauwecker PE, Steward O. Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. Proc Natl Acad Sci USA 1997;94:4103–8. [13] Schauwecker PE. Genetic basis of kainate-induced excitotoxicity in mice: phenotypic modulation of seizure-induced cell death. Epilepsy Res 2003;55:201–10. [14] Shinnar S, Berg AT, Moshe SL, et al. How long do new-onset seizures in children last? Ann Neurol 2001;49:659–64.
Raman Sankar Division of Pediatric Neurology David Geffen School of Medicine University of California at Los Angeles Los Angeles, CA, USA E-mail address: [email protected] Received 17 August 2005; accepted 17 August 2005 Available online 20 October 2005
Fax: +1 310 825 5834.